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Barrios N, Riordan W, Garcia-Rivas V, Peltier MR, Roberts W, Verplaetse TL, Kohler R, Zhou H, Banini BA, McKee SA, Cosgrove KP, Zakiniaeiz Y. Preclinical and clinical sex differences in the effects of alcohol on measures of brain dopamine: a systematic review. Biol Sex Differ 2025; 16:24. [PMID: 40200334 PMCID: PMC11980350 DOI: 10.1186/s13293-025-00706-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 03/21/2025] [Indexed: 04/10/2025] Open
Abstract
INTRODUCTION Dopamine is involved in reward processing and plays a critical role in the development and progression of alcohol use disorder (AUD). However, little is known about the effect of sex on the relationship between dopamine and alcohol use/AUD. There is a critical need to identify the neurobiological mechanisms that contribute to sex differences in AUD to inform treatment approaches. This study aimed to review existing literature on sex differences in the effects of alcohol on brain dopamine measures in animals and individuals with heavy drinking/AUD. METHODS A systematic review was conducted using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. PubMed was searched from inception to July 23rd, 2024. RESULTS Of the 1,412 articles identified, 10 met study criteria (1 human, 9 animal), including in vivo (two positron emission tomography, four microdialysis) and ex vivo (two liquid chromatography, two fast-scan cyclic voltammetry) studies. Six studies included an alcohol challenge; three showed that females had greater alcohol-induced dopamine release than males in the ventral striatum and frontal cortex, while three showed no sex-related differences. Notably, the latter three studies examined sex in a combined AUD/control group or measured dopamine levels days after alcohol exposure. Two studies that examined the effects of prenatal alcohol exposure showed that prenatal-alcohol-exposed male offspring versus sex-matched air-exposed controls had greater prefrontal cortical dopamine D1 receptor availability, and prenatal-alcohol-exposed female offspring versus sex-matched air-exposed controls had greater striatal dopamine concentration. Two studies investigating the mu-opioid receptor (MOR) regulation of alcohol-induced dopamine release showed a faster decline in females relative to males while the other study found females may be less dependent on MOR activity at lower doses of alcohol relative to higher doses. CONCLUSIONS This systematic review showed mixed results regarding sex differences in brain dopamine measures in alcohol-exposed animals and individuals with AUD, which may arise from differences in the timing, quantity, and duration of alcohol exposure, species, conditions, models, and techniques. More research examining the effect of sex on the relationship between alcohol use and brain dopamine measures is needed to enhance our understanding of AUD development, progression, and treatment in both females and males.
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Affiliation(s)
- Nathalie Barrios
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA
| | - Will Riordan
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA
| | - Vernon Garcia-Rivas
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA
| | - MacKenzie R Peltier
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA
- Psychology Service, Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
| | - Walter Roberts
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA
| | - Terril L Verplaetse
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA
| | - Robert Kohler
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA
| | - Hang Zhou
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA
| | - Bubu A Banini
- Section of Digestive Diseases, Department of Internal Medicine, School of Medicine, Yale University, New Haven, USA
| | - Sherry A McKee
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA
| | - Kelly P Cosgrove
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA
- Yale Positron Emission Tomography (PET) Center, School of Medicine, Yale University, New Haven, CT, USA
- Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, New Haven, CT, USA
| | - Yasmin Zakiniaeiz
- Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA.
- , 40 Temple Street, Suite 7C, New Haven, CT, 06519, USA.
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Worhunsky PD, Mignosa MM, Gallezot JD, Pittman B, Nabulsi NB, Stryjewski A, Jalilian-Khave L, Trinko R, DiLeone RJ, Carson RE, Malison RT, Potenza MN, Angarita GA. Vitamin D's Capacity to Increase Amphetamine-Induced Dopamine Release in Healthy Humans: A Clinical Translational [ 11C]-PHNO Positron Emission Tomography Study. Biol Psychiatry 2025; 97:651-658. [PMID: 39395473 PMCID: PMC11839384 DOI: 10.1016/j.biopsych.2024.09.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 09/11/2024] [Accepted: 09/18/2024] [Indexed: 10/14/2024]
Abstract
BACKGROUND Dopaminergic tone and phasic release have transdiagnostic relevance. Preclinical research suggests that the active form of vitamin D, calcitriol, increases subcortical tyrosine hydroxylase, D2/D3 receptors, and amphetamine-stimulated dopamine release in rodents. Comparable studies have not been conducted in humans. METHODS Healthy, vitamin D-sufficient adults (N = 18, 32.8 ± 6.6 years; 33% female) participated in a randomized, double-blind, placebo-controlled within-subjects study involving 4 total scans over 2 visits consisting of same-day preamphetamine and postamphetamine (0.3 mg/kg) [11C]-PHNO positron emission tomography scanning to examine D2/D3 receptor availability (nondisplaceable binding potential [BPND]) following active calcitriol (1.5 μg night before experimental day and 1.5 μg morning of experimental day) or placebo at least 6 days apart. Parametric images of [11C]-PHNO positron emission tomography BPND were computed using a simplified reference tissue model with the cerebellum as reference. Blood samples were acquired to measure serum calcitriol, amphetamine, and calcium levels. Regions of interest examined were the dorsal caudate, dorsal putamen, ventral striatum, globus pallidus, and substantia nigra. RESULTS For preamphetamine scans, there was a medication × region of interest interaction (F4,153 = 2.59, p = .039) and a main effect of medication (F1,153 = 4.88, p = .029) on BPND, with higher BPND values on calcitriol in the ventral striatum (t153 = 2.89, p = .004) and dorsal putamen (t153 = 2.15, p = .033). There was a main effect of medication on postamphetamine change in BPND (F4,153 = 5.93, p = .016), with greater decreases in calcitriol in the ventral striatum (t153 = 3.00, p = .003), substantia nigra (t153 = 2.49, p = .014), and dorsal caudate (t153 = 2.29, p = .023). CONCLUSIONS Results provide translational support for vitamin D to target dopaminergic tone, with implications for clinical disorders that involve dysregulated dopamine function.
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Affiliation(s)
- Patrick D Worhunsky
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
| | - Marcella M Mignosa
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; The Clinical Neuroscience Research Unit, Connecticut Mental Health Center, New Haven, Connecticut
| | - Jean-Dominique Gallezot
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut
| | - Brian Pittman
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
| | - Nabeel B Nabulsi
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut
| | - Adam Stryjewski
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
| | - Laya Jalilian-Khave
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
| | - Richard Trinko
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; The Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut
| | - Ralph J DiLeone
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; The Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut; Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut
| | - Richard E Carson
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut
| | - Robert T Malison
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; The Clinical Neuroscience Research Unit, Connecticut Mental Health Center, New Haven, Connecticut
| | - Marc N Potenza
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut; Connecticut Council on Problem Gambling, Wethersfield, Connecticut; Child Study Center, Yale University School of Medicine, New Haven, Connecticut; Connecticut Mental Health Center, New Haven, Connecticut
| | - Gustavo A Angarita
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; The Clinical Neuroscience Research Unit, Connecticut Mental Health Center, New Haven, Connecticut.
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Farahbakhsh ZZ, Holleran KM, Sens JP, Fordahl SC, Mauterer MI, López AJ, Cuzon Carlson VC, Kiraly DD, Grant KA, Jones SR, Siciliano CA. Synchrony between midbrain gene transcription and dopamine terminal regulation is modulated by chronic alcohol drinking. Nat Commun 2025; 16:1944. [PMID: 39994195 PMCID: PMC11850823 DOI: 10.1038/s41467-025-56715-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 01/28/2025] [Indexed: 02/26/2025] Open
Abstract
Alcohol use disorder is marked by disrupted behavioral and emotional states which persist into abstinence. The enduring synaptic alterations that remain despite the absence of alcohol are of interest for interventions to prevent relapse. Here, 28 male rhesus macaques underwent over 20 months of alcohol drinking interspersed with three 30-day forced abstinence periods. After the last abstinence period, we paired direct sub-second dopamine monitoring via ex vivo voltammetry in nucleus accumbens core with RNA-sequencing of the ventral tegmental area. We found persistent augmentation of dopamine transporter function, kappa opioid receptor sensitivity, and putative dynorphin release - all inhibitory regulators which act to decrease extracellular dopamine. Surprisingly, though transcript expression was not altered, the relationship between gene expression and functional readouts of these encoded proteins was highly dynamic and altered by drinking history. These results outline the long-lasting synaptic impact of alcohol use and suggest that assessment of transcript-function relationships is critical for the rational design of precision therapeutics.
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Affiliation(s)
- Zahra Z Farahbakhsh
- Department of Pharmacology, Vanderbilt Brain Institute, Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, 37232, USA
| | - Katherine M Holleran
- Wake Forest University School of Medicine, Department of Physiology and Pharmacology, Winston-Salem, NC, 27157, USA
| | - Jonathon P Sens
- Wake Forest University School of Medicine, Department of Physiology and Pharmacology, Winston-Salem, NC, 27157, USA
| | - Steve C Fordahl
- The University of North Carolina at Greensboro, The Department of Nutrition, Greensboro, NC, 27412, USA
| | - Madelyn I Mauterer
- Wake Forest University School of Medicine, Department of Physiology and Pharmacology, Winston-Salem, NC, 27157, USA
| | - Alberto J López
- Department of Pharmacology, Vanderbilt Brain Institute, Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, 37232, USA
| | - Verginia C Cuzon Carlson
- Oregon National Primate Research Center, Oregon Health & Science University, Division of Neuroscience, Portland, OR, USA
| | - Drew D Kiraly
- Wake Forest University School of Medicine, Department of Physiology and Pharmacology, Winston-Salem, NC, 27157, USA
| | - Kathleen A Grant
- Oregon National Primate Research Center, Oregon Health & Science University, Division of Neuroscience, Portland, OR, USA
| | - Sara R Jones
- Wake Forest University School of Medicine, Department of Physiology and Pharmacology, Winston-Salem, NC, 27157, USA
| | - Cody A Siciliano
- Department of Pharmacology, Vanderbilt Brain Institute, Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, 37232, USA.
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Le TM, Oba T, Li CSR. Diminished reward circuit response underlies pain avoidance learning deficits in problem drinkers. Neuroimage Clin 2025; 45:103762. [PMID: 40009903 PMCID: PMC11908557 DOI: 10.1016/j.nicl.2025.103762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 02/09/2025] [Accepted: 02/21/2025] [Indexed: 02/28/2025]
Abstract
Individuals engaging in problem drinking show impaired proactive pain avoidance. As successful pain avoidance is intrinsically rewarding, this impairment suggests reward deficiency, as hypothesized for those with alcohol and substance misuse. Nevertheless, how reward circuit dysfunctions impact avoidance learning and contribute to drinking behavior remains poorly understood. Here, we combined functional imaging and a probabilistic learning go/nogo task to examine the neural processes underlying proactive pain avoidance learning in 103 adult drinkers. We hypothesized that greater drinking severity would be associated with poorer avoidance learning and that the deficits would be accompanied by weakened activity and connectivity of the reward circuit. Our behavioral findings indeed showed a negative relationship between drinking severity and learning from successful pain avoidance. We identified hypoactivation of the posterior cingulate cortex (PCC), a brain region important in avoidance, as the neural correlate of lower learning rate in association with problem drinking. The reward circuit, including the medial orbitofrontal cortex, ventral tegmental area, and substantia nigra, also exhibited diminished activation and connectivity with the PCC with greater drinking severity and learning deficits. Finally, path modeling suggested a pathway in which problem drinking disengaged the reward circuit. The weakened circuit subsequently induced PCC hypoactivation, resulting in poorer pain avoidance learning. As the learning dysfunction worsened alcohol use, the pathway represents a self-perpetuating cycle of drinking and distress. Together, these findings substantiate a role of reward deficiency in problem drinkers' compromised proactive avoidance, thus identifying a potential target for intervention aimed at mitigating harmful alcohol use.
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Affiliation(s)
- Thang M Le
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA.
| | - Takeyuki Oba
- Human Informatics and Interaction Research Institute, the National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
| | - Chiang-Shan R Li
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT 06520, USA; Wu Tsai Institute, Yale University, New Haven, CT 06510, USA
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Asp AJ, Boschen SL, Chang SY, Kim J, Silvernail JL, Lujan JL. An ultra low frequency spike timing dependent plasticity based approach for reducing alcohol drinking. Sci Rep 2024; 14:30907. [PMID: 39730615 DOI: 10.1038/s41598-024-81390-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 11/26/2024] [Indexed: 12/29/2024] Open
Abstract
Alcohol use disorder (AUD) is a chronic relapsing brain disorder characterized by an impaired ability to stop or control alcohol consumption despite adverse social, occupational, or health consequences. AUD affects nearly one-third of adults at some point during their lives, with an associated cost of approximately $249 billion annually in the U.S. alone. The effects of alcohol consumption are expected to increase significantly during the COVID-19 pandemic, with alcohol sales increasing by approximately 54%, potentially exacerbating health concerns and risk-taking behaviors. Unfortunately, existing pharmacological and behavioral therapies for AUD are associated with poor success rates, with approximately 40% of individuals relapsing within three years of treatment.Pre-clinical studies have shown that chronic alcohol consumption leads to significant changes in synaptic function within the dorsal medial striatum (DMS), one of the brain regions associated with AUD and responsible for mediating goal-directed behavior. Specifically, chronic alcohol consumption has been associated with hyperactivity of dopamine receptor 1 (D1) medium spiny neurons (MSN) and hypoactivity of dopamine receptor 2 (D1) MSNs within the DMS. Optogenetic, chemogenetic, and transgenic approaches have demonstrated that reducing the D1/D2 MSN signaling imbalance decreases alcohol self-administration in rodent models of AUD.Here, we present an electrical stimulation approach that uses ultra-low (≤ 1 Hz) frequency (ULF) spike-timing-dependent plasticity (STDP) in mouse models of AUD to reduce DMS D1/D2 MSN signaling imbalances by stimulating D1-MSN afferents into the GPi and ACC glutamatergic projections to the DMS in a time-locked stimulation sequence. Our data suggest that GPi/ACC ULF-STDP selectively decreases DMS D1-MSN hyperactivity leading to reduced alcohol consumption without evoking undesired affective behaviors using electrical stimulation rather than approaches requiring genetic modification. This work represents a step towards fulfilling the unmet need for a reliable method of treating severe AUD through cell-type-specific control with clinically available neuromodulation tools.
