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Hrickova M, Ruda-Kucerova J. Do AMPA/kainate antagonists possess potential in the treatment of addiction? Evidence from animal behavioural studies. Prog Neuropsychopharmacol Biol Psychiatry 2025; 138:111355. [PMID: 40187601 DOI: 10.1016/j.pnpbp.2025.111355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 02/19/2025] [Accepted: 03/30/2025] [Indexed: 04/07/2025]
Abstract
Substance addiction is a complex mental disorder with significant unmet treatment needs, especially in terms of effective medications. Craving in addiction is closely linked to the interaction between dopamine and glutamate in the brain's reward pathway. Therefore, drugs targeting glutamatergic signaling may have potential for treatment. This review examines the potential of AMPA/kainate glutamatergic receptor antagonists in reducing addictive-like behaviours in experimental rodents. To this end, the text summarizes the behavioural results of preclinical studies on stimulant substances (cocaine, amphetamine, methamphetamine, MDMA), nicotine, opioids (morphine and heroin), and alcohol. These experiments employ various protocols and routes of administration, using different strains of mice and rats. The main behavioural methods used in the research include behavioural sensitization protocols, drug-induced locomotor activity assessments, conditioned behaviours, and operant self-administration models. The reviewed literature demonstrates the benefit of AMPA/kainate antagonists, mainly in the most studied cocaine dependence, and particularly in attenuating cocaine-seeking behaviour via microinjection into the nucleus accumbens core. Regarding other addictive substances, despite some conflicting results, there is a substantial body of literature showing promising outcomes following systemic or intracerebral administration of AMPA/kainate antagonists. The main issue is the variability of the research protocols used across laboratories, including differences in animal species, strains, sex and environmental conditions. Moreover, each addictive substance exhibits distinct mechanisms of action and addiction development, rendering the pursuit of a universal drug for addiction treatment unrealistic. Nevertheless, AMPA/kainate antagonists seem to have potential as a supportive treatment in addiction to cocaine as well as other substances.
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Affiliation(s)
- Maria Hrickova
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jana Ruda-Kucerova
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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Bastos-Gonçalves R, Coimbra B, Rodrigues AJ. The mesopontine tegmentum in reward and aversion: From cellular heterogeneity to behaviour. Neurosci Biobehav Rev 2024; 162:105702. [PMID: 38718986 DOI: 10.1016/j.neubiorev.2024.105702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 04/06/2024] [Accepted: 05/01/2024] [Indexed: 05/18/2024]
Abstract
The mesopontine tegmentum, comprising the pedunculopontine tegmentum (PPN) and the laterodorsal tegmentum (LDT), is intricately connected to various regions of the basal ganglia, motor systems, and limbic systems. The PPN and LDT can regulate the activity of different brain regions of these target systems, and in this way are in a privileged position to modulate motivated behaviours. Despite recent findings, the PPN and LDT have been largely overlooked in discussions about the neural circuits associated with reward and aversion. This review aims to provide a timely and comprehensive resource on past and current research, highlighting the PPN and LDT's connectivity and influence on basal ganglia and limbic, and motor systems. Seminal studies, including lesion, pharmacological, and optogenetic/chemogenetic approaches, demonstrate their critical roles in modulating reward/aversive behaviours. The review emphasizes the need for further investigation into the associated cellular mechanisms, in order to clarify their role in behaviour and contribution for different neuropsychiatric disorders.
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Affiliation(s)
- Ricardo Bastos-Gonçalves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Bárbara Coimbra
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
| | - Ana João Rodrigues
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
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3
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Mulloy SM, Aback EM, Gao R, Engel S, Pawaskar K, Win C, Moua A, Hillukka L, Lee AM. Subregion and sex differences in ethanol activation of cholinergic and glutamatergic cells in the mesopontine tegmentum. Sci Rep 2024; 14:46. [PMID: 38168499 PMCID: PMC10762073 DOI: 10.1038/s41598-023-50526-1] [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: 11/08/2023] [Accepted: 12/20/2023] [Indexed: 01/05/2024] Open
Abstract
Ethanol engages cholinergic signaling and elicits endogenous acetylcholine release. Acetylcholine input to the midbrain originates from the mesopontine tegmentum (MPT), which is composed of the laterodorsal tegmentum (LDT) and the pedunculopontine tegmental nucleus (PPN). We investigated the effect of acute and chronic ethanol administration on cholinergic and glutamatergic neuron activation in the PPN and LDT in male and female mice. We show that ethanol activates neurons of the PPN and not the LDT in male mice. Chronic 15 daily injections of 2 g/kg ethanol induced Fos expression in cholinergic and glutamatergic PPN neurons in male mice, whereas ethanol did not increase cholinergic and glutamatergic neuronal activation in the LDT. A single acute 4 g/kg injection, but not a single 2 g/kg injection, induced cholinergic neuron activation in the male PPN but not the LDT. In contrast, acute or chronic ethanol at either dose or duration had no effect on the activation of cholinergic or glutamatergic neurons in the MPT of female mice. Female mice had higher baseline level of activation in cholinergic neurons compared with males. We also found a population of co-labeled cholinergic and glutamatergic neurons in the PPN and LDT which were highly active in the saline- and ethanol-treated groups in both sexes. These findings illustrate the complex differential effects of ethanol across dose, time point, MPT subregion and sex.
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Affiliation(s)
- S M Mulloy
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA
| | - E M Aback
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - R Gao
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - S Engel
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - K Pawaskar
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - C Win
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - A Moua
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - L Hillukka
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - A M Lee
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
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Mulloy SM, Aback EM, Gao R, Engel S, Pawaskar K, Win C, Moua A, Hillukka L, Lee AM. Subregion and sex differences in ethanol activation of cholinergic and glutamatergic cells in the mesopontine tegmentum. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.08.566053. [PMID: 38014248 PMCID: PMC10680559 DOI: 10.1101/2023.11.08.566053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Ethanol engages cholinergic signaling and elicits endogenous acetylcholine release. Acetylcholine input to the midbrain originates from the mesopontine tegmentum (MPT), which is composed of the laterodorsal tegmentum (LDT) and the pedunculopontine tegmental nucleus (PPN). We investigated the effect of acute and chronic ethanol administration on cholinergic and glutamatergic neuron activation in the PPN and LDT in male and female mice. We show that ethanol selectively activates neurons of the PPN and not the LDT in male mice. Acute 4.0 g/kg and chronic 15 daily injections of 2.0 g/kg i.p. ethanol induced Fos expression in cholinergic and glutamatergic PPN neurons in male mice, whereas cholinergic and glutamatergic neurons of the LDT were unresponsive. In contrast, acute or chronic ethanol at either dose or duration had no effect on the activation of cholinergic or glutamatergic neurons in the MPT of female mice. Female mice had higher level of baseline activation in cholinergic neurons compared with males. We also found a population of co-labeled cholinergic and glutamatergic neurons in the PPN and LDT which were highly active in the saline- and ethanol-treated groups in both sexes. These findings illustrate the complex differential effects of ethanol across dose, time point, MPT subregion and sex.
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Affiliation(s)
- S M Mulloy
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA
| | - E M Aback
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - R Gao
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - S Engel
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - K Pawaskar
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - C Win
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - A Moua
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - L Hillukka
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | - A M Lee
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
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Pla-Tenorio J, Roig AM, García-Cesaní PA, Santiago LA, Sepulveda-Orengo MT, Noel RJ. Astrocytes: Role in pathogenesis and effect of commonly misused drugs in the HIV infected brain. CURRENT RESEARCH IN NEUROBIOLOGY 2023; 5:100108. [PMID: 38020814 PMCID: PMC10663134 DOI: 10.1016/j.crneur.2023.100108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 06/05/2023] [Accepted: 08/18/2023] [Indexed: 12/01/2023] Open
Abstract
The roles of astrocytes as reservoirs and producers of a subset of viral proteins in the HIV infected brain have been studied extensively as a key to understanding HIV-associated neurocognitive disorders (HAND). However, their comprehensive role in the context of intersecting substance use and neurocircuitry of the reward pathway and HAND has yet to be fully explained. Use of methamphetamines, cocaine, or opioids in the context of HIV infection have been shown to lead to a faster progression of HAND. Glutamatergic, dopaminergic, and GABAergic systems are implicated in the development of HAND-induced cognitive impairments. A thorough review of scientific literature exploring the variety of mechanisms in which these drugs exert their effects on the HIV brain and astrocytes has revealed marked areas of convergence in overexcitation leading to increased drug-seeking behavior, inflammation, apoptosis, and irreversible neurotoxicity. The present review investigates astrocytes, the neural pathways, and mechanisms of drug disruption that ultimately play a larger holistic role in terms of HIV progression and drug use. There are opportunities for future research, therapeutic intervention, and preventive strategies to diminish HAND in the subset population of patients with HIV and substance use disorder.
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Affiliation(s)
- Jessalyn Pla-Tenorio
- Ponce Health Sciences University, School of Medicine, Department of Basic Sciences, 395 Industrial Reparada, Zona 2, Ponce, PR, 00716, Puerto Rico
| | - Angela M. Roig
- Seattle Children's Hospital, MS OC.7.830, 4800 Sand Point Way NE, Seattle, WA, 98105-0371, United States
| | - Paulina A. García-Cesaní
- Bella Vista Hospital, Family Medicine Residency, Carr. 349 Km 2.7, Cerro Las Mesas, Mayaguez, PR, 00681, Puerto Rico
| | - Luis A. Santiago
- Ponce Health Sciences University, School of Medicine, Department of Basic Sciences, 395 Industrial Reparada, Zona 2, Ponce, PR, 00716, Puerto Rico
| | - Marian T. Sepulveda-Orengo
- Ponce Health Sciences University, School of Medicine, Department of Basic Sciences, 395 Industrial Reparada, Zona 2, Ponce, PR, 00716, Puerto Rico
| | - Richard J. Noel
- Ponce Health Sciences University, School of Medicine, Department of Basic Sciences, 395 Industrial Reparada, Zona 2, Ponce, PR, 00716, Puerto Rico
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Zhao P, Jiang T, Wang H, Jia X, Li A, Gong H, Li X. Upper brainstem cholinergic neurons project to ascending and descending circuits. BMC Biol 2023; 21:135. [PMID: 37280580 DOI: 10.1186/s12915-023-01625-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 05/12/2023] [Indexed: 06/08/2023] Open
Abstract
BACKGROUND Based on their anatomical location, rostral projections of nuclei are classified as ascending circuits, while caudal projections are classified as descending circuits. Upper brainstem neurons participate in complex information processing and specific sub-populations preferentially project to participating ascending or descending circuits. Cholinergic neurons in the upper brainstem have extensive collateralizations in both ascending and descending circuits; however, their single-cell projection patterns remain unclear because of the lack of comprehensive characterization of individual neurons. RESULTS By combining fluorescent micro-optical sectional tomography with sparse labeling, we acquired a high-resolution whole-brain dataset of pontine-tegmental cholinergic neurons (PTCNs) and reconstructed their detailed morphology using semi-automatic reconstruction methods. As the main source of acetylcholine in some subcortical areas, individual PTCNs had abundant axons with lengths up to 60 cm and 5000 terminals and innervated multiple brain regions from the spinal cord to the cortex in both hemispheres. Based on various collaterals in the ascending and descending circuits, individual PTCNs were grouped into four subtypes. The morphology of cholinergic neurons in the pedunculopontine nucleus was more divergent, whereas the laterodorsal tegmental nucleus neurons contained richer axonal branches and dendrites. In the ascending circuits, individual PTCNs innervated the thalamus in three different patterns and projected to the cortex via two separate pathways. Moreover, PTCNs targeting the ventral tegmental area and substantia nigra had abundant collaterals in the pontine reticular nuclei, and these two circuits contributed oppositely to locomotion. CONCLUSIONS Our results suggest that individual PTCNs have abundant axons, and most project to various collaterals in the ascending and descending circuits simultaneously. They target regions with multiple patterns, such as the thalamus and cortex. These results provide a detailed organizational characterization of cholinergic neurons to understand the connexional logic of the upper brainstem.
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Affiliation(s)
- Peilin Zhao
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, 430074, China
- Institute of neurological diseases, North Sichuan Medical University, Nanchong, 637100, China
| | - Tao Jiang
- Research Unit of Multimodal Cross Scale Neural Signal Detection and Imaging, Chinese Academy of Medical Sciences, HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, 215123, China
| | - Huading Wang
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Xueyan Jia
- Research Unit of Multimodal Cross Scale Neural Signal Detection and Imaging, Chinese Academy of Medical Sciences, HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, 215123, China
| | - Anan Li
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, 430074, China
- Research Unit of Multimodal Cross Scale Neural Signal Detection and Imaging, Chinese Academy of Medical Sciences, HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, 215123, China
| | - Hui Gong
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, 430074, China
- Research Unit of Multimodal Cross Scale Neural Signal Detection and Imaging, Chinese Academy of Medical Sciences, HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, 215123, China
| | - Xiangning Li
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, 430074, China.
- Research Unit of Multimodal Cross Scale Neural Signal Detection and Imaging, Chinese Academy of Medical Sciences, HUST-Suzhou Institute for Brainsmatics, JITRI, Suzhou, 215123, China.
- Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou, 570228, China.
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Kourosh-Arami M, Gholami M, Alavi-Kakhki SS, Komaki A. Neural correlates and potential targets for the contribution of orexin to addiction in cortical and subcortical areas. Neuropeptides 2022; 95:102259. [PMID: 35714437 DOI: 10.1016/j.npep.2022.102259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 05/14/2022] [Accepted: 05/15/2022] [Indexed: 02/01/2023]
Abstract
The orexin (hypocretin) is one of the hypothalamic neuropeptides that plays a critical role in some behaviors including feeding, sleep, arousal, reward processing, and drug addiction. This variety of functions can be described by a united function for orexins in translating states of heightened motivation, for example during physiological requirement states or following exposure to reward opportunities, into planned goal-directed behaviors. An addicted state is characterized by robust activation of orexin neurons from the environment, which triggers downstream circuits to facilitate behavior directed towards obtaining the drug. Two orexin receptors 1 (OX1R) and 2 (OX2R) are widely distributed in the brain. Here, we will introduce and describe the cortical and subcortical brain areas involved in addictive-like behaviors and the impact of orexin on addiction.
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Affiliation(s)
- Masoumeh Kourosh-Arami
- Department of Neuroscience, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Masoumeh Gholami
- Department of Physiology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Seyed Sajjad Alavi-Kakhki
- Student Research Committee, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Alireza Komaki
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
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Zhao P, Wang H, Li A, Sun Q, Jiang T, Li X, Gong H. The Mesoscopic Connectome of the Cholinergic Pontomesencephalic Tegmentum. Front Neuroanat 2022; 16:843303. [PMID: 35655583 PMCID: PMC9152021 DOI: 10.3389/fnana.2022.843303] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 03/29/2022] [Indexed: 11/25/2022] Open
Abstract
The pontomesencephalic tegmentum, comprising the pedunculopontine nucleus and laterodorsal tegmental nucleus, is involved in various functions via complex connections; however, the organizational structure of these circuits in the whole brain is not entirely clear. Here, combining viral tracing with fluorescent micro-optical sectional tomography, we comprehensively investigated the input and output circuits of two cholinergic subregions in a continuous whole-brain dataset. We found that these nuclei receive abundant input with similar spatial distributions but with different quantitative measures and acquire similar neuromodulatory afferents from the ascending reticular activation system. Meanwhile, these cholinergic nuclei project to similar targeting areas throughout multiple brain regions and have different spatial preferences in 3D. Moreover, some cholinergic connections are unidirectional, including projections from the pedunculopontine nucleus and laterodorsal tegmental nucleus to the ventral posterior complex of the thalamus, and have different impacts on locomotion and anxiety. These results reveal the integrated cholinergic connectome of the midbrain, thus improving the present understanding of the organizational structure of the pontine-tegmental cholinergic system from its anatomical structure to its functional modulation.
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Affiliation(s)
- Peilin Zhao
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, China
| | - Huading Wang
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, China
| | - Anan Li
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, China
- HUST-Suzhou Institute for Brainsmatics, Jiangsu Industrial Technology Research Institute (JITRI), Suzhou, China
| | - Qingtao Sun
- HUST-Suzhou Institute for Brainsmatics, Jiangsu Industrial Technology Research Institute (JITRI), Suzhou, China
| | - Tao Jiang
- HUST-Suzhou Institute for Brainsmatics, Jiangsu Industrial Technology Research Institute (JITRI), Suzhou, China
| | - Xiangning Li
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, China
- HUST-Suzhou Institute for Brainsmatics, Jiangsu Industrial Technology Research Institute (JITRI), Suzhou, China
- *Correspondence: Xiangning Li,
| | - Hui Gong
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, MoE Key Laboratory for Biomedical Photonics, Huazhong University of Science and Technology, Wuhan, China
- HUST-Suzhou Institute for Brainsmatics, Jiangsu Industrial Technology Research Institute (JITRI), Suzhou, China
- Hui Gong,
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Polli FS, Kohlmeier KA. Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence. World J Psychiatry 2022; 12:212-235. [PMID: 35317337 PMCID: PMC8900586 DOI: 10.5498/wjp.v12.i2.212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 08/07/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
As we cycle between the states of wakefulness and sleep, a bilateral cholinergic nucleus in the pontine brain stem, the laterodorsal tegmentum (LDT), plays a critical role in controlling salience processing, attention, behavioral arousal, and electrophysiological signatures of the sub- and microstates of sleep. Disorders involving abnormal alterations in behavioral and motivated states, such as drug dependence, likely involve dysfunctions in LDT signaling. In addition, as the LDT exhibits connectivity with the thalamus and mesocortical circuits, as well as receives direct, excitatory input from the prefrontal cortex, a role for the LDT in cognitive symptoms characterizing attention-deficit/hyperactivity disorder (ADHD) including impulsivity, inflexibility, and dysfunctions of attention is suggested. Prenatal nicotine exposure (PNE) is associated with a higher risk for later life development of drug dependence and ADHD, suggesting alteration in development of brain regions involved in these behaviors. PNE has been shown to alter glutamate and cholinergic signaling within the LDT. As glutamate and acetylcholine are major excitatory mediators, these alterations would likely alter excitatory output to target regions in limbic motivational circuits and to thalamic and cortical networks mediating executive control. Further, PNE alters neuronal development and transmission within prefrontal cortex and limbic areas that send input to the LDT, which would compound effects of differential processing within the PNE LDT. When taken together, alterations in signaling in the LDT are likely to play a role in negative behavioral outcomes seen in PNE individuals, including a heightened risk of drug dependence and ADHD behaviors.