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Affiliation(s)
- Anders J Asp
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, 55905, USA
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, 55905, USA
| | | | - Su-Youne Chang
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, 55905, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, 55905, USA
| | - Jiwon Kim
- Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Jodi L Silvernail
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, 55905, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, 55905, USA
| | - J Luis Lujan
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, 55905, USA.
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, 55905, USA.
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Chumin EJ, Dzemidzic M, Yoder KK. Intra-striatal dopaminergic inter-subject covariance in social drinkers and non-treatment-seeking alcohol use disorder participants. Addict Biol 2024; 29:e70008. [PMID: 39576234 PMCID: PMC11583815 DOI: 10.1111/adb.70008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 10/14/2024] [Accepted: 10/23/2024] [Indexed: 11/24/2024]
Abstract
One of the neurobiological correlates of alcohol use disorder (AUD) is the disruption of striatal dopaminergic function. Although regional differences in dopamine (DA) tone/function have been well studied, interregional relationships (represented as inter-subject covariance) have not been investigated and may offer a novel avenue for understanding DA tone. Positron emission tomography (PET) data with [11C]raclopride in 22 social drinking controls and 17 AUD participants were used to generate group-level striatal covariance (partial Pearson correlation) networks, which were compared edgewise as well as on global network metrics and community structure. An exploratory analysis examined the impact of tobacco cigarette use status. Striatal covariance was validated in an independent publicly available [18F]fallypride PET sample of healthy volunteers. Striatal covariance of control participants from both data sets showed a clear bipartition of the network into two distinct communities, one in the anterior and another in the posterior striatum. This organization was disrupted in the AUD participants' network, which showed significantly lower network metrics compared with the control participants' network. Stratification by cigarette use suggests differential consequences on group covariance networks. This work demonstrates that network neuroscience can quantify group differences in striatal DA and that its interregional interactions offer new insight into the consequences of AUD.
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Affiliation(s)
- Evgeny J. Chumin
- Psychological and Brain SciencesIndiana UniversityBloomingtonIndianaUSA
- Radiology and Imaging SciencesIndiana University School of MedicineIndianapolisIndianaUSA
- Stark Neurosciences Research InstituteIndiana University School of MedicineIndianapolisIndianaUSA
| | - Mario Dzemidzic
- Radiology and Imaging SciencesIndiana University School of MedicineIndianapolisIndianaUSA
- Stark Neurosciences Research InstituteIndiana University School of MedicineIndianapolisIndianaUSA
- NeurologyIndiana University School of MedicineIndianapolisIndianaUSA
| | - Karmen K. Yoder
- Radiology and Imaging SciencesIndiana University School of MedicineIndianapolisIndianaUSA
- Stark Neurosciences Research InstituteIndiana University School of MedicineIndianapolisIndianaUSA
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7
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Bocarsly ME, Shaw MJ, Ventriglia E, Anderson LG, Goldbach HC, Teresi CE, Bravo M, Bock R, Hong P, Kwon HB, Khawaja IM, Raman R, Murray EM, Bonaventura J, Burke DA, Michaelides M, Alvarez VA. Preexisting risk-avoidance and enhanced alcohol relief are driven by imbalance of the striatal dopamine receptors in mice. Nat Commun 2024; 15:9093. [PMID: 39438478 PMCID: PMC11496688 DOI: 10.1038/s41467-024-53414-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 10/10/2024] [Indexed: 10/25/2024] Open
Abstract
Alcohol use disorder (AUD) is frequently comorbid with anxiety disorders, yet whether alcohol abuse precedes or follows the expression of anxiety remains unclear. Rodents offer control over the first drink, an advantage when testing the causal link between anxiety and AUD. Here, we utilized a risk-avoidance task to determine anxiety-like behaviors before and after alcohol exposure. We found that alcohol's anxiolytic efficacy varied among inbred mice and mice with high risk-avoidance showed heightened alcohol relief. While dopamine D1 receptors in the striatum are required for alcohol's relief, their levels alone were not correlated with relief. Rather, the ratio between striatal D1 and D2 receptors was a determinant factor for risk-avoidance and alcohol relief. We show that increasing striatal D1 to D2 receptor ratio was sufficient to promote risk-avoidance and enhance alcohol relief, even at initial exposure. Mice with high D1 to D2 receptor ratio were more prone to continue drinking despite adverse effects, a hallmark of AUD. These findings suggest that an anxiety phenotype may be a predisposing factor for AUD.
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Affiliation(s)
- Miriam E Bocarsly
- Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, NIH, Bethesda, MD, USA.
- Department of Pharmacology, Physiology and Neuroscience, Brain Health Institute, Rutgers New Jersey Medical School, Newark, NJ, USA.
| | - Marlisa J Shaw
- Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, NIH, Bethesda, MD, USA
- NIH Academy Enrichment Program, Office of OITE, NIH, Bethesda, MD, USA
| | - Emilya Ventriglia
- National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, MD, USA
| | | | - Hannah C Goldbach
- Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, NIH, Bethesda, MD, USA
- National Institute on Mental Health, NIH, Bethesda, MD, USA
| | - Catherine E Teresi
- Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, NIH, Bethesda, MD, USA
- Center on Compulsive Behaviors, NIH, Bethesda, MD, USA
| | - Marilyn Bravo
- Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, NIH, Bethesda, MD, USA
| | - Roland Bock
- Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, NIH, Bethesda, MD, USA
- National Institute on Mental Health, NIH, Bethesda, MD, USA
| | - Patrick Hong
- Department of Pharmacology, Physiology and Neuroscience, Brain Health Institute, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Han Bin Kwon
- Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, NIH, Bethesda, MD, USA
| | - Imran M Khawaja
- Department of Pharmacology, Physiology and Neuroscience, Brain Health Institute, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Rishi Raman
- Department of Pharmacology, Physiology and Neuroscience, Brain Health Institute, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Erin M Murray
- Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, NIH, Bethesda, MD, USA
| | - Jordi Bonaventura
- National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, MD, USA
- Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain
| | - Dennis A Burke
- Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, NIH, Bethesda, MD, USA
| | - Michael Michaelides
- National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, MD, USA
| | - Veronica A Alvarez
- Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, NIH, Bethesda, MD, USA.
- National Institute on Drug Abuse, Intramural Research Program, NIH, Baltimore, MD, USA.
- National Institute on Mental Health, NIH, Bethesda, MD, USA.
- Center on Compulsive Behaviors, NIH, Bethesda, MD, USA.
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Singleton SP, Velidi P, Schilling L, Luppi AI, Jamison K, Parkes L, Kuceyeski A. Altered Structural Connectivity and Functional Brain Dynamics in Individuals With Heavy Alcohol Use Elucidated via Network Control Theory. BIOLOGICAL PSYCHIATRY. COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2024; 9:1010-1018. [PMID: 38839036 PMCID: PMC11456392 DOI: 10.1016/j.bpsc.2024.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/03/2024] [Accepted: 05/18/2024] [Indexed: 06/07/2024]
Abstract
BACKGROUND Heavy alcohol use and its associated conditions, such as alcohol use disorder, impact millions of individuals worldwide. While our understanding of the neurobiological correlates of alcohol use has evolved substantially, we still lack models that incorporate whole-brain neuroanatomical, functional, and pharmacological information under one framework. METHODS Here, we utilized diffusion and functional magnetic resonance imaging to investigate alterations to brain dynamics in 130 individuals with a high amount of current alcohol use. We compared these alcohol-using individuals to 308 individuals with minimal use of any substances. RESULTS We found that individuals with heavy alcohol use had less dynamic and complex brain activity, and through leveraging network control theory, had increased control energy to complete transitions between activation states. Furthermore, using separately acquired positron emission tomography data, we deployed an in silico evaluation demonstrating that decreased D2 receptor levels, as found previously in individuals with alcohol use disorder, may relate to our observed findings. CONCLUSIONS This work demonstrates that whole-brain, multimodal imaging information can be combined under a network control framework to identify and evaluate neurobiological correlates and mechanisms of heavy alcohol use.
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Affiliation(s)
- S Parker Singleton
- Department of Radiology, Weill Cornell Medicine, New York University, New York, New York.
| | - Puneet Velidi
- Department of Statistics and Data Science, Cornell University, Ithaca, New York
| | - Louisa Schilling
- Department of Radiology, Weill Cornell Medicine, New York University, New York, New York
| | - Andrea I Luppi
- Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Keith Jamison
- Department of Radiology, Weill Cornell Medicine, New York University, New York, New York
| | - Linden Parkes
- Department of Psychiatry, Rutgers University, Piscataway, New Jersey
| | - Amy Kuceyeski
- Department of Radiology, Weill Cornell Medicine, New York University, New York, New York
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Tereshchenko SY, Afonicheva KV, Marchenko IV, Shubina MV, Smolnikova MV. Polymorphic variants of the dopamine receptor gene DRD2 (rs6277, rs1800497) in adolescents with problematic video game use. Vavilovskii Zhurnal Genet Selektsii 2024; 28:667-674. [PMID: 40200916 PMCID: PMC11975965 DOI: 10.18699/vjgb-24-74] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 06/30/2024] [Accepted: 07/15/2024] [Indexed: 04/10/2025] Open
Abstract
Problematic video games use, as a specific form of problematic Internet use, is widespread among adolescents and can have negative effects on their mental and somatic well-being. An increasing incidence of addictive video gaming, as well as the overuse of the Internet, among the young population makes the current study of susceptibility factors, including the genetic component, relevant. There has been a number of investigations related to the involvement of gene variants of the neurotransmitter system in the development of Internet addiction, with the results being different for various ethnic groups. The dopamine type 2 receptor gene (DRD2) is one of the candidate genes for susceptibility to video game addiction. The aim of the work was to study polymorphic variants of the dopamine receptor gene DRD2 (rs6277, rs1800497) in Russian adolescents with problematic use of computer video games. A sampling of 407 adolescents aged 14.1 ± 1.8 years was tested, of which 56 (13.8 %) were identified as having problems with the pathological use of video games use based on the GASA scale results. Boys in the sample proved to be addicted to video games more than girls (p = 0.041). As a result of comparing the allele frequency of DRD2 (rs6277), a tendency to a higher frequency of the minor allele T was revealed in the group of adolescents with problematic video game use compared with adolescents without problematic video game use (i. e. 0.563 and 0.466, respectively, p = 0.06). When using the dominant inheritance model, it was revealed that adolescents with problematic use of video games were statistically significantly more likely to carry the T (CT+TT) allele (p = 0.04, OR = 2.14, CI = 1.01-4.53). The T allele DRD2 (rs6277) is associated with low expression of the dopamine receptor D2 and leads to decreasing the density and affinity of extrastriatal dopamine type 2 receptors, which is associated with impaired social communication as well. We suggest that the presence of CT and TT genotypes of rs6277 DRD2 may be a potential risk factor for developing problematic video game use in adolescents.
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Affiliation(s)
- S Yu Tereshchenko
- Scientific Research Institute of Medical Problems of the North - a separate division of the Federal Research Center "Krasnoyarsk Science Center" of the Siberian Branch of the Russian Academy of Sciences, Krasnoyarsk, Russia
| | - K V Afonicheva
- Scientific Research Institute of Medical Problems of the North - a separate division of the Federal Research Center "Krasnoyarsk Science Center" of the Siberian Branch of the Russian Academy of Sciences, Krasnoyarsk, Russia
| | - I V Marchenko
- Scientific Research Institute of Medical Problems of the North - a separate division of the Federal Research Center "Krasnoyarsk Science Center" of the Siberian Branch of the Russian Academy of Sciences, Krasnoyarsk, Russia
| | - M V Shubina
- Scientific Research Institute of Medical Problems of the North - a separate division of the Federal Research Center "Krasnoyarsk Science Center" of the Siberian Branch of the Russian Academy of Sciences, Krasnoyarsk, Russia
| | - M V Smolnikova
- Scientific Research Institute of Medical Problems of the North - a separate division of the Federal Research Center "Krasnoyarsk Science Center" of the Siberian Branch of the Russian Academy of Sciences, Krasnoyarsk, Russia
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10
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Krupa H, Gearhardt AN, Lewandowski A, Avena NM. Food Addiction. Brain Sci 2024; 14:952. [PMID: 39451967 PMCID: PMC11506718 DOI: 10.3390/brainsci14100952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 10/26/2024] Open
Abstract
In this review, we aim to draw a connection between drug addiction and overconsumption of highly palatable food (OHPF) by discussing common behaviors and neurochemical pathways shared by these two states. OHPF can stimulate reward pathways in the brain that parallel those triggered by drug use, increasing the risk of dependency. Behavioral similarities between food and drug addiction can be addressed by tracking their stages: loss of control when eating (bingeing), withdrawal, craving, sensitization, and cross-sensitization. The brain adapts to addiction by way of the mesolimbic dopamine system, endogenous opioids and receptors, acetylcholine and dopamine balance, and adaptations of serotonin in neuroanatomy. Studies from the current literature are reviewed to determine how various neurological chemicals contribute to the reinforcement of drug addiction and OHPF. Finally, protocols for treating food addiction are discussed, including both clinical and pharmacological modalities. There is consistent evidence that OHPF changes brain chemistry and leads to addiction in similar ways to drugs. However, more long-term research is needed on food addiction, binge eating, and their neurobiological effects.
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Affiliation(s)
- Haley Krupa
- Marian Regional Medical Center, Santa Maria, CA 93454, USA;
| | | | | | - Nicole M. Avena
- Icahn School of Medicine at Mount Sinai, New York, NY 10021, USA
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11
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Jones JD, Arout CA, Luba R, Murugesan D, Madera G, Gorsuch L, Schusterman R, Martinez S. The influence of drug class on reward in substance use disorders. Pharmacol Biochem Behav 2024; 240:173771. [PMID: 38670466 PMCID: PMC11162950 DOI: 10.1016/j.pbb.2024.173771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/26/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024]
Abstract
In the United States, the societal costs associated with drug use surpass $500 billion annually. The rewarding and reinforcing properties that drive the use of these addictive substances are typically examined concerning the neurobiological effects responsible for their abuse potential. In this review, terms such as "abuse potential," "drug," and "addictive properties" are used due to their relevance to the methodological, theoretical, and conceptual framework for understanding the phenomenon of drug-taking behavior and the associated body of preclinical and clinical literature. The use of these terms is not intended to cast aspersions on individuals with substance use disorders (SUD). Understanding what motivates substance use has been a focus of SUD research for decades. Much of this corpus of work has focused on the shared effects of each drug class to increase dopaminergic transmission within the central reward pathways of the brain, or the "reward center." However, the precise influence of each drug class on dopamine signaling, and the extent thereof, differs considerably. Furthermore, the aforementioned substances have effects on several neurobiological targets that mediate and modulate their addictive properties. The current manuscript sought to review the influence of drug class on the rewarding effects of each of the major pharmacological classes of addictive drugs (i.e., psychostimulants, opioids, nicotine, alcohol, and cannabinoids). Our review suggests that even subtle differences in drug effects can result in significant variability in the subjective experience of the drug, altering rewarding and other reinforcing effects. Additionally, this review will argue that reward (i.e., the attractive and motivational property of a stimulus) alone is not sufficient to explain the abuse liability of these substances. Instead, abuse potential is best examined as a function of both positive and negative reinforcing drug effects (i.e., stimuli that the subject will work to attain and stimuli that the subject will work to end or avoid, respectively). Though reward is central to drug use, the factors that motivate and maintain drug taking are varied and complex, with much to be elucidated.