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Affiliation(s)
- Filip S Polli
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
| | - Kristi A Kohlmeier
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
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Peart DR, Andrade AK, Logan CN, Knackstedt LA, Murray JE. Regulation of Cocaine-related Behaviors by Estrogen and Progesterone. Neurosci Biobehav Rev 2022; 135:104584. [DOI: 10.1016/j.neubiorev.2022.104584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 01/30/2022] [Accepted: 02/12/2022] [Indexed: 10/19/2022]
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Hernandez NS, Weir VR, Ragnini K, Merkel R, Zhang Y, Mace K, Rich MT, Pierce RC, Schmidt HD. GLP-1 receptor signaling in the laterodorsal tegmental nucleus attenuates cocaine seeking by activating GABAergic circuits that project to the VTA. Mol Psychiatry 2021; 26:4394-4408. [PMID: 33257815 PMCID: PMC8164646 DOI: 10.1038/s41380-020-00957-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 10/27/2020] [Accepted: 11/06/2020] [Indexed: 11/09/2022]
Abstract
An emerging preclinical literature suggests that targeting central glucagon-like peptide-1 receptors (GLP-1Rs) may represent a novel approach to treating cocaine use disorder. However, the exact neural circuits and cell types that mediate the suppressive effects of GLP-1R agonists on cocaine-seeking behavior are largely unknown. The laterodorsal tegmental nucleus (LDTg) expresses GLP-1Rs and functions as a neuroanatomical hub connecting the nucleus tractus solitarius (NTS), the primary source of central GLP-1, with midbrain and forebrain nuclei known to regulate cocaine-seeking behavior. The goal of this study was to characterize the role of LDTg GLP-1R-expressing neurons and their projections to the ventral tegmental area (VTA) in the reinstatement of cocaine-seeking behavior, an animal model of relapse. Here, we showed that administration of the GLP-1R agonist exendin-4 (Ex-4) directly into the LDTg significantly attenuated cocaine seeking at a dose that did not affect sucrose seeking, ad libitum food intake, or body weight. In addition, our studies revealed that selectively activating NTS-to-LDTg circuits attenuated cocaine seeking via a GLP-1R-dependent mechanism. We also demonstrated, for the first time, that GLP-1Rs are expressed primarily on GABAergic neurons in the LDTg and that the efficacy of Ex-4 to reduce cocaine seeking depends, in part, on activation of LDTg-to-VTA GABAergic projections. Taken together, these studies identify a central mechanism by which Ex-4 attenuates cocaine seeking and highlight GABAergic GLP-1R-expressing circuits in the midbrain as important anti-craving pathways in regulating cocaine craving-induced relapse.
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Affiliation(s)
- Nicole S. Hernandez
- Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Vanessa R. Weir
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104
| | - Kael Ragnini
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104
| | - Riley Merkel
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104
| | - Yafang Zhang
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104
| | - Kyla Mace
- Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Phildelphia, PA 19104
| | - Matthew T. Rich
- Brain Health Institute and Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854
| | - R. Christopher Pierce
- Brain Health Institute and Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854
| | - Heath D. Schmidt
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104
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Suarez AN, Liu CM, Cortella AM, Noble EE, Kanoski SE. Ghrelin and Orexin Interact to Increase Meal Size Through a Descending Hippocampus to Hindbrain Signaling Pathway. Biol Psychiatry 2020; 87:1001-1011. [PMID: 31836175 PMCID: PMC7188579 DOI: 10.1016/j.biopsych.2019.10.012] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 10/01/2019] [Accepted: 10/19/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Memory and cognitive processes influence the amount of food consumed during a meal, yet the neurobiological mechanisms mediating these effects are poorly understood. The hippocampus (HPC) has recently emerged as a brain region that integrates feeding-relevant biological signals with learning and memory processes to regulate feeding. We investigated whether the gut-derived hormone ghrelin acts in the ventral HPC (vHPC) to increase meal size through interactions with gut-derived satiation signaling. METHODS Interactions between vHPC ghrelin signaling, gut-derived satiation signaling, feeding, and interoceptive discrimination learning were assessed via rodent behavioral neuropharmacological approaches. Downstream neural pathways were identified using transsynaptic virus-based tracing strategies. RESULTS vHPC ghrelin signaling counteracted the food intake-reducing effects produced by various peripheral biological satiation signals, including cholecystokinin, exendin-4 (a glucagon-like peptide-1 receptor agonist), amylin, and mechanical distension of the stomach. Furthermore, vHPC ghrelin signaling produced interoceptive cues that generalized to a perceived state of energy deficit, thereby providing a potential mechanism for the attenuation of satiation processing. Neuroanatomical tracing identified a multiorder connection from vHPC neurons to lateral hypothalamic area orexin (hypocretin)-producing neurons that project to the laterodorsal tegmental nucleus in the hindbrain. Lastly, vHPC ghrelin signaling increased spontaneous meal size via downstream orexin receptor signaling in the laterodorsal tegmental nucleus. CONCLUSIONS vHPC ghrelin signaling increases meal size by counteracting the efficacy of various gut-derived satiation signals. These effects occur via downstream orexin signaling to the hindbrain laterodorsal tegmental nucleus, thereby highlighting a novel hippocampus-hypothalamus-hindbrain pathway regulating meal size control.
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Affiliation(s)
- Andrea N. Suarez
- Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA.,Neuroscience Graduate Program, University of Southern California, Los Angeles, California, USA
| | - Clarissa M. Liu
- Neuroscience Graduate Program, University of Southern California, Los Angeles, California, USA
| | - Alyssa M. Cortella
- Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA
| | - Emily E. Noble
- Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA
| | - Scott E. Kanoski
- Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA.,Neuroscience Graduate Program, University of Southern California, Los Angeles, California, USA,Correspondence: Dr. Scott E. Kanoski, Department of Biological Sciences, University of Southern California, 3560 Watt Way, PED 107, Los Angeles, CA 90089-0652, USA, Tel: +1 213 821 5762, Fax: +1 213 740 6159.
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13
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Turner C, De Luca M, Wolfheimer J, Hernandez N, Madsen KL, Schmidt HD. Administration of a novel high affinity PICK1 PDZ domain inhibitor attenuates cocaine seeking in rats. Neuropharmacology 2020; 164:107901. [PMID: 31805281 PMCID: PMC6954965 DOI: 10.1016/j.neuropharm.2019.107901] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 11/27/2019] [Accepted: 12/02/2019] [Indexed: 12/17/2022]
Abstract
Protein interacting with C kinase-1 (PICK1) regulates intra-cellular trafficking of GluA2-containing AMPA receptors, a process known to play a critical role in cocaine-seeking behavior. This suggests that PICK1 may represent a molecular target for developing novel pharmacotherapies to treat cocaine craving-induced relapse. Emerging evidence indicates that inhibition of PICK1 attenuates the reinstatement of cocaine-seeking behavior, an animal model of relapse. Here, we show that systemic administration of TAT-P4-(DATC5)2, a novel high-affinity peptide inhibitor of the PICK1 PDZ domain, dose-dependently attenuated the reinstatement of cocaine seeking in rats at doses that did not produce operant learning deficits or suppress locomotor activity. We also show that systemic TAT-P4-(DATC5)2 penetrated the brain where it was visualized in the nucleus accumbens shell. Consistent with these effects, infusions of TAT-P4-(DATC5)2 directly into the accumbens shell reduced cocaine, but not sucrose, seeking. The effects of TAT-P4-(DATC5)2 on cocaine seeking are likely due, in part, to inhibition of PICK1 in medium spiny neurons (MSNs) of the accumbens shell as TAT-P4-(DATC5)2 was shown to accumulate in striatal neurons and bind PICK1. Taken together, these findings highlight a novel role for PICK1 in the reinstatement of cocaine seeking and support future studies examining the efficacy of peptide inhibitors of PICK1 in animal and human models of cocaine relapse.
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Affiliation(s)
- Christopher Turner
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Marta De Luca
- Department of Neurosciences, Faculty of Health Sciences, University of Copenhagen Blegdamsvej 3, DK, 2200, Copenhagen, Denmark
| | - Jordan Wolfheimer
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Nicole Hernandez
- Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kenneth Lindegaard Madsen
- Department of Neurosciences, Faculty of Health Sciences, University of Copenhagen Blegdamsvej 3, DK, 2200, Copenhagen, Denmark
| | - Heath D Schmidt
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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14
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Kohlmeier KA, Polli FS. Plasticity in the Brainstem: Prenatal and Postnatal Experience Can Alter Laterodorsal Tegmental (LDT) Structure and Function. Front Synaptic Neurosci 2020; 12:3. [PMID: 32116639 PMCID: PMC7019863 DOI: 10.3389/fnsyn.2020.00003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 01/14/2020] [Indexed: 12/16/2022] Open
Abstract
The brainstem has traditionally been considered an area of the brain with autonomous control of mostly homeostatic functions such as heart rate, respiration, and the sleep and wakefulness state, which would preclude the necessity to exhibit the high degree of synaptic or cellular mechanisms of plasticity typical of regions of the brain responsible for flexible, executive control, such as the medial prefrontal cortex or the hippocampus. The perception that the brainstem does not share the same degree of flexibility to alter synaptic strength and/or wiring within local circuits makes intuitive sense, as it is not easy to understand how "soft wiring" would be an advantage when considering the importance of faithful and consistent performance of the homeostatic, autonomic functions that are controlled by the brainstem. However, many of the molecular and cellular requirements which underlie strengthening of synapses seen in brain regions involved in higher-level processing are present in brainstem nuclei, and recent research suggest that the view of the brainstem as "hard wired," with rigid and static connectivity and with unchanging synaptic strength, is outdated. In fact, information from studies within the last decades, including work conducted in our group, leads us to propose that the brainstem can dynamically alter synaptic proteins, and change synaptic connections in response to prenatal or postnatal stimuli, and this would likely alter functionality and output. This article reviews recent research that has provided information resulting in our revision of the view of the brainstem as static and non-changing by using as example recent information gleaned from a brainstem pontine nucleus, the laterodorsal tegmentum (LDT). The LDT has demonstrated mechanisms underlying synaptic plasticity, and plasticity has been exhibited in the postnatal LDT following exposure to drugs of abuse. Further, exposure of the brain during gestation to drugs of abuse results in alterations in development of signaling pathways in the LDT. As the LDT provides a high degree of innervation of mesoaccumbal and mesocortical circuits involved in salience, as well as thalamocortical circuits involved in control of arousal and orientation, changes in synaptic strength would be expected to alter output, which would significantly impact behavioral state, motivated behavior and directed attention. Further, alterations in developmental trajectory within the LDT following prenatal exposure to drugs of abuse would be expected to impact on later life expression of motivation and arousal.
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Affiliation(s)
- Kristi A. Kohlmeier
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
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15
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Preconception maternal cocaine self-administration increases the reinforcing efficacy of cocaine in male offspring. Psychopharmacology (Berl) 2019; 236:3429-3437. [PMID: 31236644 PMCID: PMC6895412 DOI: 10.1007/s00213-019-05307-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 06/18/2019] [Indexed: 02/06/2023]
Abstract
RATIONALE Although the influence of gestational cocaine exposure on offspring has been the focus of a sustained research effort, the effect of preconception cocaine self-administration by dams on progeny has received far less attention. METHOD In the current study, adult female rats were allowed to self-administer cocaine 2 h a day for 60 days and then after a 10-day wash out period, bred to naïve males. Maternal behavior was measured in dams until weaning. When male and female progeny reached adulthood, anxiety-like behavior, memory, and cocaine self-administration were assessed in separate cohorts of rats. RESULTS Despite a total of at least 30 days of cocaine abstinence, the quality of maternal behaviors was negatively affected by previous cocaine exposure as reflected by less time spent with pups as well as an excess of other maladaptive maternal behaviors. Measures of anxiety-like behavior and memory were not affected by maternal cocaine intake in either male or female offspring. In contrast, male, but not female, the progeny of dams exposed to cocaine showed increased reinforcing efficacy of cocaine as measured by cocaine self-administration under a progressive ratio schedule. The fact that cocaine self-administration was influenced only in the male offspring of cocaine-exposed dams argues against this phenotype being linked to altered maternal behavior, although this possibility cannot be ruled out completely. CONCLUSIONS Collectively, these results indicate that preconception cocaine self-administration by dams results in the relatively selective enhancement of cocaine addiction-like behavior in male offspring.
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16
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Nunes EJ, Bitner L, Hughley SM, Small KM, Walton SN, Rupprecht LE, Addy NA. Cholinergic Receptor Blockade in the VTA Attenuates Cue-Induced Cocaine-Seeking and Reverses the Anxiogenic Effects of Forced Abstinence. Neuroscience 2019; 413:252-263. [PMID: 31271832 DOI: 10.1016/j.neuroscience.2019.06.028] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/31/2019] [Accepted: 06/19/2019] [Indexed: 02/08/2023]
Abstract
Drug relapse after periods of abstinence is a common feature of substance abuse. Moreover, anxiety and other mood disorders are often co-morbid with substance abuse. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate drug-seeking and anxiety-related behavior in rodent models. However, it is unclear if overlapping VTA cholinergic mechanisms mediate drug relapse and anxiety-related behaviors associated with drug abstinence. We examined the effects of VTA cholinergic receptor blockade on cue-induced cocaine seeking and anxiety during cocaine abstinence. Male Sprague-Dawley rats were trained to self-administer intravenous cocaine (~0.5 mg/kg/infusion, FR1 schedule) for 10 days, followed by 14 days of forced abstinence. VTA infusion of the non-selective nicotinic acetylcholine receptor antagonist mecamylamine (0, 10, and 30 μg/side) or the non-selective muscarinic receptor antagonist scopolamine (0, 2.4 and 24 μg /side) significantly decreased cue-induced cocaine seeking. In cocaine naïve rats, VTA mecamylamine or scopolamine also led to dose-dependent increases in open arm time in the elevated plus maze (EPM). In contrast, rats that received I.V. cocaine, compared to received I.V. saline rats, displayed an anxiogenic response on day 14 of abstinence as reflected by decreased open arm time in the EPM. Furthermore, low doses of VTA mecamylamine (10 μg /side) or scopolamine (2.4 μg /side), that did not alter EPM behavior in cocaine naive rats, were sufficient to reverse the anxiogenic effects of cocaine abstinence. Together, these data point to an overlapping role of VTA cholinergic mechanisms to regulate relapse and mood disorder-related responses during cocaine abstinence.
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Affiliation(s)
- Eric J Nunes
- Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, USA
| | - Lillian Bitner
- Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, USA
| | - Shannon M Hughley
- Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, USA
| | - Keri M Small
- Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, USA
| | - Sofia N Walton
- Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, USA
| | - Laura E Rupprecht
- Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, USA
| | - Nii A Addy
- Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06511, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06511, USA.
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17
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Hernandez NS, Schmidt HD. Central GLP-1 receptors: Novel molecular targets for cocaine use disorder. Physiol Behav 2019; 206:93-105. [PMID: 30930091 DOI: 10.1016/j.physbeh.2019.03.026] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 03/20/2019] [Accepted: 03/26/2019] [Indexed: 12/25/2022]
Abstract
Given that the search for effective pharmacotherapies for cocaine use disorder has, thus far, been fruitless, there remains a critical need for conceptually innovative approaches toward identifying new medications to treat this disease. A better understanding of the neurocircuits and neurobiological mechanisms underlying cocaine taking and seeking may identify molecular substrates that could serve as targets for novel pharmacotherapies to treat cocaine use disorder. Recent preclinical evidence suggests that glucagon-like peptide-1 (GLP-1) receptor agonists could be re-purposed to treat cocaine craving-induced relapse. This review endeavors to comprehensively summarize the current literature investigating the efficacy of GLP-1 receptor agonists in reducing the rewarding and reinforcing effects of cocaine in animal models of cocaine use disorder. The role of central endogenous GLP-1 circuits in voluntary cocaine taking and seeking is also discussed. Behavioral, neurochemical, electrophysiological and molecular biology studies indicate that central GLP-1 receptor activation functionally modulates the mesolimbic reward system and decreases addiction-like phenotypes in rodents. Overall, an emerging preclinical literature provides compelling evidence to advance GLP-1 receptor agonists into clinical trials testing the efficacy of these medications in preventing cocaine craving-induced relapse.
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Affiliation(s)
- N S Hernandez
- Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America
| | - H D Schmidt
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, United States of America.
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18
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Patterson L, Rushton SP, Attems J, Thomas AJ, Morris CM. Degeneration of dopaminergic circuitry influences depressive symptoms in Lewy body disorders. Brain Pathol 2019; 29:544-557. [PMID: 30582885 PMCID: PMC6767514 DOI: 10.1111/bpa.12697] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 12/06/2018] [Indexed: 12/14/2022] Open
Abstract
Aims Depression is commonly observed even in prodromal stages of Lewy body disorders (LBD), and is associated with cognitive impairment and a faster rate of cognitive decline. Given the role of dopamine in the development of movement disorders, but also in motivation and reward, we investigated neurodegenerative pathology in dopaminergic circuitry in Parkinson's disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) patients in relation to depressive symptoms. Methods α‐synuclein, hyperphosphorylated tau and amyloid‐beta pathology was assessed in 17 DLB, 14 PDD and 8 PD cases within striatal and midbrain subregions, with neuronal cell density assessed in substantia nigra and ventral tegmental area. Additionally, we used a structural equation modeling (SEM) approach to investigate the extent to which brain connectivity might influence the deposition of pathological proteins within dopaminergic pathways. Results A significantly higher α‐synuclein burden was observed in the substantia nigra (P = 0.006), ventral tegmental area (P = 0.011) and nucleus accumbens (P = 0.031) in LBD patients with depression. Significant negative correlations were observed between cell density in substantia nigra with Lewy body (LB) Braak stage (P = 0.013), whereas cell density in ventral tegmental area showed negative correlations with LB Braak stage (P = 0.026) and neurofibrillary tangle Braak stage (P = 0.007). Conclusions Dopaminergic α‐synuclein pathology appears to drive depression. Selective targeting of dopaminergic pathways may therefore provide symptomatic relief for depressive symptoms in LBD patients.
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Affiliation(s)
- Lina Patterson
- Alzheimer's Society Doctoral Training Centre, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
| | - Steven P Rushton
- School of Biology, Newcastle University, Ridley Building, Newcastle upon Tyne, UK
| | - Johannes Attems
- Alzheimer's Society Doctoral Training Centre, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.,Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK
| | - Alan J Thomas
- Alzheimer's Society Doctoral Training Centre, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.,Gateshead Health NHS Foundation Trust, Queen Elizabeth Hospital, Gateshead, UK
| | - Christopher M Morris
- NIHR Biomedical Research Centre Newcastle, Biomedical Research Building, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK
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19
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Steketee JD, Liu K. Effects of repeated cocaine administration on dopamine D1 receptor modulation of mesocorticolimbic GABA and glutamate transmission. Brain Res 2018; 1698:106-113. [PMID: 30075100 DOI: 10.1016/j.brainres.2018.07.029] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 06/27/2018] [Accepted: 07/30/2018] [Indexed: 11/30/2022]
Abstract
Repeated cocaine exposure alters medial prefrontal cortex (mPFC) function to allow for enhanced excitatory transmission to the nucleus accumbens and ventral tegmental area (VTA). Previous studies have demonstrated changes in receptor function in the mPFC in animals repeatedly exposed to cocaine that produced increased excitatory output. The present report tested the hypothesis that daily injections of cocaine would enhance D1 receptor responsiveness by infusing the D1 receptor agonist SKF 38393 into the mPFC and monitoring glutamate and/or GABA release in the mPFC, nucleus accumbens and VTA of saline- and cocaine-pretreated animals using in vivo microdialysis. The data demonstrated that intra-mPFC SKF 38393 reduced GABA and glutamate levels in the mPFC in control animals. Intra-mPFC SKF 38393 had no effect on glutamate levels in animals 1 day after daily cocaine treatments, increased mPFC glutamate at 7 days of withdrawal and reverted to decreasing glutamate at 30 days of withdrawal. SKF 38393 induced reduction in mPFC GABA is lost at 7 and 30 days of withdrawal. Intra-mPFC SKF 38393 did not alter glutamate levels in the nucleus accumbens or VTA of control animals. Infusion of SKF 38393 into the mPFC of animals previously exposed to cocaine increased and reduced glutamate release in the nucleus accumbens after 7 and 30 days of withdrawal, respectively and increased glutamate levels in the VTA 7 and 30 days after daily cocaine injections. The data suggest that repeated cocaine exposure alters D1 receptor function in the mPFC that could contribute to enhanced behavioral responses that occur following repeated cocaine.