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Affiliation(s)
- Jermaine D Jones
- Division on Substance Use Disorders, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA.
| | - Caroline A Arout
- Division on Substance Use Disorders, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA
| | - Rachel Luba
- Division on Substance Use Disorders, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA
| | - Dillon Murugesan
- CUNY School of Medicine, 160 Convent Avenue, New York, NY 10031, USA
| | - Gabriela Madera
- Division on Substance Use Disorders, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA
| | - Liam Gorsuch
- Department of Psychiatry, The University of British Columbia, 430-5950 University Blvd., Vancouver V6T 1Z3, BC, Canada
| | - Rebecca Schusterman
- Division on Substance Use Disorders, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA
| | - Suky Martinez
- Division on Substance Use Disorders, Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA
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12
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Pati D, Taxier LR, Xia M, Lee SI, Conley SY, Sides T, Boyt KM, Hunker AC, Zweifel LS, Kash TL. Dopamine D2 receptors in the bed nucleus of the stria terminalis modulate alcohol-related behaviors. ADDICTION NEUROSCIENCE 2024; 11:100157. [PMID: 39741698 PMCID: PMC11687822 DOI: 10.1016/j.addicn.2024.100157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Dysregulation of the dopamine (DA) system is a hallmark of substance use disorders, including alcohol use disorder (AUD). Of the DA receptor subtypes, the DA D2 receptors (D2Rs) play a key role in the reinforcing effects of alcohol. D2Rs are expressed in numerous brain regions associated with the regulation of appetitive behaviors. One such region is the bed nucleus of the stria terminalis (BNST), which has been linked to the development and maintenance of AUD. Recently, we identified alcohol withdrawal-related neuroadaptations in the periaqueductal gray/dorsal raphe to BNST DA circuit in male mice. However, the role of D2R-expressing BNST neurons in voluntary alcohol consumption is not well characterized. In this study, we used a CRISPR-Cas9-based viral approach, to selectively reduce the expression of D2Rs in BNST GABA neurons (BNST vgat Drd2) and interrogated the impact on alcohol-related behaviors. In male mice, reduced BNST vgat Drd2 expression potentiated the stimulatory effects of alcohol and increased voluntary consumption of 20% w/v alcohol in a two-bottle choice intermittent access paradigm. This effect was not specific to alcohol, as BNST vgat Drd2 knockdown also increased sucrose intake in male mice. Interestingly, reduction in BNST vgat Drd2 expression in female mice did not alter alcohol-related behaviors but lowered the threshold for mechanical pain sensitivity. Collectively, our findings suggest a role for postsynaptic BNST D2Rs in the modulation of sex-specific behavioral responses to alcohol and sucrose.
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Affiliation(s)
- Dipanwita Pati
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Lisa R. Taxier
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Mengfan Xia
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Sophia I. Lee
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Sara Y. Conley
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Curriculum of Neuroscience, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Tori Sides
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Kristen M. Boyt
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Avery C. Hunker
- Department of Pharmacology, University of Washington, Seattle, WA, USA
| | - Larry S. Zweifel
- Department of Pharmacology, University of Washington, Seattle, WA, USA
- Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA, USA
| | - Thomas L. Kash
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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13
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Farahbakhsh ZZ, Holleran KM, Sens JP, Fordahl SC, Mauterer MI, López AJ, Cuzon Carlson VC, Kiraly DD, Grant KA, Jones SR, Siciliano CA. Synchrony between midbrain gene transcription and dopamine terminal regulation is modulated by chronic alcohol drinking. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.15.584711. [PMID: 38559169 PMCID: PMC10979957 DOI: 10.1101/2024.03.15.584711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Alcohol use disorder is marked by disrupted behavioral and emotional states which persist into abstinence. The enduring synaptic alterations that remain despite the absence of alcohol are of interest for interventions to prevent relapse. Here, 28 male rhesus macaques underwent over 20 months of alcohol drinking interspersed with three 30-day forced abstinence periods. After the last abstinence period, we paired direct sub-second dopamine monitoring via ex vivo voltammetry in nucleus accumbens slices with RNA-sequencing of the ventral tegmental area. We found persistent augmentation of dopamine transporter function, kappa opioid receptor sensitivity, and dynorphin release - all inhibitory regulators which act to decrease extracellular dopamine. Surprisingly, though transcript expression was not altered, the relationship between gene expression and functional readouts of these encoded proteins was highly dynamic and altered by drinking history. These results outline the long-lasting synaptic impact of alcohol use and suggest that assessment of transcript-function relationships is critical for the rational design of precision therapeutics.
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14
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Söderpalm B, Ericson M. Alcohol and the dopamine system. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2024; 175:21-73. [PMID: 38555117 DOI: 10.1016/bs.irn.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
The mesolimbic dopamine pathway plays a major role in drug reinforcement and is likely involved also in the development of drug addiction. Ethanol, like most addictive drugs, acutely activates the mesolimbic dopamine system and releases dopamine, and ethanol-associated stimuli also appear to trigger dopamine release. In addition, chronic exposure to ethanol reduces the baseline function of the mesolimbic dopamine system. The molecular mechanisms underlying ethanol´s interaction with this system remain, however, to be unveiled. Here research on the actions of ethanol in the mesolimbic dopamine system, focusing on the involvement of cystein-loop ligand-gated ion channels, opiate receptors, gastric peptides and acetaldehyde is briefly reviewed. In summary, a great complexity as regards ethanol´s mechanism(s) of action along the mesolimbic dopamine system has been revealed. Consequently, several new targets and possibilities for pharmacotherapies for alcohol use disorder have emerged.
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Affiliation(s)
- Bo Söderpalm
- Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Addiction and Dependency, Sahlgrenska University Hospital, Gothenburg, Sweden.
| | - Mia Ericson
- Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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15
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Singleton SP, Velidi P, Schilling L, Luppi AI, Jamison K, Parkes L, Kuceyeski A. Altered structural connectivity and functional brain dynamics in individuals with heavy alcohol use. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.27.568762. [PMID: 38077021 PMCID: PMC10705230 DOI: 10.1101/2023.11.27.568762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2023]
Abstract
Heavy alcohol use and its associated conditions, such as alcohol use disorder (AUD), impact millions of individuals worldwide. While our understanding of the neurobiological correlates of AUD has evolved substantially, we still lack models incorporating whole-brain neuroanatomical, functional, and pharmacological information under one framework. Here, we utilize diffusion and functional magnetic resonance imaging to investigate alterations to brain dynamics in N = 130 individuals with a high amount of current alcohol use. We compared these alcohol using individuals to N = 308 individuals with minimal use of any substances. We find that individuals with heavy alcohol use had less dynamic and complex brain activity, and through leveraging network control theory, had increased control energy to complete transitions between activation states. Further, using separately acquired positron emission tomography (PET) data, we deploy an in silico evaluation demonstrating that decreased D2 receptor levels, as found previously in individuals with AUD, may relate to our observed findings. This work demonstrates that whole-brain, multimodal imaging information can be combined under a network control framework to identify and evaluate neurobiological correlates and mechanisms of AUD.
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Affiliation(s)
- S Parker Singleton
- Department of Radiology, Weill Cornell Medicine, New York, New York, U.S.A
| | - Puneet Velidi
- Department of Statistics and Data Science, Cornell University, Ithaca, New York, U.S.A
| | - Louisa Schilling
- Montreal Neurological Institute, McGill Univeristy, Montreal, CA
| | - Andrea I Luppi
- Department of Radiology, Weill Cornell Medicine, New York, New York, U.S.A
| | - Keith Jamison
- Department of Radiology, Weill Cornell Medicine, New York, New York, U.S.A
| | - Linden Parkes
- Department of Psychiatry, Rutgers University, Piscataway, NJ 08854, USA
| | - Amy Kuceyeski
- Department of Radiology, Weill Cornell Medicine, New York, New York, U.S.A
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16
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Khan AF, Adewale Q, Lin SJ, Baumeister TR, Zeighami Y, Carbonell F, Palomero-Gallagher N, Iturria-Medina Y. Patient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson's disease. Nat Commun 2023; 14:6009. [PMID: 37752107 PMCID: PMC10522603 DOI: 10.1038/s41467-023-41677-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 09/08/2023] [Indexed: 09/28/2023] Open
Abstract
Parkinson's disease involves multiple neurotransmitter systems beyond the classical dopaminergic circuit, but their influence on structural and functional alterations is not well understood. Here, we use patient-specific causal brain modeling to identify latent neurotransmitter receptor-mediated mechanisms contributing to Parkinson's disease progression. Combining the spatial distribution of 15 receptors from post-mortem autoradiography with 6 neuroimaging-derived pathological factors, we detect a diverse set of receptors influencing gray matter atrophy, functional activity dysregulation, microstructural degeneration, and dendrite and dopaminergic transporter loss. Inter-individual variability in receptor mechanisms correlates with symptom severity along two distinct axes, representing motor and psychomotor symptoms with large GABAergic and glutamatergic contributions, and cholinergically-dominant visuospatial, psychiatric and memory dysfunction. Our work demonstrates that receptor architecture helps explain multi-factorial brain re-organization, and suggests that distinct, co-existing receptor-mediated processes underlie Parkinson's disease.
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Affiliation(s)
- Ahmed Faraz Khan
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
- McConnell Brain Imaging Center, Montreal Neurological Institute, Montreal, QC, Canada
- Ludmer Centre for Neuroinformatics & Mental Health, Montreal, QC, Canada
| | - Quadri Adewale
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
- McConnell Brain Imaging Center, Montreal Neurological Institute, Montreal, QC, Canada
- Ludmer Centre for Neuroinformatics & Mental Health, Montreal, QC, Canada
| | - Sue-Jin Lin
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
- McConnell Brain Imaging Center, Montreal Neurological Institute, Montreal, QC, Canada
- Ludmer Centre for Neuroinformatics & Mental Health, Montreal, QC, Canada
| | - Tobias R Baumeister
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
- McConnell Brain Imaging Center, Montreal Neurological Institute, Montreal, QC, Canada
- Ludmer Centre for Neuroinformatics & Mental Health, Montreal, QC, Canada
| | - Yashar Zeighami
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
- Douglas Research Centre, Department of Psychiatry, McGill University, Montreal, QC, Canada
| | | | - Nicola Palomero-Gallagher
- Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany
- Cécile and Oskar Vogt Institute of Brain Research, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
- Department of Psychiatry, Psychotherapy, and Psychosomatics, Medical Faculty, RWTH Aachen, and JARA - Translational Brain Medicine, Aachen, Germany
| | - Yasser Iturria-Medina
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
- McConnell Brain Imaging Center, Montreal Neurological Institute, Montreal, QC, Canada.
- Ludmer Centre for Neuroinformatics & Mental Health, Montreal, QC, Canada.
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17
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Koob GF, Vendruscolo L. Theoretical Frameworks and Mechanistic Aspects of Alcohol Addiction: Alcohol Addiction as a Reward Deficit/Stress Surfeit Disorder. Curr Top Behav Neurosci 2023. [PMID: 37421551 DOI: 10.1007/7854_2023_424] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/10/2023]
Abstract
Alcohol use disorder (AUD) can be defined by a compulsion to seek and take alcohol, the loss of control in limiting intake, and the emergence of a negative emotional state when access to alcohol is prevented. Alcohol use disorder impacts multiple motivational mechanisms and can be conceptualized as a disorder that includes a progression from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). Compulsive drug seeking that is associated with AUD can be derived from multiple neuroadaptations, but the thesis argued herein is that a key component involves the construct of negative reinforcement. Negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from the dysregulation of specific neurochemical elements that are involved in reward and stress within basal forebrain structures that involve the ventral striatum and extended amygdala, respectively. Specific neurochemical elements in these structures include decreases in reward neurotransmission (e.g., decreases in dopamine and opioid peptide function in the ventral striatum) and the recruitment of brain stress systems (e.g., corticotropin-releasing factor [CRF]) in the extended amygdala, which contributes to hyperkatifeia and greater alcohol intake that is associated with dependence. Glucocorticoids and mineralocorticoids may play a role in sensitizing the extended amygdala CRF system. Other components of brain stress systems in the extended amygdala that may contribute to the negative motivational state of withdrawal include norepinephrine in the bed nucleus of the stria terminalis, dynorphin in the nucleus accumbens, hypocretin and vasopressin in the central nucleus of the amygdala, and neuroimmune modulation. Decreases in the activity of neuropeptide Y, nociception, endocannabinoids, and oxytocin in the extended amygdala may also contribute to hyperkatifeia that is associated with alcohol withdrawal. Such dysregulation of emotional processing may also significantly contribute to pain that is associated with alcohol withdrawal and negative urgency (i.e., impulsivity that is associated with hyperkatifeia during hyperkatifeia). Thus, an overactive brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of AUD. The combination of the loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for a negative emotional state that is responsible for the negative reinforcement that at least partially drives the compulsivity of AUD.
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Affiliation(s)
- George F Koob
- Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
| | - Leandro Vendruscolo
- Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
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18
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Pati D, Lee SI, Conley SY, Sides T, Boyt KM, Hunker AC, Zweifel LS, Kash TL. Dopamine D2 receptors in the bed nucleus of the stria terminalis modulate alcohol-related behaviors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.13.544820. [PMID: 37398115 PMCID: PMC10312666 DOI: 10.1101/2023.06.13.544820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Dysregulation of the dopamine (DA) system is a hallmark of substance abuse disorders, including alcohol use disorder (AUD). Of the DA receptor subtypes, the DA D2 receptors (D2Rs) play a key role in the reinforcing effects of alcohol. D2Rs are expressed in numerous brain regions associated with the regulation of appetitive behaviors. One such region is the bed nucleus of the stria terminalis (BNST), which has been linked to the development and maintenance of AUD. Recently, we identified alcohol withdrawal-related neuroadaptations in the periaqueductal gray/dorsal raphe to BNST DA circuit in male mice. However, the role of D2R-expressing BNST neurons in voluntary alcohol consumption is not well characterized. In this study, we used a CRISPR-Cas9-based viral approach, to selectively reduce the expression of D2Rs in BNST VGAT neurons and interrogated the impact of BNST D2Rs in alcohol-related behaviors. In male mice, reduced D2R expression potentiated the stimulatory effects of alcohol and increased voluntary consumption of 20% w/v alcohol in a two-bottle choice intermittent access paradigm. This effect was not specific to alcohol, as D2R deletion also increased sucrose intake in male mice. Interestingly, cell-specific deletion of BNST D2Rs in female mice did not alter alcohol-related behaviors but lowered the threshold for mechanical pain sensitivity. Collectively, our findings suggest a role for postsynaptic BNST D2Rs in the modulation of sex-specific behavioral responses to alcohol and sucrose.