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Affiliation(s)
- Jeffery D Steketee
- Department Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
| | - Kun Liu
- Department Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, United States
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20
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Kaneda K. Neuroplasticity in cholinergic neurons of the laterodorsal tegmental nucleus contributes to the development of cocaine addiction. Eur J Neurosci 2018; 50:2239-2246. [DOI: 10.1111/ejn.13962] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 04/20/2018] [Accepted: 05/04/2018] [Indexed: 11/27/2022]
Affiliation(s)
- Katsuyuki Kaneda
- Laboratory of Molecular Pharmacology Institute of Medical, Pharmaceutical and Health Sciences Kanazawa University Kanazawa 920‐1192 Japan
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21
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Dopamine D1 and D3 receptor polypharmacology as a potential treatment approach for substance use disorder. Neurosci Biobehav Rev 2018; 89:13-28. [PMID: 29577963 DOI: 10.1016/j.neubiorev.2018.03.020] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 03/19/2018] [Accepted: 03/19/2018] [Indexed: 12/29/2022]
Abstract
In the search for efficacious pharmacotherapies to treat cocaine addiction much attention has been given to agents targeting dopamine D1 or D3 receptors because of the involvement of these receptors in drug-related behaviors. D1-like and D3 receptor partial agonists and antagonists have been shown to reduce drug reward, reinstatement of drug seeking and conditioned place preference in rodents and non-human primates. However, translation of these encouraging results to clinical settings has been limited due to a number of factors including toxicity, poor pharmacokinetic properties and extrapyramidal and sedative side effects. This review highlights the role of D1 and D3 receptors in drug reward and seeking, the discovery of D1-D3 heteromers and their potential as targets in the treatment of addiction.
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22
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Choi JK, Lim G, Chen YCI, Jenkins BG. Abstinence to chronic methamphetamine switches connectivity between striatal, hippocampal and sensorimotor regions and increases cerebral blood volume response. Neuroimage 2018. [PMID: 29518566 DOI: 10.1016/j.neuroimage.2018.02.059] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
Methamphetamine (meth), and other psychostimulants such as cocaine, present a persistent problem for society with chronic users being highly prone to relapse. We show, in a chronic methamphetamine administration model, that discontinuation of drug for more than a week produces much larger changes in overall meth-induced brain connectivity and cerebral blood volume (CBV) response than changes that occur immediately following meth administration. Areas showing the largest changes were hippocampal, limbic striatum and sensorimotor cortical regions as well as brain stem areas including the pedunculopontine tegmentum (PPTg) and pontine nuclei - regions known to be important in mediating reinstatement of drug-taking after abstinence. These changes occur concomitantly with behavioral sensitization and appear to be mediated through increases in dopamine D1 and D3 and decreases in D2 receptor protein and mRNA expression. We further identify a novel region of dorsal caudate/putamen, with a low density of calbindin neurons, that has an opposite hemodynamic response to meth than the rest of the caudate/putamen and accumbens and shows very strong correlation with dorsal CA1 and CA3 hippocampus. This correlation switches following meth abstinence from CA1/CA3 to strong connections with ventral hippocampus (ventral subiculum) and nucleus accumbens. These data provide novel evidence for temporal alterations in brain connectivity where chronic meth can subvert hippocampal - striatal interactions from cognitive control regions to regions that mediate drug reinstatement. Our results also demonstrate that the signs and magnitudes of the induced CBV changes following challenge with meth or a D3-preferring agonist are a complementary read out of the relative changes that occur in D1, D2 and D3 receptors using protein or mRNA levels.
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Affiliation(s)
- Ji-Kyung Choi
- A.A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02129, USA.
| | - Grewo Lim
- Department of Anesthesiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02129, USA
| | - Yin-Ching Iris Chen
- A.A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02129, USA
| | - Bruce G Jenkins
- A.A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02129, USA.
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23
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Murakami G, Edamura M, Furukawa T, Kawasaki H, Kosugi I, Fukuda A, Iwashita T, Nakahara D. MHC class I in dopaminergic neurons suppresses relapse to reward seeking. SCIENCE ADVANCES 2018; 4:eaap7388. [PMID: 29546241 PMCID: PMC5851664 DOI: 10.1126/sciadv.aap7388] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 02/07/2018] [Indexed: 05/12/2023]
Abstract
Major histocompatibility complex class I (MHCI) is an important immune protein that is expressed in various brain regions, with its deficiency leading to extensive synaptic transmission that results in learning and memory deficits. Although MHCI is highly expressed in dopaminergic neurons, its role in these neurons has not been examined. We show that MHCI expressed in dopaminergic neurons plays a key role in suppressing reward-seeking behavior. In wild-type mice, cocaine self-administration caused persistent reduction of MHCI specifically in dopaminergic neurons, which was accompanied by enhanced glutamatergic synaptic transmission and relapse to cocaine seeking. Functional MHCI knockout promoted this addictive phenotype for cocaine and a natural reward, namely, sucrose. In contrast, wild-type mice overexpressing a major MHCI gene (H2D) in dopaminergic neurons showed suppressed cocaine seeking. These results show that persistent cocaine-induced reduction of MHCI in dopaminergic neurons is necessary for relapse to cocaine seeking.
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Affiliation(s)
- Gen Murakami
- Department of Psychology and Behavioral Neuroscience, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
- Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
- Department of Liberal Arts, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan
| | - Mitsuhiro Edamura
- Department of Psychology and Behavioral Neuroscience, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
| | - Tomonori Furukawa
- Department of Neurophysiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
| | - Hideya Kawasaki
- Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
| | - Isao Kosugi
- Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
| | - Atsuo Fukuda
- Department of Neurophysiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
| | - Toshihide Iwashita
- Department of Regenerative and Infectious Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
| | - Daiichiro Nakahara
- Department of Psychology and Behavioral Neuroscience, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
- Department of Psychiatry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan
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24
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Reiner DJ, Leon RM, McGrath LE, Koch-Laskowski K, Hahn JD, Kanoski SE, Mietlicki-Baase EG, Hayes MR. Glucagon-Like Peptide-1 Receptor Signaling in the Lateral Dorsal Tegmental Nucleus Regulates Energy Balance. Neuropsychopharmacology 2018; 43:627-637. [PMID: 28920591 PMCID: PMC5770766 DOI: 10.1038/npp.2017.225] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 09/12/2017] [Accepted: 09/13/2017] [Indexed: 01/05/2023]
Abstract
The neurobiological substrates that mediate the anorectic effects of both endogenous glucagon-like peptide-1 (GLP-1) and exogenous GLP-1 receptor (GLP-1R) agonists are an active area of investigation. As the lateral dorsal tegmental nucleus (LDTg) expresses the GLP-1R and represents a potential neuroanatomical hub connecting the nucleus tractus solitarius (NTS), the major central source of GLP-1, with the other nuclei in the midbrain and forebrain, we tested the hypothesis that GLP-1R signaling in the LDTg controls food intake. Direct activation of LDTg GLP-1R suppresses food intake through a reduction in average meal size and independent of nausea/malaise. Immunohistochemical data show that GLP-1-producing neurons in the NTS project to the LDTg, providing anatomical evidence of endogenous central GLP-1 in the LDTg. Pharmacological blockade of LDTg GLP-1Rs with exendin-(9-39) dose-dependently increases food intake and attenuates the hypophagic effects of gastric distension. As GLP-1 mimetics are administered systemically in humans, we evaluated whether peripherally administered GLP-1R agonists access the LDTg to affect feeding. Immunohistochemical data show that a systemically administered fluorescent GLP-1R agonist accesses the LDTg and is juxtaposed with neurons. Additionally, blockade of LDTg GLP-1Rs attenuates the hypophagic effects of a systemic GLP-1R agonist. Together, these data indicate that LDTg GLP-1R signaling controls energy balance and underscores the role of the LDTg in integrating energy balance-relevant signals to modulate feeding.