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Affiliation(s)
- Dipanwita Pati
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sophia I. Lee
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sara Y. Conley
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Curriculum of Neuroscience, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Tori Sides
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kristen M. Boyt
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Avery C. Hunker
- Department of Pharmacology, University of Washington, Seattle, WA, USA
| | - Larry S. Zweifel
- Department of Pharmacology, University of Washington, Seattle, WA, USA
- Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA, USA
| | - Thomas L. Kash
- Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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19
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Czoty PW, Tryhus AM, Solingapuram Sai KK, Nader SH, Epperly PM. Association of dopamine D2-like and D 3 receptor function with initial sensitivity to cocaine reinforcement in male rhesus monkeys. Brain Res 2023; 1807:148323. [PMID: 36914041 PMCID: PMC10150948 DOI: 10.1016/j.brainres.2023.148323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 03/03/2023] [Accepted: 03/07/2023] [Indexed: 03/15/2023]
Abstract
Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their importance in mediating the abuse-related effects of cocaine, brain dopamine receptors are logical candidates for investigation. We analyzed data from two recently published studies that characterized availability of dopamine D2-like receptors (D2R) with [11C]raclopride PET imaging and dopamine D3 receptor (D3R) sensitivity with quinpirole-induced yawning in cocaine-naïve rhesus monkeys who subsequently acquired cocaine self-administration and completed a cocaine self-administration dose-effect curve. The present analysis compared D2R availability in several brain areas and characteristics of quinpirole-induced yawning, both acquired when monkeys were drug-naïve, with measures of initial sensitivity to cocaine. D2R availability in the caudate nucleus was negatively correlated with the ED50 of the cocaine self-administration curve, although the significance of this relationship was driven by an outlier and was not present after the outlier was removed. No other significant associations were observed between D2R availability in any examined brain region and measures of sensitivity to cocaine reinforcement. However, there was a significant negative correlation between D3R sensitivity, represented by the ED50 of the quinpirole-induced yawning curve, and the dose at which monkeys acquired cocaine self-administration. We also report no change from baseline D2R availability when a second PET scan was conducted after completion of the dose-effect curves. These data suggest the utility of D3R sensitivity, but not D2R availability, as a biomarker for vulnerability and resilience to cocaine. The well-established relationships between dopamine receptors and cocaine reinforcement in cocaine-experienced humans and animals may require extensive cocaine exposure.
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Affiliation(s)
- Paul W Czoty
- Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States.
| | - Aaron M Tryhus
- Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States
| | - Kiran K Solingapuram Sai
- Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States
| | - Susan H Nader
- Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States
| | - Phillip M Epperly
- Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States
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20
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Szulc M, Kujawski R, Pacholak A, Poprawska M, Czora-Poczwardowska K, Geppert B, Mikołajczak PŁ. Cannabidiol as a Modulator of the Development of Alcohol Tolerance in Rats. Nutrients 2023; 15:nu15071702. [PMID: 37049542 PMCID: PMC10097131 DOI: 10.3390/nu15071702] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/27/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023] Open
Abstract
The study aimed to explore in vivo the influence of cannabidiol (CBD) on the development of alcohol tolerance in rats. Rats were treated with ethanol (3.0 g/kg, i.p.) and CBD (20 mg/kg, p.o.) for nine successive days, and rectal body temperature, sedation (sleeping time), and blood alcohol concentration (BAC) were measured. In the prefrontal cortex, hippocampus, and striatum, the cannabinoid (CB1R and CB2R) and dopaminergic (DRD1, DRD2, DRD4, DRD5) receptors’ mRNA level changes were analyzed using the quantitative RT-PCR method. CBD inhibited the development of tolerance to the hypothermic and sedative action of alcohol, coupled with BAC elevation. On a molecular level, the most pronounced effects of the CBD + ethanol interaction in the striatum were observed, where CBD reversed the downregulation of CB2R gene transcription caused by ethanol. For CB1R, DRD1, and DRD2 mRNAs, the CBD + ethanol interaction produced opposite effects than for CB2R ones. In turn, for the transcription of genes encoding dopaminergic receptors, the most potent effect of alcohol as CBD occurred in the hippocampus. However, the combined CBD and alcohol administration showed the same effect for each substance administered separately. Since tolerance is considered a prelude to drug addiction, obtained results allow us to emphasize the thesis that CBD can inhibit the development of alcohol dependence in rats.
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Affiliation(s)
- Michał Szulc
- Department of Pharmacology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
| | - Radosław Kujawski
- Department of Pharmacology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
| | - Amanda Pacholak
- Institute of Chemical Technology and Engineering, Poznan University of Technology, Berdychowo 4, 60-965 Poznan, Poland
| | - Marta Poprawska
- Department of Pharmacology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
| | | | - Bogna Geppert
- Department of Forensic Medicine, Collegium Medicum, University of Zielona Góra, Zyty 28, 65-046 Zielona Góra, Poland
| | - Przemysław Ł. Mikołajczak
- Department of Pharmacology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
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21
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Ribeiro G, Maia A, Cotovio G, Oliveira FPM, Costa DC, Oliveira-Maia AJ. Striatal dopamine D2-like receptors availability in obesity and its modulation by bariatric surgery: a systematic review and meta-analysis. Sci Rep 2023; 13:4959. [PMID: 36973321 PMCID: PMC10042861 DOI: 10.1038/s41598-023-31250-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 03/08/2023] [Indexed: 03/29/2023] Open
Abstract
There is significant evidence linking a 'reward deficiency syndrome' (RDS), comprising decreased availability of striatal dopamine D2-like receptors (DD2lR) and addiction-like behaviors underlying substance use disorders and obesity. Regarding obesity, a systematic review of the literature with a meta-analysis of such data is lacking. Following a systematic review of the literature, we performed random-effects meta-analyses to determine group differences in case-control studies comparing DD2lR between individuals with obesity and non-obese controls and prospective studies of pre- to post-bariatric surgery DD2lR changes. Cohen's d was used to measure effect size. Additionally, we explored factors potentially associated with group differences in DD2lR availability, such as obesity severity, using univariate meta-regression. In a meta-analysis including positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies, striatal DD2lR availability did not significantly differ between obesity and controls. However, in studies comprising patients with class III obesity or higher, group differences were significant, favoring lower DD2lR availability in the obesity group. This effect of obesity severity was corroborated by meta-regressions showing inverse associations between the body mass index (BMI) of the obesity group and DD2lR availability. Post-bariatric changes in DD2lR availability were not found, although a limited number of studies were included in this meta-analysis. These results support lower DD2lR in higher classes of obesity which is a more targeted population to explore unanswered questions regarding the RDS.
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Affiliation(s)
- Gabriela Ribeiro
- Champalimaud Research and Clinical Centre, Champalimaud Foundation, Av. de Brasília, Doca de Pedrouços, 1400-038, Lisboa, Portugal
- Lisbon Academic Medical Centre PhD Program, Faculdade de Medicina da Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal
- Nova Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056, Lisboa, Portugal
- Nutrition and Metabolism Department, Nova Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056, Lisboa, Portugal
| | - Ana Maia
- Champalimaud Research and Clinical Centre, Champalimaud Foundation, Av. de Brasília, Doca de Pedrouços, 1400-038, Lisboa, Portugal
- Nova Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056, Lisboa, Portugal
- Department of Psychiatry and Mental Health, Centro Hospitalar de Lisboa Ocidental, Rua da Junqueira, 126, 1340-019, Lisboa, Portugal
| | - Gonçalo Cotovio
- Champalimaud Research and Clinical Centre, Champalimaud Foundation, Av. de Brasília, Doca de Pedrouços, 1400-038, Lisboa, Portugal
- Nova Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056, Lisboa, Portugal
- Department of Psychiatry and Mental Health, Centro Hospitalar de Lisboa Ocidental, Rua da Junqueira, 126, 1340-019, Lisboa, Portugal
| | - Francisco P M Oliveira
- Champalimaud Research and Clinical Centre, Champalimaud Foundation, Av. de Brasília, Doca de Pedrouços, 1400-038, Lisboa, Portugal
| | - Durval C Costa
- Champalimaud Research and Clinical Centre, Champalimaud Foundation, Av. de Brasília, Doca de Pedrouços, 1400-038, Lisboa, Portugal
| | - Albino J Oliveira-Maia
- Champalimaud Research and Clinical Centre, Champalimaud Foundation, Av. de Brasília, Doca de Pedrouços, 1400-038, Lisboa, Portugal.
- Nova Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056, Lisboa, Portugal.
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22
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Barnett WH, Kuznetsov A, Lapish CC. Distinct cortico-striatal compartments drive competition between adaptive and automatized behavior. PLoS One 2023; 18:e0279841. [PMID: 36943842 PMCID: PMC10030038 DOI: 10.1371/journal.pone.0279841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 12/15/2022] [Indexed: 03/23/2023] Open
Abstract
Cortical and basal ganglia circuits play a crucial role in the formation of goal-directed and habitual behaviors. In this study, we investigate the cortico-striatal circuitry involved in learning and the role of this circuitry in the emergence of inflexible behaviors such as those observed in addiction. Specifically, we develop a computational model of cortico-striatal interactions that performs concurrent goal-directed and habit learning. The model accomplishes this by distinguishing learning processes in the dorsomedial striatum (DMS) that rely on reward prediction error signals as distinct from the dorsolateral striatum (DLS) where learning is supported by salience signals. These striatal subregions each operate on unique cortical input: the DMS receives input from the prefrontal cortex (PFC) which represents outcomes, and the DLS receives input from the premotor cortex which determines action selection. Following an initial learning of a two-alternative forced choice task, we subjected the model to reversal learning, reward devaluation, and learning a punished outcome. Behavior driven by stimulus-response associations in the DLS resisted goal-directed learning of new reward feedback rules despite devaluation or punishment, indicating the expression of habit. We repeated these simulations after the impairment of executive control, which was implemented as poor outcome representation in the PFC. The degraded executive control reduced the efficacy of goal-directed learning, and stimulus-response associations in the DLS were even more resistant to the learning of new reward feedback rules. In summary, this model describes how circuits of the dorsal striatum are dynamically engaged to control behavior and how the impairment of executive control by the PFC enhances inflexible behavior.
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Affiliation(s)
- William H. Barnett
- Department of Psychology, Indiana University—Purdue University Indianapolis, Indianapolis, Indiana, United States of America
| | - Alexey Kuznetsov
- Department of Mathematics, Indiana University—Purdue University Indianapolis, Indianapolis, Indiana, United States of America
| | - Christopher C. Lapish
- Department of Psychology, Indiana University—Purdue University Indianapolis, Indianapolis, Indiana, United States of America
- Stark Neurosciences Research Institute, Indiana University—Purdue University Indianapolis, Indianapolis, Indiana, United States of America
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23
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Sitzia G, Lovinger DM. Circuit dysfunctions of associative and sensorimotor basal ganglia loops in alcohol use disorder: insights from animal models. ADDICTION NEUROSCIENCE 2023; 5:100056. [PMID: 36567745 PMCID: PMC9788651 DOI: 10.1016/j.addicn.2022.100056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Persons that develop Alcohol Use Disorder (AUD) experience behavioral changes that include compulsion to seek and take alcohol despite its negative consequences on the person's psychosocial, health and economic spheres, inability to limit alcohol intake and a negative emotional/ motivational state that emerges during withdrawal. During all the stages of AUD executive functions, i.e. the person's ability to direct their behavior towards a goal, working memory and cognitive flexibility are eroded. Animal models of AUD recapitulate aspects of action selection impairment and offer the opportunity to benchmark the underlying circuit mechanisms. Here we propose a circuit-based approach to AUD research focusing on recent advances in behavioral analysis, neuroanatomy, genetics, and physiology to guide future research in the field.
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Affiliation(s)
- Giacomo Sitzia
- Current Address: Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Rockville, USA
- Molecular Neurophysiology Laboratory, Department of Physiology and Pharmacology, Karolinska Institutet, 17164 Stockholm, Sweden
| | - David M. Lovinger
- Current Address: Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Rockville, USA
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24
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Valyear MD, LeCocq MR, Brown A, Villaruel FR, Segal D, Chaudhri N. Learning processes in relapse to alcohol use: lessons from animal models. Psychopharmacology (Berl) 2023; 240:393-416. [PMID: 36264342 DOI: 10.1007/s00213-022-06254-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 10/02/2022] [Indexed: 11/29/2022]
Abstract
RATIONALE Alcohol use is reliably preceded by discrete and contextual stimuli which, through diverse learning processes, acquire the capacity to promote alcohol use and relapse to alcohol use. OBJECTIVE We review contemporary extinction, renewal, reinstatement, occasion setting, and sex differences research within a conditioning framework of relapse to alcohol use to inform the development of behavioural and pharmacological therapies. KEY FINDINGS Diverse learning processes and corresponding neurobiological substrates contribute to relapse to alcohol use. Results from animal models indicate that cortical, thalamic, accumbal, hypothalamic, mesolimbic, glutamatergic, opioidergic, and dopaminergic circuitries contribute to alcohol relapse through separable learning processes. Behavioural therapies could be improved by increasing the endurance and generalizability of extinction learning and should incorporate whether discrete cues and contexts influence behaviour through direct excitatory conditioning or occasion setting mechanisms. The types of learning processes that most effectively influence responding for alcohol differ in female and male rats. CONCLUSION Sophisticated conditioning experiments suggest that diverse learning processes are mediated by distinct neural circuits and contribute to relapse to alcohol use. These experiments also suggest that gender-specific behavioural and pharmacological interventions are a way towards efficacious therapies to prevent relapse to alcohol use.
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Affiliation(s)
- Milan D Valyear
- Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montréal, QC, Canada. .,Department of Psychology, McGill University, 1205 Ave. Dr. Penfield, Room N8/5, Montréal, QC, H3A 1B1, Canada.
| | - Mandy R LeCocq
- Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montréal, QC, Canada
| | - Alexa Brown
- Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montréal, QC, Canada
| | - Franz R Villaruel
- Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montréal, QC, Canada
| | - Diana Segal
- Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montréal, QC, Canada
| | - Nadia Chaudhri
- Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montréal, QC, Canada
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25
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Beck A, Ebrahimi C, Rosenthal A, Charlet K, Heinz A. The Dopamine System in Mediating Alcohol Effects in Humans. Curr Top Behav Neurosci 2023. [PMID: 36705911 DOI: 10.1007/7854_2022_415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Brain-imaging studies show that the development and maintenance of alcohol use disorder (AUD) is determined by a complex interaction of different neurotransmitter systems and multiple psychological factors. In this context, the dopaminergic reinforcement system appears to be of fundamental importance. We focus on the excitatory and depressant effects of acute versus chronic alcohol intake and its impact on dopaminergic neurotransmission. Furthermore, we describe alterations in dopaminergic neurotransmission as associated with symptoms of alcohol dependence. We specifically focus on neuroadaptations to chronic alcohol consumption and their effect on central processing of alcohol-associated and reward-related stimuli. Altered reward processing, complex conditioning processes, impaired reinforcement learning, and increased salience attribution to alcohol-associated stimuli enable alcohol cues to drive alcohol seeking and consumption. Finally, we will discuss how the neurobiological and neurochemical mechanisms of alcohol-associated alterations in reward processing and learning can interact with stress, cognition, and emotion processing.
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Affiliation(s)
- Anne Beck
- Faculty of Health, Health and Medical University, Potsdam, Germany
| | - Claudia Ebrahimi
- Department of Psychiatry and Neurosciences, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany
| | - Annika Rosenthal
- Department of Psychiatry and Neurosciences, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany
| | - Katrin Charlet
- Department of Psychiatry and Neurosciences, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany
| | - Andreas Heinz
- Department of Psychiatry and Neurosciences, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany.
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26
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Klausen MK, Jensen ME, Møller M, Le Dous N, Jensen AMØ, Zeeman VA, Johannsen CF, Lee A, Thomsen GK, Macoveanu J, Fisher PM, Gillum MP, Jørgensen NR, Bergmann ML, Enghusen Poulsen H, Becker U, Holst JJ, Benveniste H, Volkow ND, Vollstädt-Klein S, Miskowiak KW, Ekstrøm CT, Knudsen GM, Vilsbøll T, Fink-Jensen A. Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial. JCI Insight 2022; 7:e159863. [PMID: 36066977 PMCID: PMC9675448 DOI: 10.1172/jci.insight.159863] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 08/31/2022] [Indexed: 11/17/2022] Open
Abstract
BackgroundAlcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patients with AUD is unknown.MethodsIn a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26 weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed functional MRI (fMRI) and single-photon emission CT (SPECT) brain scans.ResultsA total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared with placebo, it significantly attenuated fMRI alcohol cue reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, dopamine transporter availability was lower in the exenatide group compared with the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI > 30 kg/m2). Adverse events were mainly gastrointestinal.ConclusionThis randomized controlled trial on the effects of a GLP-1 receptor agonist in AUD patients provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction.Trial registrationEudraCT: 2016-003343-11. ClinicalTrials.gov (NCT03232112).FundingNovavi Foundation; Research Foundation, Mental Health Services, Capital Region of Denmark; Research Foundation, Capital Region of Denmark; Ivan Nielsen Foundation; A.P. Moeller Foundation; Augustinus Foundation; Woerzner Foundation; Grosserer L.F. Foghts Foundation; Hartmann Foundation; Aase and Ejnar Danielsen Foundation; P.A. Messerschmidt and Wife Foundation; and Lundbeck Foundation.
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Affiliation(s)
- Mette Kruse Klausen
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mathias Ebbesen Jensen
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Marco Møller
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Nina Le Dous
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | | | | | | | - Alycia Lee
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, and
- Mannheim Center for Translational Neurosciences, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany
| | - Gerda Krog Thomsen
- Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Julian Macoveanu
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | | | - Matthew Paul Gillum
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences and
| | - Niklas Rye Jørgensen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Centre of Diagnostic Investigation, University of Copenhagen, Copenhagen, Denmark
| | - Marianne Lerbæk Bergmann
- Department of Biochemistry and Immunology, University Hospital of Southern Denmark, Vejle, Denmark
| | - Henrik Enghusen Poulsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Pharmacology, Bispebjerg/Frederiksberg Hospital, University Hospital Copenhagen, Copenhagen, Denmark
| | - Ulrik Becker
- National Institute of Public Health, University of Southern Denmark and University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences and
| | - Helene Benveniste
- Department of Anesthesiology and Pediatric Anesthesiology, Yale University, New Haven, Connecticut, USA
| | - Nora D. Volkow
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Sabine Vollstädt-Klein
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, and
- Mannheim Center for Translational Neurosciences, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany
| | - Kamilla Woznica Miskowiak
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Psychology
| | | | - Gitte Moos Knudsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Tina Vilsbøll
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark
| | - Anders Fink-Jensen
- Psychiatric Centre Copenhagen, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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27
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Schacht JP, Yeongbin Im, Hoffman M, Voronin KE, Book SW, Anton RF. Effects of pharmacological and genetic regulation of COMT activity in alcohol use disorder: a randomized, placebo-controlled trial of tolcapone. Neuropsychopharmacology 2022; 47:1953-1960. [PMID: 35523943 PMCID: PMC9073504 DOI: 10.1038/s41386-022-01335-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/08/2022] [Accepted: 04/25/2022] [Indexed: 11/09/2022]
Abstract
Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone's effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934.
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Affiliation(s)
- Joseph P Schacht
- Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA.
| | - Yeongbin Im
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Michaela Hoffman
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Konstantin E Voronin
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Sarah W Book
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Raymond F Anton
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
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28
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Dai KZ, Choi IB, Levitt R, Blegen MB, Kaplan AR, Matsui A, Shin JH, Bocarsly ME, Simpson EH, Kellendonk C, Alvarez VA, Dobbs LK. Dopamine D2 receptors bidirectionally regulate striatal enkephalin expression: Implications for cocaine reward. Cell Rep 2022; 40:111440. [PMID: 36170833 PMCID: PMC9620395 DOI: 10.1016/j.celrep.2022.111440] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 08/04/2022] [Accepted: 09/09/2022] [Indexed: 11/24/2022] Open
Abstract
Low dopamine D2 receptor (D2R) availability in the striatum can predispose for cocaine abuse; though how low striatal D2Rs facilitate cocaine reward is unclear. Overexpression of D2Rs in striatal neurons or activation of D2Rs by acute cocaine suppresses striatal Penk mRNA. Conversely, low D2Rs in D2-striatal neurons increases striatal Penk mRNA and enkephalin peptide tone, an endogenous mu-opioid agonist. In brain slices, met-enkephalin and inhibition of enkephalin catabolism suppresses intra-striatal GABA transmission. Pairing cocaine with intra-accumbens met-enkephalin during place conditioning facilitates acquisition of preference, while mu-opioid receptor antagonist blocks preference in wild-type mice. We propose that heightened striatal enkephalin potentiates cocaine reward by suppressing intra-striatal GABA to enhance striatal output. Surprisingly, a mu-opioid receptor antagonist does not block cocaine preference in mice with low striatal D2Rs, implicating other opioid receptors. The bidirectional regulation of enkephalin by D2R activity and cocaine offers insights into mechanisms underlying the vulnerability for cocaine abuse. Low striatal D2 receptor levels are associated with cocaine abuse. Dai et al. bidirectionally alter striatal D2 receptor levels to probe the downstream mechanisms underlying this abuse liability. They provide evidence that enhanced enkephalin tone resulting from low D2 receptors is associated with suppressed intra-striatal GABA and potentiated cocaine reward.
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Affiliation(s)
- Kathy Z Dai
- Laboratory on Neurobiology of Compulsive Behaviors, NIAAA, IRP, NIH, Bethesda, MD, USA
| | - In Bae Choi
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
| | - Ryan Levitt
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
| | - Mariah B Blegen
- Laboratory on Neurobiology of Compulsive Behaviors, NIAAA, IRP, NIH, Bethesda, MD, USA
| | - Alanna R Kaplan
- Laboratory on Neurobiology of Compulsive Behaviors, NIAAA, IRP, NIH, Bethesda, MD, USA
| | - Aya Matsui
- Laboratory on Neurobiology of Compulsive Behaviors, NIAAA, IRP, NIH, Bethesda, MD, USA
| | - J Hoon Shin
- Laboratory on Neurobiology of Compulsive Behaviors, NIAAA, IRP, NIH, Bethesda, MD, USA
| | - Miriam E Bocarsly
- Laboratory on Neurobiology of Compulsive Behaviors, NIAAA, IRP, NIH, Bethesda, MD, USA; Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Rutgers Brain Health Institute, Newark, NJ, USA
| | - Eleanor H Simpson
- Department of Psychiatry, Columbia University Medical Center, New York, NY, USA; Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, NY, USA
| | - Christoph Kellendonk
- Department of Psychiatry, Columbia University Medical Center, New York, NY, USA; Department of Molecular Pharmacology and Therapeutics, Columbia University Medical Center, New York, NY, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
| | - Veronica A Alvarez
- Laboratory on Neurobiology of Compulsive Behaviors, NIAAA, IRP, NIH, Bethesda, MD, USA; Center on Compulsive Behaviors, IRP, NIH, Bethesda, MD, USA
| | - Lauren K Dobbs
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA; Department of Neuroscience, Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, USA.
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29
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Joshi A, Schott M, la Fleur SE, Barrot M. Role of the striatal dopamine, GABA and opioid systems in mediating feeding and fat intake. Neurosci Biobehav Rev 2022; 139:104726. [PMID: 35691472 DOI: 10.1016/j.neubiorev.2022.104726] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 12/08/2021] [Accepted: 06/05/2022] [Indexed: 10/18/2022]
Abstract
Food intake, which is a highly reinforcing behavior, provides nutrients required for survival in all animals. However, when fat and sugar consumption goes beyond the daily needs, it can favor obesity. The prevalence and severity of this health problem has been increasing with time. Besides covering nutrient and energy needs, food and in particular its highly palatable components, such as fats, also induce feelings of joy and pleasure. Experimental evidence supports a role of the striatal complex and of the mesolimbic dopamine system in both feeding and food-related reward processing, with the nucleus accumbens as a key target for reward or reinforcing-associated signaling during food intake behavior. In this review, we provide insights concerning the impact of feeding, including fat intake, on different types of receptors and neurotransmitters present in the striatal complex. Reciprocally, we also cover the evidence for a modulation of palatable food intake by different neurochemical systems in the striatal complex and in particular the nucleus accumbens, with a focus on dopamine, GABA and the opioid system.
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Affiliation(s)
- Anil Joshi
- Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France; Amsterdam UMC, University of Amsterdam, Laboratory of Endocrinology, Department of Clinical Chemistry, Amsterdam Gastroenterology & Metabolism, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Department of Endocrinology & Metabolism, Amsterdam Neuroscience, Amsterdam, the Netherlands; Metabolism and Reward Group, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, the Netherlands
| | - Marion Schott
- Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France
| | - Susanne Eva la Fleur
- Amsterdam UMC, University of Amsterdam, Laboratory of Endocrinology, Department of Clinical Chemistry, Amsterdam Gastroenterology & Metabolism, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Department of Endocrinology & Metabolism, Amsterdam Neuroscience, Amsterdam, the Netherlands; Metabolism and Reward Group, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, the Netherlands.
| | - Michel Barrot
- Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France.
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30
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King CP, Meyer PJ. The incentive amplifying effects of nicotine: Roles in alcohol seeking and consumption. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2022; 93:171-218. [PMID: 35341566 DOI: 10.1016/bs.apha.2021.10.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Nicotine has a unique profile among drugs of abuse. To the noninitiated user, nicotine has powerful aversive effects and its relatively weak euphorigenic effects undergo rapid tolerance. Despite this, nicotine is commonly abused despite negative heath consequences, and nicotine users have enormous difficulty quitting. Further, nicotine is one of the most commonly co-abused substances, in that it is often taken in combination with other drugs. One explanation of this polydrug use is that nicotine has multiple appetitive and consummatory conditioning effects. For example, nicotine is a reinforcement enhancer in that it can potently increase the incentive value of other stimuli, including those surrounding drugs of abuse such as alcohol. In addition, nicotine also has a unique profile of neurobiological effects that alter regulation of alcohol intake and interoception. This review discusses the psychological and biological mechanisms surrounding nicotine's appetitive conditioning and consummatory effects, particularly its interactions with alcohol.
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Affiliation(s)
- Christopher P King
- Department of Psychology, State University of New York at Buffalo, Buffalo, NY, United States; Clinical and Research Institute on Addictions, State University of New York at Buffalo, Buffalo, NY, United States
| | - Paul J Meyer
- Department of Psychology, State University of New York at Buffalo, Buffalo, NY, United States.
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31
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Atlas of type 2 dopamine receptors in the human brain: Age and sex dependent variability in a large PET cohort. Neuroimage 2022; 255:119149. [PMID: 35367652 DOI: 10.1016/j.neuroimage.2022.119149] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The dopamine system contributes to a multitude of functions ranging from reward and motivation to learning and movement control, making it a key component in goal-directed behavior. Altered dopaminergic function is observed in neurological and psychiatric conditions. Numerous factors have been proposed to influence dopamine function, but due to small sample sizes and heterogeneous data analysis methods in previous studies their specific and joint contributions remain unresolved. METHODS In this cross-sectional register-based study we investigated how age, sex, body mass index (BMI), as well as cerebral hemisphere and regional volume influence striatal type 2 dopamine receptor (D2R) availability in the human brain. We analyzed a large historical dataset (n=156, 120 males and 36 females) of [11C]raclopride PET scans performed between 2004 and 2018. RESULTS Striatal D2R availability decreased through age for both sexes (2-5 % in striatal ROIs per 10 years) and was higher in females versus males throughout age (7-8% in putamen). BMI and striatal D2R availability were weakly associated. There was no consistent lateralization of striatal D2R. The observed effects were independent of regional volumes. These results were validated using two different spatial normalization methods, and the age and sex effects also replicated in an independent sample (n=135). CONCLUSIONS D2R availability is dependent on age and sex, which may contribute to the vulnerability of neurological and psychiatric conditions involving altering D2R expression.