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Affiliation(s)
- David J Reiner
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Department of Biological Sciences, University of Pennsylvania, Center for Neurobiology and Behavior, Philadelphia, PA, USA
| | - Rosa M Leon
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Department of Biological Sciences, University of Pennsylvania, Center for Neurobiology and Behavior, Philadelphia, PA, USA
| | - Lauren E McGrath
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Department of Biological Sciences, University of Pennsylvania, Center for Neurobiology and Behavior, Philadelphia, PA, USA
| | - Kieran Koch-Laskowski
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Department of Biological Sciences, University of Pennsylvania, Center for Neurobiology and Behavior, Philadelphia, PA, USA
| | - Joel D Hahn
- Neurobiology Section, University of Southern California, Los Angeles, CA, USA
| | - Scott E Kanoski
- Human and Evolutionary Biology Section, University of Southern California, Los Angeles, CA, USA
| | - Elizabeth G Mietlicki-Baase
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Department of Biological Sciences, University of Pennsylvania, Center for Neurobiology and Behavior, Philadelphia, PA, USA
| | - Matthew R Hayes
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Department of Biological Sciences, University of Pennsylvania, Center for Neurobiology and Behavior, Philadelphia, PA, USA,Department of Psychiatry, University of Pennsylvania, Center for Neurobiology and Behavior, 125 S. 31st St, Philadelphia, PA 19104, USA, Tel: +1 215 573 6070, Fax: +1 215 573 2041, E-mail:
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Hsu TM, McCutcheon JE, Roitman MF. Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons. Front Psychiatry 2018; 9:410. [PMID: 30233430 PMCID: PMC6129766 DOI: 10.3389/fpsyt.2018.00410] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/13/2018] [Indexed: 01/08/2023] Open
Abstract
Motivated behaviors are often initiated in response to perturbations of homeostasis. Indeed, animals and humans have fundamental drives to procure (appetitive behaviors) and eventually ingest (consummatory behaviors) substances based on deficits in body fluid (e.g., thirst) and energy balance (e.g., hunger). Consumption, in turn, reinforces motivated behavior and is therefore considered rewarding. Over the years, the constructs of homeostatic (within the purview of the hypothalamus) and reward (within the purview of mesolimbic circuitry) have been used to describe need-based vs. need-free consumption. However, many experiments have demonstrated that mesolimbic circuits and "higher-order" brain regions are also profoundly influenced by changes to physiological state, which in turn generate behaviors that are poised to maintain homeostasis. Mesolimbic pathways, particularly dopamine neurons of the ventral tegmental area (VTA) and their projections to nucleus accumbens (NAc), can be robustly modulated by a variety of energy balance signals, including post-ingestive feedback relaying nutrient content and hormonal signals reflecting hunger and satiety. Moreover, physiological states can also impact VTA-NAc responses to non-nutritive rewards, such as drugs of abuse. Coupled with recent evidence showing hypothalamic structures are modulated in anticipation of replenished need, classic boundaries between circuits that convey perturbations in homeostasis and those that drive motivated behavior are being questioned. In the current review, we examine data that have revealed the importance of mesolimbic dopamine neurons and their downstream pathways as a dynamic neurobiological mechanism that provides an interface between physiological state, perturbations to homeostasis, and reward-seeking behaviors.
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Affiliation(s)
- Ted M Hsu
- Department of Psychology, University of Illinois at Chicago, Chicago, IL, United States
| | - James E McCutcheon
- Department of Neuroscience, Psychology and Behavior, University of Leicester, Leicester, United Kingdom
| | - Mitchell F Roitman
- Department of Psychology, University of Illinois at Chicago, Chicago, IL, United States
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26
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Reiner DJ, Mietlicki-Baase EG, Olivos DR, McGrath LE, Zimmer DJ, Koch-Laskowski K, Krawczyk J, Turner CA, Noble EE, Hahn JD, Schmidt HD, Kanoski SE, Hayes MR. Amylin Acts in the Lateral Dorsal Tegmental Nucleus to Regulate Energy Balance Through Gamma-Aminobutyric Acid Signaling. Biol Psychiatry 2017; 82:828-838. [PMID: 28237459 PMCID: PMC5503810 DOI: 10.1016/j.biopsych.2016.12.028] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 12/13/2016] [Accepted: 12/28/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND The pancreatic- and brain-derived hormone amylin promotes negative energy balance and is receiving increasing attention as a promising obesity therapeutic. However, the neurobiological substrates mediating amylin's effects are not fully characterized. We postulated that amylin acts in the lateral dorsal tegmental nucleus (LDTg), an understudied neural processing hub for reward and homeostatic feeding signals. METHODS We used immunohistochemical and quantitative polymerase chain reaction analyses to examine expression of the amylin receptor complex in rat LDTg tissue. Behavioral experiments were performed to examine the mechanisms underlying the hypophagic effects of amylin receptor activation in the LDTg. RESULTS Immunohistochemical and quantitative polymerase chain reaction analyses show expression of the amylin receptor complex in the LDTg. Activation of LDTg amylin receptors by the agonist salmon calcitonin dose-dependently reduces body weight, food intake, and motivated feeding behaviors. Acute pharmacological studies and longer-term adeno-associated viral knockdown experiments indicate that LDTg amylin receptor signaling is physiologically and potentially preclinically relevant for energy balance control. Finally, immunohistochemical data indicate that LDTg amylin receptors are expressed on gamma-aminobutyric acidergic neurons, and behavioral results suggest that local gamma-aminobutyric acid receptor signaling mediates the hypophagia after LDTg amylin receptor activation. CONCLUSIONS These findings identify the LDTg as a novel nucleus with therapeutic potential in mediating amylin's effects on energy balance through gamma-aminobutyric acid receptor signaling.
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Affiliation(s)
- David J Reiner
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Elizabeth G Mietlicki-Baase
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Diana R Olivos
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Lauren E McGrath
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Derek J Zimmer
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Kieran Koch-Laskowski
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Joanna Krawczyk
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Christopher A Turner
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Emily E Noble
- Department of Biological Sciences, Human and Evolutionary Biology Section, Los Angeles, California
| | - Joel D Hahn
- Neurobiology Section, University of Southern California, Los Angeles, California
| | - Heath D Schmidt
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Scott E Kanoski
- Department of Biological Sciences, Human and Evolutionary Biology Section, Los Angeles, California
| | - Matthew R Hayes
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, Philadelphia, Pennsylvania.
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Galaj E, Nisanov R, Ranaldi R. Blockade of muscarinic acetylcholine receptors in the ventral tegmental area blocks the acquisition of reward-related learning. Behav Brain Res 2017; 329:20-25. [PMID: 28442362 DOI: 10.1016/j.bbr.2017.04.037] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 04/17/2017] [Indexed: 12/15/2022]
Abstract
In the present study we investigated whether stimulation of muscarinic acetylcholine (mACh) receptors in the ventral tegmental area (VTA) plays a role in the acquisition of food-based conditioned approach learning. Rats were exposed to 3 (in Experiment 1) or 7 (in Experiment 2) conditioning sessions in which 30, randomly presented light (CS) presentations were paired with delivery of food pellets (US), followed by one session with no light or food and finally one CS-only test session with only light stimulus presentations. Bilateral microinjections of scopolamine (a mACh receptor antagonist) were made either prior to each conditioning session (Experiment 1; to test effects on acquisition) or prior to the CS-only test (Experiment 2; to test effects on performance of the learned response). Scopolamine produced a dose-related significant reduction in the acquisition of conditioned approach but had no effect on its performance. These results suggest that mACh receptor stimulation in the VTA plays a necessary role in the acquisition of reward-related learning.
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Affiliation(s)
- E Galaj
- Neuropsychology Doctoral Program, The Graduate Center of the City University of New York, New York, NY 10016, USA
| | - R Nisanov
- Neuropsychology Doctoral Program, The Graduate Center of the City University of New York, New York, NY 10016, USA
| | - R Ranaldi
- Neuropsychology Doctoral Program, The Graduate Center of the City University of New York, New York, NY 10016, USA; Department of Psychology, Queens College, City University of New York, Flushing NY 11367, USA.
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28
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Scherf T, Angenstein F. Hippocampal CA3 activation alleviates fMRI-BOLD responses in the rat prefrontal cortex induced by electrical VTA stimulation. PLoS One 2017; 12:e0172926. [PMID: 28241047 PMCID: PMC5328285 DOI: 10.1371/journal.pone.0172926] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 02/10/2017] [Indexed: 11/25/2022] Open
Abstract
Functional magnetic resonance imaging (fMRI) was used to identify brain- wide networks that are activated by electrical stimulation of either the ventral tegmental area (VTA) or hippocampal CA3 region. Stimulation of either one of these regions caused significant BOLD responses in common structures, such as the septum and left and right hippocampus, but also in unique structures, such as the medial prefrontal cortex region/anterior cingulum region (mPFC/ACC) and striatum, which were only activated during VTA stimulation. Concurrent stimulations of the two structures resulted in no additive BOLD responses but significantly reduced BOLD responses in the mPFC/ACC when compared with sole VTA stimulation. This reduction is caused by costimulation of the hippocampal CA3 region, which was itself not sufficient to modify BOLD signal intensities in the mPFC/ACC. Under this experimental condition, functional connectivity between VTA and mPFC/ACC in terms of neurophysiological interactions was causative, driven by direct electrical stimulation of VTA projecting neurons, the resulting functional connectivity in terms of correlated BOLD time series becoming masked as soon as hippocampal projections concurrently coactivated mPFC neurons. This result warns against misinterpretation of the absence of functional connectivity in fMRI data sets, because strong existing neurophysiological interactions can be obscured by unrelated network activities.
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Affiliation(s)
- Thomas Scherf
- Functional Neuroimaging Group, Deutsches Zentrum für neurodegenerative Erkrankungen (DZNE), Magdeburg, Germany
| | - Frank Angenstein
- Functional Neuroimaging Group, Deutsches Zentrum für neurodegenerative Erkrankungen (DZNE), Magdeburg, Germany
- Leibniz Institute for Neurobiology, Magdeburg, Germany
- * E-mail: ,
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29
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Lambert MØ, Ipsen TH, Kohlmeier KA. Acute cocaine exposure elicits rises in calcium in arousal-related laterodorsal tegmental neurons. Pharmacol Res Perspect 2016; 5:e00282. [PMID: 28596834 PMCID: PMC5461641 DOI: 10.1002/prp2.282] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 10/25/2016] [Indexed: 12/17/2022] Open
Abstract
Cocaine has strong reinforcing properties, which underlie its high addiction potential. Reinforcement of use of addictive drugs is associated with rises in dopamine (DA) in mesoaccumbal circuitry. Excitatory afferent input to mesoaccumbal circuitry sources from the laterodorsal tegmental nucleus (LDT). Chronic, systemic cocaine exposure has been shown to have cellular effects on LDT cells, but acute actions of local application have never been demonstrated. Using calcium imaging, we show that acute application of cocaine to mouse brain slices induces calcium spiking in cells of the LDT. Spiking was attenuated by tetrodotoxin (TTX) and low calcium solutions, and abolished by prior exhaustion of intracellular calcium stores. Further, DA receptor antagonists reduced these transients, whereas DA induced rises with similar spiking kinetics. Amphetamine, which also results in elevated levels of synaptic DA, but via a different pharmacological action than cocaine, induced calcium spiking with similar profiles. Although large differences in spiking were not noted in an animal model associated with a heightened proclivity of acquiring addiction‐related behavior, the prenatal nicotine exposed mouse (PNE), subtle differences in cocaine's effect on calcium spiking were noted, indicative of a reduction in action of cocaine in the LDT associated with exposure to nicotine during gestation. When taken together, our data indicate that acute actions of cocaine do include effects on LDT cells. Considering the role of intracellular calcium in cellular excitability, and of the LDT in addiction circuitry, our data suggest that cocaine effects in this nucleus may contribute to the high addiction potential of this drug.
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Affiliation(s)
- Mads Ødum Lambert
- Department of Drug Design and Pharmacology Faculty of Health Sciences Universitetsparken 2 University of Copenhagen Copenhagen 2100 Denmark
| | - Theis Højland Ipsen
- Department of Drug Design and Pharmacology Faculty of Health Sciences Universitetsparken 2 University of Copenhagen Copenhagen 2100 Denmark
| | - Kristi Anne Kohlmeier
- Department of Drug Design and Pharmacology Faculty of Health Sciences Universitetsparken 2 University of Copenhagen Copenhagen 2100 Denmark
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30
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Helbing C, Brocka M, Scherf T, Lippert MT, Angenstein F. The role of the mesolimbic dopamine system in the formation of blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex during high-frequency stimulation of the rat perforant pathway. J Cereb Blood Flow Metab 2016; 36:2177-2193. [PMID: 26661229 PMCID: PMC5363663 DOI: 10.1177/0271678x15615535] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 06/17/2015] [Accepted: 07/14/2015] [Indexed: 11/17/2022]
Abstract
Several human functional magnetic resonance imaging studies point to an activation of the mesolimbic dopamine system during reward, addiction and learning. We previously found activation of the mesolimbic system in response to continuous but not to discontinuous perforant pathway stimulation in an experimental model that we now used to investigate the role of dopamine release for the formation of functional magnetic resonance imaging responses. The two stimulation protocols elicited blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. Inhibition of dopamine D1/5 receptors abolished the formation of functional magnetic resonance imaging responses in the medial prefrontal/anterior cingulate cortex during continuous but not during discontinuous pulse stimulations, i.e. only when the mesolimbic system was activated. Direct electrical or optogenetic stimulation of the ventral tegmental area caused strong dopamine release but only electrical stimulation triggered significant blood-oxygen level-dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. These functional magnetic resonance imaging responses were not affected by the D1/5 receptor antagonist SCH23390 but reduced by the N-methyl-D-aspartate receptor antagonist MK801. Therefore, glutamatergic ventral tegmental area neurons are already sufficient to trigger blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. Although dopamine release alone does not affect blood-oxygen-level dependent responses it can act as a switch, permitting the formation of blood-oxygen-level dependent responses.
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Affiliation(s)
- Cornelia Helbing
- Special Lab for Non-Invasive Brain Imaging, Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Marta Brocka
- Department of Systems Physiology, Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Thomas Scherf
- Functional Neuromaging Group, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Magdeburg, Germany
| | - Michael T Lippert
- Department of Systems Physiology, Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Frank Angenstein
- Special Lab for Non-Invasive Brain Imaging, Leibniz Institute for Neurobiology, Magdeburg, Germany .,Functional Neuromaging Group, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Magdeburg, Germany
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31
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Taoka N, Kamiizawa R, Wada S, Minami M, Kaneda K. Chronic cocaine exposure induces noradrenergic modulation of inhibitory synaptic transmission to cholinergic neurons of the laterodorsal tegmental nucleus. Eur J Neurosci 2016; 44:3035-3045. [DOI: 10.1111/ejn.13405] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 08/23/2016] [Accepted: 09/16/2016] [Indexed: 01/30/2023]
Affiliation(s)
- Naofumi Taoka
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences; Hokkaido University; Sapporo Japan
| | - Ryota Kamiizawa
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences; Hokkaido University; Sapporo Japan
| | - Shintaro Wada
- Laboratory of Molecular Pharmacology; Institute of Medical, Pharmaceutical and Health Sciences; Kanazawa University; Kakuma-machi Kanazawa 920-1192 Japan
| | - Masabumi Minami
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences; Hokkaido University; Sapporo Japan
| | - Katsuyuki Kaneda
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences; Hokkaido University; Sapporo Japan
- Laboratory of Molecular Pharmacology; Institute of Medical, Pharmaceutical and Health Sciences; Kanazawa University; Kakuma-machi Kanazawa 920-1192 Japan
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32
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Scofield MD, Heinsbroek JA, Gipson CD, Kupchik YM, Spencer S, Smith ACW, Roberts-Wolfe D, Kalivas PW. The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis. Pharmacol Rev 2016; 68:816-71. [PMID: 27363441 PMCID: PMC4931870 DOI: 10.1124/pr.116.012484] [Citation(s) in RCA: 416] [Impact Index Per Article: 46.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.
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Affiliation(s)
- M D Scofield
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
| | - J A Heinsbroek
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
| | - C D Gipson
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
| | - Y M Kupchik
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
| | - S Spencer
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
| | - A C W Smith
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
| | - D Roberts-Wolfe
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
| | - P W Kalivas
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina (M.D.S., J.A.H., S.S., D.R.-W., P.W.K.); Department of Psychology, Arizona State University, Tempe, Arizona (C.D.G.); Department of Neuroscience, Hebrew University, Jerusalem, Israel (Y.M.K.); and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York (A.C.W.S.)
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Grasing K. A threshold model for opposing actions of acetylcholine on reward behavior: Molecular mechanisms and implications for treatment of substance abuse disorders. Behav Brain Res 2016; 312:148-62. [PMID: 27316344 DOI: 10.1016/j.bbr.2016.06.022] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 06/11/2016] [Accepted: 06/13/2016] [Indexed: 12/26/2022]
Abstract
The cholinergic system plays important roles in both learning and addiction. Medications that modify cholinergic tone can have pronounced effects on behaviors reinforced by natural and drug reinforcers. Importantly, enhancing the action of acetylcholine (ACh) in the nucleus accumbens and ventral tegmental area (VTA) dopamine system can either augment or diminish these behaviors. A threshold model is presented that can explain these seemingly contradictory results. Relatively low levels of ACh rise above a lower threshold, facilitating behaviors supported by drugs or natural reinforcers. Further increases in cholinergic tone that rise above a second upper threshold oppose the same behaviors. Accordingly, cholinesterase inhibitors, or agonists for nicotinic or muscarinic receptors, each have the potential to produce biphasic effects on reward behaviors. Pretreatment with either nicotinic or muscarinic antagonists can block drug- or food- reinforced behavior by maintaining cholinergic tone below its lower threshold. Potential threshold mediators include desensitization of nicotinic receptors and biphasic effects of ACh on the firing of medium spiny neurons. Nicotinic receptors with high- and low- affinity appear to play greater roles in reward enhancement and inhibition, respectively. Cholinergic inhibition of natural and drug rewards may serve as mediators of previously described opponent processes. Future studies should evaluate cholinergic agents across a broader range of doses, and include a variety of reinforced behaviors.
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Affiliation(s)
- Kenneth Grasing
- From the Substance Abuse Research Laboratory, 151, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, United States; From the Division of Clinical Pharmacology, Department of Medicine, University of Kansas School of Medicine, Kansas City, KS 66160, United States.
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34
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Schmidt HD, Mietlicki-Baase EG, Ige KY, Maurer JJ, Reiner DJ, Zimmer DJ, Van Nest DS, Guercio LA, Wimmer ME, Olivos DR, De Jonghe BC, Hayes MR. Glucagon-Like Peptide-1 Receptor Activation in the Ventral Tegmental Area Decreases the Reinforcing Efficacy of Cocaine. Neuropsychopharmacology 2016; 41:1917-28. [PMID: 26675243 PMCID: PMC4869061 DOI: 10.1038/npp.2015.362] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 12/11/2015] [Accepted: 12/11/2015] [Indexed: 01/26/2023]
Abstract
Cocaine addiction continues to be a significant public health problem for which there are currently no effective FDA-approved treatments. Thus, there is a clear need to identify and develop novel pharmacotherapies for cocaine addiction. Recent evidence indicates that activation of glucagon-like peptide-1 (GLP-1) receptors in the ventral tegmental area (VTA) reduces intake of highly palatable food. As the neural circuits and neurobiological mechanisms underlying drug taking overlap to some degree with those regulating food intake, these findings suggest that activation of central GLP-1 receptors may also attenuate cocaine taking. Here, we show that intra-VTA administration of the GLP-1 receptor agonist exendin-4 (0.05 μg) significantly reduced cocaine, but not sucrose, self-administration in rats. We also demonstrate that cocaine taking is associated with elevated plasma corticosterone levels and that systemic infusion of cocaine activates GLP-1-expressing neurons in the nucleus tractus solitarius (NTS), a hindbrain nucleus that projects monosynaptically to the VTA. To determine the potential mechanisms by which cocaine activates NTS GLP-1-expressing neurons, we microinjected corticosterone (0.5 μg) directly into the hindbrain fourth ventricle. Intraventricular corticosterone attenuated cocaine self-administration and this effect was blocked in animals pretreated with the GLP-1 receptor antagonist exendin-(9-39) (10 μg) in the VTA. Finally, AAV-shRNA-mediated knockdown of VTA GLP-1 receptors was sufficient to augment cocaine self-administration. Taken together, these findings indicate that increased activation of NTS GLP-1-expressing neurons by corticosterone may represent a homeostatic response to cocaine taking, thereby reducing the reinforcing efficacy of cocaine. Therefore, central GLP-1 receptors may represent a novel target for cocaine addiction pharmacotherapies.