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32
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Effects of the Fyn kinase inhibitor saracatinib on ventral striatal activity during performance of an fMRI monetary incentive delay task in individuals family history positive or negative for alcohol use disorder. A pilot randomised trial. Neuropsychopharmacology 2022; 47:840-846. [PMID: 34475522 PMCID: PMC8882177 DOI: 10.1038/s41386-021-01157-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 08/04/2021] [Accepted: 08/09/2021] [Indexed: 02/07/2023]
Abstract
Altered striatal regulation of the GluN2B subunit of N-methyl-D-aspartate (NMDA) glutamate receptors by the Fyn/Src family of protein tyrosine kinases has been implicated in animal alcohol consumption. Previously, we have described differences between individuals positive (FHP) and negative (FHN) for familial alcohol use disorder (AUD) in the ventral striatal (VS) activation associated with monetary incentive delay task (MIDT) performance during functional magnetic resonance imaging (fMRI). Here, we used AZD0530 (saracatinib), a centrally active Fyn/Src inhibitor to probe the role of Fyn/Src regulation of NMDA receptors (NMDAR) in VS activation differences between FHP and FHN individuals during fMRI MIDT performance. We studied 21 FHN and 22 FHP individuals, all without AUD. In two sessions, spaced 1 week apart, we administered 125 mg of saracatinib or placebo in a double-blind manner, prior to measuring VS signal during fMRI MIDT performance. MIDT comprises reward prospect, anticipation, and outcome phases. During the initial (prospect of reward) task phase, there was a significant group-by-condition interaction such that, relative to placebo, saracatinib reduced VS BOLD signal in FHP and increased it in FHN individuals. This study provides the first human evidence that elevated signaling in striatal protein kinase A-dependent pathways may contribute to familial AUD risk via amplifying the neural response to the prospect of reward. As Fyn kinase is responsible for NMDAR upregulation, these data are consistent with previous evidence for upregulated NMDAR function within reward circuitry in AUD risk. These findings also suggest a possible therapeutic role for Src/Fyn kinase inhibitors in AUD risk.
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33
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Grinevich VP, Krupitsky EM, Gainetdinov RR, Budygin EA. Linking Ethanol-Addictive Behaviors With Brain Catecholamines: Release Pattern Matters. Front Behav Neurosci 2022; 15:795030. [PMID: 34975429 PMCID: PMC8716449 DOI: 10.3389/fnbeh.2021.795030] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/26/2021] [Indexed: 12/30/2022] Open
Abstract
Using a variety of animal models that simulate key features of the alcohol use disorder (AUD), remarkable progress has been made in identifying neurochemical targets that may contribute to the development of alcohol addiction. In this search, the dopamine (DA) and norepinephrine (NE) systems have been long thought to play a leading role in comparison with other brain systems. However, just recent development and application of optogenetic approaches into the alcohol research field provided opportunity to identify neuronal circuits and specific patterns of neurotransmission that govern the key components of ethanol-addictive behaviors. This critical review summarizes earlier findings, which initially disclosed catecholamine substrates of ethanol actions in the brain and shows how the latest methodologies help us to reveal the significance of DA and NE release changes. Specifically, we focused on recent optogenetic investigations aimed to reveal cause-effect relationships between ethanol-drinking (seeking and taking) behaviors and catecholamine dynamics in distinct brain pathways. These studies gain the knowledge that is needed for the better understanding addiction mechanisms and, therefore, for development of more effective AUD treatments. Based on the reviewed findings, new messages for researches were indicated, which may have broad applications beyond the field of alcohol addiction.
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Affiliation(s)
- Vladimir P Grinevich
- Department of Neurobiology, Sirius University of Science and Technology, Sochi, Russia
| | - Evgeny M Krupitsky
- V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, St. Petersburg, Russia.,Laboratory of Clinical Psychopharmacology of Addictions, St.-Petersburg First Pavlov State Medical University, St. Petersburg, Russia
| | - Raul R Gainetdinov
- Department of Neurobiology, Sirius University of Science and Technology, Sochi, Russia.,Institute of Translational Biomedicine and St. Petersburg State University Hospital, St. Petersburg State University, St. Petersburg, Russia
| | - Evgeny A Budygin
- Department of Neurobiology, Sirius University of Science and Technology, Sochi, Russia
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34
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Gamma camera imaging in psychiatric disorders. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00222-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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35
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Graham DP, Harding MJ, Nielsen DA. Pharmacogenetics of Addiction Therapy. Methods Mol Biol 2022; 2547:437-490. [PMID: 36068473 DOI: 10.1007/978-1-0716-2573-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Drug addiction is a serious relapsing disease that has high costs to society and to the individual addicts. Treatment of these addictions is still in its nascency, with only a few examples of successful therapies. Therapeutic response depends upon genetic, biological, social, and environmental components. A role for genetic makeup in the response to treatment has been shown for several addiction pharmacotherapies with response to treatment based on individual genetic makeup. In this chapter, we will discuss the role of genetics in pharmacotherapies, specifically for cocaine, alcohol, and opioid dependences. The continued elucidation of the role of genetics should aid in the development of new treatments and increase the efficacy of existing treatments.
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Affiliation(s)
- David P Graham
- Michael E. DeBakey Veterans Affairs Medical Center, and the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA
| | - Mark J Harding
- Michael E. DeBakey Veterans Affairs Medical Center, and the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA
| | - David A Nielsen
- Michael E. DeBakey Veterans Affairs Medical Center, and the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.
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36
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The Role of Dopamine D3 Receptors in Tobacco Use Disorder: A Synthesis of the Preclinical and Clinical Literature. Curr Top Behav Neurosci 2022; 60:203-228. [PMID: 36173599 DOI: 10.1007/7854_2022_392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Tobacco smoking is a significant cause of preventable morbidity and mortality globally. Current pharmacological approaches to treat tobacco use disorder (TUD) are only partly effective and novel approaches are needed. Dopamine has a well-established role in substance use disorders, including TUD, and there has been a long-standing interest in developing agents that target the dopaminergic system to treat substance use disorders. Dopamine has 5 receptor subtypes (DRD1 to DRD5). Given the localization and safety profile of the dopamine receptor D3 (DRD3), it is of therapeutic potential for TUD. In this chapter, the preclinical and clinical literature investigating the role of DRD3 in processes relevant to TUD will be reviewed, including in nicotine reinforcement, drug reinstatement, conditioned stimuli and cue-reactivity, executive function, and withdrawal. Similarities and differences in findings from the animal and human work will be synthesized and findings will be discussed in relation to the therapeutic potential of targeting DRD3 in TUD.
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37
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Ghin F, Beste C, Stock AK. Neurobiological mechanisms of control in alcohol use disorder - moving towards mechanism-based non-invasive brain stimulation treatments. Neurosci Biobehav Rev 2021; 133:104508. [PMID: 34942268 DOI: 10.1016/j.neubiorev.2021.12.031] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 12/14/2021] [Accepted: 12/19/2021] [Indexed: 12/13/2022]
Abstract
Alcohol use disorder (AUD) is characterized by excessive habitual drinking and loss of control over alcohol intake despite negative consequences. Both of these aspects foster uncontrolled drinking and high relapse rates in AUD patients. Yet, common interventions mostly focus on the phenomenological level, and prioritize the reduction of craving and withdrawal symptoms. Our review provides a mechanistic understanding of AUD and suggests alternative therapeutic approaches targeting the mechanisms underlying dysfunctional alcohol-related behaviours. Specifically, we explain how repeated drinking fosters the development of rigid drinking habits and is associated with diminished cognitive control. These behavioural and cognitive effects are then functionally related to the neurobiochemical effects of alcohol abuse. We further explain how alterations in fronto-striatal network activity may constitute the neurobiological correlates of these alcohol-related dysfunctions. Finally, we discuss limitations in current pharmacological AUD therapies and suggest non-invasive brain stimulation (like TMS and tDCS interventions) as a potential addition/alternative for modulating the activation of both cortical and subcortical areas to help re-establish the functional balance between controlled and automatic behaviour.
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Affiliation(s)
- Filippo Ghin
- Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Germany; University Neuropsychology Center, Faculty of Medicine, TU Dresden, Germany
| | - Christian Beste
- Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Germany; University Neuropsychology Center, Faculty of Medicine, TU Dresden, Germany
| | - Ann-Kathrin Stock
- Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Germany; University Neuropsychology Center, Faculty of Medicine, TU Dresden, Germany; Biopsychology, Faculty of Psychology, TU Dresden, Dresden, Germany.
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38
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Blum K, Steinberg B, Gondre-Lewis MC, Baron D, Modestino EJ, Badgaiyan RD, Downs BW, Bagchi D, Brewer R, McLaughlin T, Bowirrat A, Gold M. A Review of DNA Risk Alleles to Determine Epigenetic Repair of mRNA Expression to Prove Therapeutic Effectiveness in Reward Deficiency Syndrome (RDS): Embracing "Precision Behavioral Management". Psychol Res Behav Manag 2021; 14:2115-2134. [PMID: 34949945 PMCID: PMC8691196 DOI: 10.2147/prbm.s292958] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 11/22/2021] [Indexed: 11/23/2022] Open
Abstract
This is a review of research on "Precision Behavioral Management" of substance use disorder (SUD). America is experiencing a high prevalence of substance use disorder, primarily involving legal and illegal opioid use. A 3000% increase in treatment for substance abuse has occurred between 2000 and 2016. Unfortunately, present day treatment of opioid abuse involves providing replacement therapy with powerful opioids to, at best, induce harm reduction, not prophylaxis. These interventions do not enhance gene expression and restore the balance of the brain reward system's neurotransmitters. We are proposing a generalized approach called "Precision Behavioral Management". This approach includes 1) using the Genetic Addiction Risk Severity (GARS, a 10 candidate polymorphic gene panel shown to predict ASI-alcohol and drug severity) to assess early pre-disposition to substance use disorder; 2) using a validated reward deficiency syndrome (RDS) questionnaire; 3) utilization of the Comprehensive Analysis of Reported Drugs (CARD™) to assess treatment compliance and abstinence from illicit drugs during treatment, and, importantly; 4) utilization of a "Pro-dopamine regulator (KB220)" (via IV or oral [KB220Z] delivery systems) to optimize gene expression, restore the balance of the Brain Reward Cascade's neurotransmitter systems and prevent relapse by induction of dopamine homeostasis, and; 5) utilization of targeted DNA polymorphic reward genes to direct mRNA genetic expression profiling during the treatment process. Incorporation of these events can be applied to not only the under-considered African-American RDS community, but all victims of RDS, as a demonstration of a paradigm shift that uniquely provides a novel putative "standard of care" based on DNA guided precision nutrition therapy to induce "dopamine homeostasis" and rebalance neurotransmitters in the Brain Reward Cascade. We are also developing a Reward Deficiency Syndrome Diagnostic Criteria (RDSDC) to assist in potential tertiary treatment.
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Affiliation(s)
- Kenneth Blum
- Center for Psychiatry, Medicine & Primary Care, Division of Addiction Research & Education, Graduate College, Western University Health Sciences, Pomona, CA, USA
- Eötvös Loránd University, Institute of Psychology, Budapest, Hungary
- Department of Psychiatry, Wright State University Boonshoft School of Medicine and Dayton VA Medical Center, Dayton, OH (IE), USA
- Department of Psychiatry, University of Vermont, Burlington, VT, USA
- Division of Nutrigenomics, The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX, USA
| | | | - Marjorie C Gondre-Lewis
- Developmental Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC, USA
| | - David Baron
- Center for Psychiatry, Medicine & Primary Care, Division of Addiction Research & Education, Graduate College, Western University Health Sciences, Pomona, CA, USA
| | | | - Rajendra D Badgaiyan
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, San Antonio, TX, USA
- Long School of Medicine, University of Texas Medical Center, San Antonio, TX, USA
| | - B William Downs
- Division of Nutrigenomics, Victory Nutrition International, Inc., Harleysville, PA, USA
| | - Debasis Bagchi
- Division of Nutrigenomics, Victory Nutrition International, Inc., Harleysville, PA, USA
| | - Raymond Brewer
- Division of Nutrigenomics, The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX, USA
| | - Thomas McLaughlin
- Department of Psychopharmacology, Center for Psychiatric Medicine, Lawrence, MA, USA
| | - Abdalla Bowirrat
- Adelson School of Medicine & Department of Molecular Biology, Ariel University, Ariel, Israel
| | - Mark Gold
- Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, USA
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39
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Seo EH, Yang HJ, Kim SG, Park SC, Lee SK, Yoon HJ. A Literature Review on the Efficacy and Related Neural Effects of Pharmacological and Psychosocial Treatments in Individuals With Internet Gaming Disorder. Psychiatry Investig 2021; 18:1149-1163. [PMID: 34872237 PMCID: PMC8721297 DOI: 10.30773/pi.2021.0207] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 10/27/2021] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE Internet gaming disorder (IGD) has attracted considerable attention as a serious mental and public health issue worldwide. Currently, there are no established treatment guidelines for IGD. Herein, we review the latest findings on the efficacy and related neural effects of pharmacological and psychosocial treatments for individuals with IGD. METHODS A database search of relevant studies published between 2007 and 2020 was conducted using PubMed and Google Scholar. Twenty-seven studies were reviewed for current evidence related to the efficacy and neural effects of pharmacological and psychosocial IGD treatments. RESULTS Pharmacological studies suggest that bupropion may play a significant role in IGD. Additionally, nuclear imaging studies on IGD have demonstrated functional impairment of the dopamine system, providing a neurobiological basis for the efficacy of dopamineenhancing drugs. Among the various psychosocial interventions, current evidence suggests that cognitive behavioral therapy may be an effective intervention for IGD. Cognitive behavioral therapy and bupropion were found to influence resting-state functional connectivity within the cortico-subcortical circuit and default mode network, suggesting a possible neural mechanism. Innovative approaches, including virtual reality treatment, residential camps, voluntary abstinence, and transcranial direct current stimulation, have shown promising results. However, methodological limitations, such as the absence of proper controls, small sample sizes, short duration, inconsistency of inclusion criteria across studies, and self-report measures of outcome, hamper conclusions regarding the efficacy of treatments. CONCLUSION Ongoing basic research and clinical trials overcoming these limitations could add to the existing knowledge on IGD and contribute to the development of evidence-based treatments.
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Affiliation(s)
- Eun Hyun Seo
- Premedical Science, College of Medicine, Chosun University, Gwangju, Republic of Korea
| | - Hae-Jung Yang
- Department of Psychiatry, Chosun University Hospital, Gwangju, Republic of Korea
| | - Seung-Gon Kim
- Department of Psychiatry, Chosun University Hospital, Gwangju, Republic of Korea.,Department of Psychiatry, College of Medicine, Chosun University, Gwangju, Republic of Korea
| | - Seon-Cheol Park
- Department of Psychiatry, Hanyang University Guri Hospital, Guri, Republic of Korea
| | - Sang-Kyu Lee
- Department of Psychiatry, College of Medicine, Hallym University, Chuncheon, Republic of Korea
| | - Hyung-Jun Yoon
- Department of Psychiatry, Chosun University Hospital, Gwangju, Republic of Korea.,Department of Psychiatry, College of Medicine, Chosun University, Gwangju, Republic of Korea
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40
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Chukwueke CC, Nona CN, McPhee MD, Mansouri E, Rubin-Kahana DS, Martinez D, Boileau I, Hendershot CS, Le Foll B. Exploring regulation and function of dopamine D3 receptors in alcohol use disorder. A PET [ 11C]-(+)-PHNO study. Neuropsychopharmacology 2021; 46:2112-2120. [PMID: 34349232 PMCID: PMC8336665 DOI: 10.1038/s41386-021-01095-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 06/24/2021] [Accepted: 07/07/2021] [Indexed: 02/07/2023]
Abstract
Preclinical studies support an important role of dopamine D3 receptors (DRD3s) in alcohol use disorder (AUD). In animals, voluntary alcohol consumption increases DRD3 expression, and pharmacological blockade of DRD3s attenuates alcohol self-administration and reinstatement of alcohol seeking. However, these findings have yet to be translated in humans. This study used positron emission tomography (PET) and [11C]-(+)-PHNO to compare receptor levels in several dopamine D2 receptor (DRD2) and DRD3 regions of interest between AUD subjects in early abstinence (n = 17; 6.59 ± 4.14 days of abstinence) and healthy controls (n = 18). We recruited non-treatment seeking subjects meeting DSM-5 criteria for AUD. We examined the relationship between DRD2/3 levels and both alcohol craving and alcohol motivation/wanting, using a cue reactivity procedure and an intravenous alcohol self-administration (IVASA) paradigm, respectively. [11C]-(+)-PHNO binding levels in AUD subjects were significantly lower than binding in HCs when looking at all DRD2/3 ROIs jointly (Wilk's Λ = .58, F(6,28) =3.33, p = 0.013, η2p = 0.42), however there were no region-specific differences. Binding values demonstrate -12.3% and -16.1% lower [11C]-(+)-PHNO binding in the SMST and SN respectively, though these differences did not withstand Bonferroni corrections. There was a positive association between [11C]-(+)-PHNO binding in the SN (almost exclusively reflective of DRD3) and alpha (lower values reflect higher alcohol demand) in the APT after Bonferroni corrections (r = 0.66, p = 0.0080). This demonstrates that AUD subjects with lower DRD3 levels in the SN exhibit increased demand for alcohol. These results replicate previous findings demonstrating reduced DRD2/3 levels while also supporting a lack of DRD3 upregulation and potential downregulation in early abstinent AUD. Furthermore, the finding that binding in the SN is associated with alcohol demand warrants further examination.
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Affiliation(s)
- Chidera C Chukwueke
- Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
| | | | - Matthew D McPhee
- Department of Psychology, University of Toronto, Toronto, Canada
| | - Esmaeil Mansouri
- Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Dafna S Rubin-Kahana
- Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, Canada
| | - Diana Martinez
- Columbia University Irving Medical Center, New York, NY, USA
- New York State Psychiatric Institute, New York, NY, USA
| | - Isabelle Boileau
- Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Department of Psychiatry, University of Toronto, Toronto, Canada
| | - Christian S Hendershot
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, USA
- Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, USA
| | - Bernard Le Foll
- Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
- Department of Psychology, University of Toronto, Toronto, Canada
- Department of Psychiatry, University of Toronto, Toronto, Canada
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada
- Department of Family and Community Medicine, University of Toronto, Toronto, Canada
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41
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Srinivasan C, Phan BN, Lawler AJ, Ramamurthy E, Kleyman M, Brown AR, Kaplow IM, Wirthlin ME, Pfenning AR. Addiction-Associated Genetic Variants Implicate Brain Cell Type- and Region-Specific Cis-Regulatory Elements in Addiction Neurobiology. J Neurosci 2021; 41:9008-9030. [PMID: 34462306 PMCID: PMC8549541 DOI: 10.1523/jneurosci.2534-20.2021] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 06/18/2021] [Accepted: 07/10/2021] [Indexed: 12/14/2022] Open
Abstract
Recent large genome-wide association studies have identified multiple confident risk loci linked to addiction-associated behavioral traits. Most genetic variants linked to addiction-associated traits lie in noncoding regions of the genome, likely disrupting cis-regulatory element (CRE) function. CREs tend to be highly cell type-specific and may contribute to the functional development of the neural circuits underlying addiction. Yet, a systematic approach for predicting the impact of risk variants on the CREs of specific cell populations is lacking. To dissect the cell types and brain regions underlying addiction-associated traits, we applied stratified linkage disequilibrium score regression to compare genome-wide association studies to genomic regions collected from human and mouse assays for open chromatin, which is associated with CRE activity. We found enrichment of addiction-associated variants in putative CREs marked by open chromatin in neuronal (NeuN+) nuclei collected from multiple prefrontal cortical areas and striatal regions known to play major roles in reward and addiction. To further dissect the cell type-specific basis of addiction-associated traits, we also identified enrichments in human orthologs of open chromatin regions of female and male mouse neuronal subtypes: cortical excitatory, D1, D2, and PV. Last, we developed machine learning models to predict mouse cell type-specific open chromatin, enabling us to further categorize human NeuN+ open chromatin regions into cortical excitatory or striatal D1 and D2 neurons and predict the functional impact of addiction-associated genetic variants. Our results suggest that different neuronal subtypes within the reward system play distinct roles in the variety of traits that contribute to addiction.SIGNIFICANCE STATEMENT We combine statistical genetic and machine learning techniques to find that the predisposition to for nicotine, alcohol, and cannabis use behaviors can be partially explained by genetic variants in conserved regulatory elements within specific brain regions and neuronal subtypes of the reward system. Our computational framework can flexibly integrate open chromatin data across species to screen for putative causal variants in a cell type- and tissue-specific manner for numerous complex traits.
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Affiliation(s)
- Chaitanya Srinivasan
- Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
| | - BaDoi N Phan
- Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
- Medical Scientist Training Program, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213
| | - Alyssa J Lawler
- Department of Biological Sciences, Mellon College of Science, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
| | - Easwaran Ramamurthy
- Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
| | - Michael Kleyman
- Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
| | - Ashley R Brown
- Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
| | - Irene M Kaplow
- Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
- Neuroscience Institute, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
| | - Morgan E Wirthlin
- Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
- Neuroscience Institute, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
| | - Andreas R Pfenning
- Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
- Department of Biological Sciences, Mellon College of Science, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
- Neuroscience Institute, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
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42
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McClarty B, Rodriguez G, Dong H. Dose Effects of Histone Deacetylase Inhibitor Tacedinaline (CI-994) on Antipsychotic Haloperidol-Induced Motor and Memory Side Effects in Aged Mice. Front Neurosci 2021; 15:674745. [PMID: 34690667 PMCID: PMC8526546 DOI: 10.3389/fnins.2021.674745] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 09/07/2021] [Indexed: 01/02/2023] Open
Abstract
Background: Elderly patients treated with antipsychotic drugs often experience increased severity and frequency of side effects, yet the mechanisms are not well understood. Studies from our group indicate age-related histone modifications at drug targeted receptor gene promoters may contribute to the increased side effects, and histone deacetylase (HDAC) inhibitors entinostat (MS-275) and valproic acid (VPA) could reverse typical antipsychotic haloperidol (HAL) induced motor-side effects. However, whether such effects could be dose dependent and whether HDAC inhibitors could improve memory function in aged mice is unknown. Methods: We co-treated selective class 1 HDAC inhibitor tacedinaline (CI-994) at different doses (10, 20, and 30 mg/kg) with HAL (0.05 mg/kg) in young (3 months) and aged (21 months) mice for 14 consecutive days, then motor and memory behavioral tests were conducted, followed by biochemical measurements. Results: CI-994 at doses of 10 and 20 mg/kg could decrease HAL-induced cataleptic episodes but only 20 mg/kg was sufficient to improve motor coordination in aged mice. Additionally, CI-994 at 10 and 20 mg/kg mitigate HAL-induced memory impairment in aged mice. Biochemical analyses showed increased acetylation of histone marks H3K27ac and H3K18ac at the dopamine 2 receptor (D2R) gene (Drd2) promoter and increased expression of the Drd2 mRNA and D2R protein in the striatum of aged mice after administration of CI-994 at 20 mg/kg. Conclusions: Our results suggest CI-994 can reduce HAL-induced motor and memory side effects in aged mice. These effects may act through an increase of acetylation at the Drd2 promoter, thereby restoring D2R expression and improving antipsychotic drug action.
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Affiliation(s)
- Bryan McClarty
- Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Guadalupe Rodriguez
- Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Hongxin Dong
- Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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43
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Klausen MK, Thomsen M, Wortwein G, Fink-Jensen A. The role of glucagon-like peptide 1 (GLP-1) in addictive disorders. Br J Pharmacol 2021; 179:625-641. [PMID: 34532853 DOI: 10.1111/bph.15677] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/21/2021] [Accepted: 06/19/2021] [Indexed: 11/29/2022] Open
Abstract
Drug-, alcohol- and tobacco use disorders are a global burden affecting millions of people. Despite decades of research, treatment options are sparse or missing, and relapse rates are high. Glucagon-like peptide-1 (GLP-1) is released in the small intestines, promotes blood glucose homeostasis, slows gastric emptying, and reduces appetite. GLP-1 receptor agonists approved for treating type 2 diabetes mellitus and obesity, have received attention as a potential anti-addiction treatment. Studies in rodents and non-human primates have demonstrated a reduction in intake of alcohol and drugs of abuse, and clinical trials have been initiated to investigate whether the preclinical findings can be translated to patients. This review will give an overview of current findings and discuss the possible mechanisms of action. We suggest that effects of GLP-1 in alcohol- and substance use disorder is mediated centrally, at least partly through dopamine signalling, but precise mechanisms are still to be uncovered.
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Affiliation(s)
- Mette Kruse Klausen
- Psychiatric Centre Copenhagen and University Hospital of Copenhagen, Copenhagen, Denmark
| | - Morgane Thomsen
- Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen and University Hospital of Copenhagen, Copenhagen, Denmark
| | - Gitta Wortwein
- Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen and University Hospital of Copenhagen, Copenhagen, Denmark
| | - Anders Fink-Jensen
- Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen and University Hospital of Copenhagen, Copenhagen, Denmark
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44
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Abrantes AM, Kunicki Z, Braun T, Miranda R, Blevins CE, Brick L, Thomas G, Marsh E, Feltus S, Stein MD. Daily associations between alcohol and sweets craving and consumption in early AUD recovery: Results from an ecological momentary assessment study. J Subst Abuse Treat 2021; 132:108614. [PMID: 34493429 DOI: 10.1016/j.jsat.2021.108614] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 07/24/2021] [Accepted: 08/17/2021] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Alcohol cravings can predict relapse in persons with alcohol use disorder (AUD). Consuming sweets is a commonly recommend strategy to quell alcohol cravings in early recovery from AUD, yet research is equivocal on whether consuming sweets mitigates alcohol cravings or relapse risk. The current study used ecological momentary assessment (EMA) data to examine real-time alcohol cravings, sweet cravings, and consumption of sweets among adults in early recovery from AUD. METHODS We used EMA methods to follow 25 adults (n = 14 women, 56%; M. age 40, S.D. 10.68) recently discharged from a partial hospitalization program for AUD for 21 days. Prompts were sent to the participants for completion four times per day via a mobile app. EMA data were disaggregated prior to analysis to examine between- and within-person effects. A series of three mixed linear models tested: 1) the contemporaneous effect of sweet and alcohol cravings, 2) alcohol cravings predicting sweet consumption later in the day, and 3) sweet consumption predicting alcohol craving later in the day. RESULTS The results of the first model revealed alcohol cravings were associated with sweet cravings early in recovery. In the second model, no effect occurred between alcohol cravings earlier in the day predicting sweet consumption later in the day. The third model suggested consuming sweets earlier in the day predicted higher alcohol cravings later in the day. DISCUSSION Sweet craving and consumption are associated with alcohol cravings among adults in early recovery from AUD. These findings suggest consuming sweets may increase alcohol cravings. If future studies can replicate this result, consuming sweets in early recovery may emerge as a potential risk for relapse in this population.
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Affiliation(s)
- Ana M Abrantes
- Behavioral Medicine and Addictions Research, Butler Hospital, Providence, RI, United States of America; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, United States of America.
| | - Zachary Kunicki
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, United States of America
| | - Tosca Braun
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, United States of America; Centers for Diabetes and Weight Control, The Miriam Hospital, Providence, RI, United States of America
| | - Robert Miranda
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, United States of America; Centers for Alcohol and Addiction Studies, Brown University, Providence, RI, United States of America
| | - Claire E Blevins
- Behavioral Medicine and Addictions Research, Butler Hospital, Providence, RI, United States of America; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, United States of America
| | - Leslie Brick
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, United States of America
| | - Graham Thomas
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, United States of America; Centers for Diabetes and Weight Control, The Miriam Hospital, Providence, RI, United States of America
| | - Eliza Marsh
- Behavioral Medicine and Addictions Research, Butler Hospital, Providence, RI, United States of America
| | - Sage Feltus
- Behavioral Medicine and Addictions Research, Butler Hospital, Providence, RI, United States of America
| | - Michael D Stein
- Behavioral Medicine and Addictions Research, Butler Hospital, Providence, RI, United States of America; Department of Health Law, Policy, and Management, Boston University School of Public Health, United States of America
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45
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Vrajová M, Šlamberová R, Hoschl C, Ovsepian SV. Methamphetamine and sleep impairments: neurobehavioral correlates and molecular mechanisms. Sleep 2021; 44:6066541. [PMID: 33406259 DOI: 10.1093/sleep/zsab001] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 11/01/2020] [Indexed: 12/12/2022] Open
Abstract
Methamphetamine is a potent and highly addictive psychostimulant, and one of the most widely used illicit drugs. Over recent years, its global usage and seizure have been on a rapid rise, with growing detrimental effects on mental and physical health, and devastating psychosocial impact pressing for intervention. Among the unwanted effects of methamphetamine, acute and long-term sleep impairments are of major concern, posing a significant therapeutic challenge, and a cause of addiction relapse. Unraveling mechanisms and functional correlates of methamphetamine-related sleep and circadian disruption are, therefore, of key relevance to translational and clinical psychiatry. In this article, we review the mounting evidence for the acute and long-term impairements of sleep-wake behavior and circadian activity caused by single or recurring methamphetamine usage and withdrawal. Factors contributing to the severity of sleep loss and related cognitive deficit, with risks of relapse are discussed. Key molecular players mediating methamphetamine-induced dopamine release and neuromodulation are considered, with wake-promoting effects in mesolimbic circuits. The effects on various sleep phases and related changes in dopamine levels in selected subcortical structures are reviewed and compared to other psychostimulants with similar action mechanisms. A critical appraisal is presented of the therapeutic use of modafinil, countering sleep, and circadian rhythm impairments. Finally, emerging knowledge gaps and methodical limitations are highlighted along with the areas for future research and therapeutic translation.
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Affiliation(s)
- Monika Vrajová
- Department of Experimental Neurobiology, National Institute of Mental Health, Klecany, Czech Republic
| | - Romana Šlamberová
- Department of Physiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Cyril Hoschl
- Department of Experimental Neurobiology, National Institute of Mental Health, Klecany, Czech Republic.,Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Klecany, Czech Republic
| | - Saak V Ovsepian
- Department of Experimental Neurobiology, National Institute of Mental Health, Klecany, Czech Republic.,Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Klecany, Czech Republic
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46
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Papenberg G, Karalija N, Salami A, Rieckmann A, Andersson M, Axelsson J, Riklund K, Lindenberger U, Lövdén M, Nyberg L, Bäckman L. Balance between Transmitter Availability and Dopamine D2 Receptors in Prefrontal Cortex Influences Memory Functioning. Cereb Cortex 2021; 30:989-1000. [PMID: 31504282 DOI: 10.1093/cercor/bhz142] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 06/04/2019] [Accepted: 06/04/2019] [Indexed: 12/11/2022] Open
Abstract
Insufficient or excessive dopaminergic tone impairs cognitive performance. We examine whether the balance between transmitter availability and dopamine (DA) D2 receptors (D2DRs) is important for successful memory performance in a large sample of adults (n = 175, 64-68 years). The Catechol-O-Methyltransferase polymorphism served as genetic proxy for endogenous prefrontal DA availability, and D2DRs in dorsolateral prefrontal cortex (dlPFC) were measured with [11C]raclopride-PET. Individuals for whom D2DR status matched DA availability showed higher levels of episodic and working-memory performance than individuals with insufficient or excessive DA availability relative to the number of receptors. A similar pattern restricted to episodic memory was observed for D2DRs in caudate. Functional magnetic resonance imaging data acquired during working-memory performance confirmed the importance of a balanced DA system for load-dependent brain activity in dlPFC. Our data suggest that the inverted-U-shaped function relating DA signaling to cognition is modulated by a dynamic association between DA availability and receptor status.
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Affiliation(s)
- Goran Papenberg
- Aging Research Center, Karolinska Institute and Stockholm University, S-17177 Stockholm, Sweden
| | - Nina Karalija
- Department of Radiation Sciences, Umeå University, S-90187 Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, S-90187 Umeå, Sweden
| | - Alireza Salami
- Aging Research Center, Karolinska Institute and Stockholm University, S-17177 Stockholm, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, S-90187 Umeå, Sweden.,Wallenberg Centre for Molecular Medicine, Umeå University, S-90187 Umeå, Sweden
| | - Anna Rieckmann
- Umeå Center for Functional Brain Imaging (UFBI), Umeå University, S-90187 Umeå, Sweden
| | - Micael Andersson
- Department of Radiation Sciences, Umeå University, S-90187 Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, S-90187 Umeå, Sweden
| | - Jan Axelsson
- Department of Radiation Sciences, Umeå University, S-90187 Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, S-90187 Umeå, Sweden
| | - Katrine Riklund
- Department of Radiation Sciences, Umeå University, S-90187 Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, S-90187 Umeå, Sweden
| | - Ulman Lindenberger
- Center for Lifespan Psychology, Max Planck Institute for Human Development, D-14195 Berlin, Germany.,Max Planck UCL Centre for Computational Psychiatry and Ageing Research, D-14195 Berlin, Germany and UK-WC1B 5EH London, UK
| | - Martin Lövdén
- Aging Research Center, Karolinska Institute and Stockholm University, S-17177 Stockholm, Sweden
| | - Lars Nyberg
- Department of Radiation Sciences, Umeå University, S-90187 Umeå, Sweden.,Umeå Center for Functional Brain Imaging (UFBI), Umeå University, S-90187 Umeå, Sweden.,Department of Integrative Medical Biology, Umeå University, S-90187 Umeå, Sweden
| | - Lars Bäckman
- Aging Research Center, Karolinska Institute and Stockholm University, S-17177 Stockholm, Sweden
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The monoamine stabilizer OSU6162 has anxiolytic-like properties and reduces voluntary alcohol intake in a genetic rat model of depression. Sci Rep 2021; 11:11856. [PMID: 34088937 PMCID: PMC8178366 DOI: 10.1038/s41598-021-91215-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 05/24/2021] [Indexed: 12/19/2022] Open
Abstract
Alcohol use disorders (AUD) often co-occur with anxiety and depressive disorders, and anxiety often drives relapse during alcohol abstinence. Optimal AUD pharmacotherapies may thus need to target both excessive alcohol intake and elevated anxiety. (−)-OSU6162 (OSU) is a monoamine stabilizer that attenuates alcohol-mediated behaviors in both preclinical and clinical settings. However, OSU’s effect on anxiety-like behavior following long-term drinking remains unknown. To this end, we utilized a genetic rat model that exhibits increased anxiety- and depression-like behaviors (Flinders Sensitive Line; FSL) and their controls (Flinders Resistant Line; FRL). Using the novelty suppressed feeding (NSF) test, we evaluated anxiety-like behaviors (1) at baseline, (2) following long-term voluntary drinking and after 24 h of alcohol deprivation, and (3) following OSU administration in the same animals. At baseline, FSL animals displayed significantly elevated anxiety-like characteristics compared to FRL. Compared to alcohol-naïve animals, long-term drinking significantly reduced anxiety-like behaviors in FSL, without any significant effects in FRL animals. Compared to vehicle, OSU administration significantly reduced anxiety-like behaviors in alcohol-naïve FSL and long-term drinking FRL animals. While there was no significant difference in alcohol intake between FSL and FRL, OSU attenuated alcohol intake in both strains. Conclusively, in addition to the compound’s previously identified ability to suppress alcohol-mediated behaviors, OSU may also possess anxiolytic properties, warranting further clinical evaluation in both AUD and anxiety disorder settings.
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Stormezand GN, Doorduin J, Chaves LT, García DV, Nienhuis FJ, Schoevers RA, Kremer BPH, Booij J, Dierckx RAJO. No evidence for decreased D2/3 receptor availability and frontal hypoperfusion in subjects with compulsive pornography use. Psychiatry Res Neuroimaging 2021; 311:111284. [PMID: 33774451 DOI: 10.1016/j.pscychresns.2021.111284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 03/19/2021] [Accepted: 03/19/2021] [Indexed: 11/21/2022]
Abstract
Pornographic addiction refers to an addiction model associated with compulsive and repeated use of pornographic material. Whether the use of pornography may indeed become addictive remains a matter of debate. The current study investigated whether compulsive pornography use (CPU) is accompanied by reduced D2/3 receptor availability in the striatum and frontal hypofunctionality. Male subjects between 18 and 50 years of age with and without CPU were recruited using online and newspaper advertisements. Questionnaires were used to the assess the severity of compulsive pornography use (CIUS) and symptoms of depression, impulsivity and sensation seeking. Dopaminergic imaging was performed using [11C]-raclopride PET. Striatal binding potentials (BPND) and regional frontal cerebral influx values (R1) of [11C]-raclopride were calculated. Arterial Spin Labeling (ASL) MRI was performed to assess regional cerebral blood flow. No group differences between striatal BPND's of [11C]-raclopride in subjects with (n = 15) and without (n = 10) CPU were detected. In CPU subjects, no correlation was found between the CIUS score and striatal BPND's. Cerebral R1 values in frontal brain regions and cerebral blood flow measurements did not differ between groups. The current study fails to provide imaging support for sharing similar neurobiological alterations as previously has been reported in other addictive modalities.
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Affiliation(s)
- Gilles N Stormezand
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
| | - Janine Doorduin
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Lumi T Chaves
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - David Vállez García
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Fokko J Nienhuis
- Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Robert A Schoevers
- Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Berry P H Kremer
- Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Jan Booij
- Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, Netherlands
| | - Rudi A J O Dierckx
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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Pandey S, Bolstad I, Lien L, Bramness JG. Factors associated with the level of prolactin in patients under remission from Alcohol Use Disorder: A gender perspective. Neuropsychopharmacol Rep 2021; 41:352-361. [PMID: 33961352 PMCID: PMC8411308 DOI: 10.1002/npr2.12182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/28/2021] [Accepted: 04/11/2021] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Prolactin mirrors the dopaminergic activity in the brain which is key to understanding alcohol use disorders (AUD). Still, patients with AUD are a heterogenous group and there seem to be gender differences in the relationship between alcohol use and the level of prolactin. In this study, we examined gender-wise relationship of alcohol use trait- and state-related factors with the level of prolactin among AUD inpatients in remission. METHODS This cross-sectional study examined the level of prolactin along with general patient characteristics and alcohol use trait- and state-related factors that could influence the level of prolactin in 112 AUD inpatients at three rehabilitation clinics in Norway. Logistic regression was performed to identify the gender-specific predictors of level of prolactin. RESULTS Male and female AUD patients had similar level of prolactin. Among females, younger age, early alcohol debut, and absence of parental drinking problem predicted higher level of prolactin. In males, presence of other substance dependence predicted a lower level of prolactin. CONCLUSIONS There were gender differences in the factors associated with the level of prolactin among the AUD patients. Especially in the female AUD patients under remission, alcohol use trait-related factors were better predictors of the level of prolactin than the alcohol use state-related factors, indicating that individuals might characteristically have varying degree of dopamine reactivity.
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Affiliation(s)
- Susmita Pandey
- Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Brumunddal, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ingeborg Bolstad
- Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Brumunddal, Norway
| | - Lars Lien
- Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Brumunddal, Norway.,Department of Health and Social Science, Innlandet University of Applied Science, Elverum, Norway
| | - Jørgen G Bramness
- Norwegian National Advisory Unit on Concurrent Substance Abuse and Mental Health Disorders, Innlandet Hospital Trust, Brumunddal, Norway.,Department of Clinical Medicine, UiT - Norway's Arctic University, Tromsø, Norway.,Norwegian Institute of Public Health, Oslo, Norway
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Gleich T, Spitta G, Butler O, Zacharias K, Aydin S, Sebold M, Garbusow M, Rapp M, Schubert F, Buchert R, Heinz A, Gallinat J. Dopamine D2/3 receptor availability in alcohol use disorder and individuals at high risk: Towards a dimensional approach. Addict Biol 2021; 26:e12915. [PMID: 32500613 DOI: 10.1111/adb.12915] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 04/09/2020] [Accepted: 04/17/2020] [Indexed: 12/14/2022]
Abstract
Alcohol use disorder (AUD) is the most common substance use disorder worldwide. Although dopamine-related findings were often observed in AUD, associated neurobiological mechanisms are still poorly understood. Therefore, in the present study, we investigate D2/3 receptor availability in healthy participants, participants at high risk (HR) to develop addiction (not diagnosed with AUD), and AUD patients in a detoxified stage, applying 18 F-fallypride positron emission tomography (18 F-PET). Specifically, D2/3 receptor availability was investigated in (1) 19 low-risk (LR) controls, (2) 19 HR participants, and (3) 20 AUD patients after alcohol detoxification. Quality and severity of addiction were assessed with clinical questionnaires and (neuro)psychological tests. PET data were corrected for age of participants and smoking status. In the dorsal striatum, we observed significant reductions of D2/3 receptor availability in AUD patients compared with LR participants. Further, receptor availability in HR participants was observed to be intermediate between LR and AUD groups (linearly decreasing). Still, in direct comparison, no group difference was observed between LR and HR groups or between HR and AUD groups. Further, the score of the Alcohol Dependence Scale (ADS) was inversely correlated with D2/3 receptor availability in the combined sample. Thus, in line with a dimensional approach, striatal D2/3 receptor availability showed a linear decrease from LR participants to HR participants to AUD patients, which was paralleled by clinical measures. Our study shows that a core neurobiological feature in AUD seems to be detectable in an early, subclinical state, allowing more individualized alcohol prevention programs in the future.
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Affiliation(s)
- Tobias Gleich
- Department of Psychiatry and Psychotherapy, Charité Campus Mitte (CCM) Charité – Universitätsmedizin Berlin Berlin Germany
| | - Gianna Spitta
- Department of Psychiatry and Psychotherapy, Charité Campus Mitte (CCM) Charité – Universitätsmedizin Berlin Berlin Germany
| | - Oisin Butler
- Max Planck Institute for Human Development Center for Lifespan Psychology Berlin Germany
| | - Kristin Zacharias
- Department of Psychiatry and Psychotherapy, Charité Campus Mitte (CCM) Charité – Universitätsmedizin Berlin Berlin Germany
| | - Semiha Aydin
- Physikalisch‐Technische Bundesanstalt (PTB) Berlin Germany
| | - Miriam Sebold
- Department of Psychiatry and Psychotherapy, Charité Campus Mitte (CCM) Charité – Universitätsmedizin Berlin Berlin Germany
- Department for Social and Preventive Medicine University of Potsdam Potsdam Germany
| | - Maria Garbusow
- Department of Psychiatry and Psychotherapy, Charité Campus Mitte (CCM) Charité – Universitätsmedizin Berlin Berlin Germany
| | - Michael Rapp
- Max Planck Institute for Human Development Center for Lifespan Psychology Berlin Germany
| | | | - Ralph Buchert
- Department of Diagnostic and Interventional Radiology and Nuclear Medicine University Medical Center Hamburg‐Eppendorf Hamburg Germany
| | - Andreas Heinz
- Department of Psychiatry and Psychotherapy, Charité Campus Mitte (CCM) Charité – Universitätsmedizin Berlin Berlin Germany
| | - Juergen Gallinat
- Department of Psychiatry and Psychotherapy University Medical Center Hamburg‐Eppendorf (UKE) Hamburg Germany
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