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Affiliation(s)
- Heath D Schmidt
- Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA,Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA,Department of Biobehavioral Health Sciences, School of Nursing, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, 125 South 31st Street, Philadelphia, PA 19104, USA, Tel: +1 215 573 8291, Fax: +1 215 573 7605, E-mail:
| | - Elizabeth G Mietlicki-Baase
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kelsey Y Ige
- Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - John J Maurer
- Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - David J Reiner
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Derek J Zimmer
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Duncan S Van Nest
- Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Leonardo A Guercio
- Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mathieu E Wimmer
- Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Diana R Olivos
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Bart C De Jonghe
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA
| | - Matthew R Hayes
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA,Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Oliva I, Wanat MJ. Ventral Tegmental Area Afferents and Drug-Dependent Behaviors. Front Psychiatry 2016; 7:30. [PMID: 27014097 PMCID: PMC4780106 DOI: 10.3389/fpsyt.2016.00030] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 02/23/2016] [Indexed: 01/10/2023] Open
Abstract
Drug-related behaviors in both humans and rodents are commonly thought to arise from aberrant learning processes. Preclinical studies demonstrate that the acquisition and expression of many drug-dependent behaviors involves the ventral tegmental area (VTA), a midbrain structure comprised of dopamine, GABA, and glutamate neurons. Drug experience alters the excitatory and inhibitory synaptic input onto VTA dopamine neurons, suggesting a critical role for VTA afferents in mediating the effects of drugs. In this review, we present evidence implicating the VTA in drug-related behaviors, highlight the diversity of neuronal populations in the VTA, and discuss the behavioral effects of selectively manipulating VTA afferents. Future experiments are needed to determine which VTA afferents and what neuronal populations in the VTA mediate specific drug-dependent behaviors. Further studies are also necessary for identifying the afferent-specific synaptic alterations onto dopamine and non-dopamine neurons in the VTA following drug administration. The identification of neural circuits and adaptations involved with drug-dependent behaviors can highlight potential neural targets for pharmacological and deep brain stimulation interventions to treat substance abuse disorders.
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Affiliation(s)
- Idaira Oliva
- Department of Biology, Neurosciences Institute, University of Texas at San Antonio , San Antonio, TX , USA
| | - Matthew J Wanat
- Department of Biology, Neurosciences Institute, University of Texas at San Antonio , San Antonio, TX , USA
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Urbano FJ, Bisagno V, González B, Celeste Rivero-Echeto M, Muñiz JA, Luster B, D'Onofrio S, Mahaffey S, Garcia-Rill E. Pedunculopontine arousal system physiology-Effects of psychostimulant abuse. ACTA ACUST UNITED AC 2015; 8:162-8. [PMID: 26779323 PMCID: PMC4688579 DOI: 10.1016/j.slsci.2015.09.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 09/21/2015] [Accepted: 09/25/2015] [Indexed: 01/26/2023]
Abstract
This review describes the interactions between the pedunculopontine nucleus (PPN), the ventral tegmental area (VTA), and the thalamocortical system. Experiments using modulators of cholinergic receptors in the PPN clarified its role on psychostimulant-induced locomotion. PPN activation was found to be involved in the animal’s voluntary search for psychostimulants. Every PPN neuron is known to generate gamma band oscillations. Voltage-gated calcium channels are key elements in the generation and maintenance of gamma band activity of PPN neurons. Calcium channels are also key elements mediating psychostimulant-induced alterations in the thalamic targets of PPN output. Thus, the PPN is a key substrate for maintaining arousal and REM sleep, but also in modulating psychostimulant self-administration.
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Affiliation(s)
- Francisco J Urbano
- Center for Translational Neuroscience, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Verónica Bisagno
- IFIBYNE-CONICET, ININFA-CONICET, University of Buenos Aires, Argentina
| | - Betina González
- IFIBYNE-CONICET, ININFA-CONICET, University of Buenos Aires, Argentina
| | | | - Javier A Muñiz
- IFIBYNE-CONICET, ININFA-CONICET, University of Buenos Aires, Argentina
| | - Brennon Luster
- Center for Translational Neuroscience, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Stasia D'Onofrio
- Center for Translational Neuroscience, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Susan Mahaffey
- Center for Translational Neuroscience, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Edgar Garcia-Rill
- Center for Translational Neuroscience, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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Root DH, Melendez RI, Zaborszky L, Napier TC. The ventral pallidum: Subregion-specific functional anatomy and roles in motivated behaviors. Prog Neurobiol 2015; 130:29-70. [PMID: 25857550 PMCID: PMC4687907 DOI: 10.1016/j.pneurobio.2015.03.005] [Citation(s) in RCA: 250] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 03/19/2015] [Accepted: 03/29/2015] [Indexed: 12/17/2022]
Abstract
The ventral pallidum (VP) plays a critical role in the processing and execution of motivated behaviors. Yet this brain region is often overlooked in published discussions of the neurobiology of mental health (e.g., addiction, depression). This contributes to a gap in understanding the neurobiological mechanisms of psychiatric disorders. This review is presented to help bridge the gap by providing a resource for current knowledge of VP anatomy, projection patterns and subregional circuits, and how this organization relates to the function of VP neurons and ultimately behavior. For example, ventromedial (VPvm) and dorsolateral (VPdl) VP subregions receive projections from nucleus accumbens shell and core, respectively. Inhibitory GABAergic neurons of the VPvm project to mediodorsal thalamus, lateral hypothalamus, and ventral tegmental area, and this VP subregion helps discriminate the appropriate conditions to acquire natural rewards or drugs of abuse, consume preferred foods, and perform working memory tasks. GABAergic neurons of the VPdl project to subthalamic nucleus and substantia nigra pars reticulata, and this VP subregion is modulated by, and is necessary for, drug-seeking behavior. Additional circuits arise from nonGABAergic neuronal phenotypes that are likely to excite rather than inhibit their targets. These subregional and neuronal phenotypic circuits place the VP in a unique position to process motivationally relevant stimuli and coherent adaptive behaviors.
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Affiliation(s)
- David H Root
- Department of Psychology, Rutgers University, 152 Frelinghuysen Road, New Brunswick, NJ 08854, United States.
| | - Roberto I Melendez
- Department of Anatomy and Neurobiology, University of Puerto Rico School of Medicine, San Juan, PR 00936, United States.
| | - Laszlo Zaborszky
- Center for Molecular and Behavioral Neuroscience, Rutgers, The State University of New Jersey, 197 University Avenue, Newark, NJ 07102, United States.
| | - T Celeste Napier
- Departments of Pharmacology and Psychiatry, Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL 60612, United States.
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Addy NA, Nunes EJ, Wickham RJ. Ventral tegmental area cholinergic mechanisms mediate behavioral responses in the forced swim test. Behav Brain Res 2015; 288:54-62. [PMID: 25865152 DOI: 10.1016/j.bbr.2015.04.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 04/01/2015] [Accepted: 04/02/2015] [Indexed: 12/29/2022]
Abstract
Recent studies revealed a causal link between ventral tegmental area (VTA) phasic dopamine (DA) activity and pro-depressive and antidepressant-like behavioral responses in rodent models of depression. Cholinergic activity in the VTA has been demonstrated to regulate phasic DA activity, but the role of VTA cholinergic mechanisms in depression-related behavior is unclear. The goal of this study was to determine whether pharmacological manipulation of VTA cholinergic activity altered behavioral responding in the forced swim test (FST) in rats. Here, male Sprague-Dawley rats received systemic or VTA-specific administration of the acetylcholinesterase inhibitor, physostigmine (systemic; 0.06 or 0.125mg/kg, intra-cranial; 1 or 2μg/side), the muscarinic acetylcholine receptor (AChR) antagonist scopolamine (2.4 or 24μg/side), or the nicotinic AChR antagonist mecamylamine (3 or 30μg/side), prior to the FST test session. In control experiments, locomotor activity was also examined following systemic and intra-cranial administration of cholinergic drugs. Physostigmine administration, either systemically or directly into the VTA, significantly increased immobility time in FST, whereas physostigmine infusion into a dorsal control site did not alter immobility time. In contrast, VTA infusion of either scopolamine or mecamylamine decreased immobility time, consistent with an antidepressant-like effect. Finally, the VTA physostigmine-induced increase in immobility was blocked by co-administration with scopolamine, but unaltered by co-administration with mecamylamine. These data show that enhancing VTA cholinergic tone and blocking VTA AChRs has opposing effects in FST. Together, the findings provide evidence for a role of VTA cholinergic mechanisms in behavioral responses in FST.
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Affiliation(s)
- N A Addy
- Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06520, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06511, USA.
| | - E J Nunes
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA
| | - R J Wickham
- Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06520, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA
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Kamii H, Kurosawa R, Taoka N, Shinohara F, Minami M, Kaneda K. Intrinsic membrane plasticity via increased persistent sodium conductance of cholinergic neurons in the rat laterodorsal tegmental nucleus contributes to cocaine-induced addictive behavior. Eur J Neurosci 2015; 41:1126-38. [DOI: 10.1111/ejn.12855] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Revised: 12/30/2014] [Accepted: 01/21/2015] [Indexed: 12/18/2022]
Affiliation(s)
- Hironori Kamii
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences; Hokkaido University; Sapporo 060-0812 Japan
| | - Ryo Kurosawa
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences; Hokkaido University; Sapporo 060-0812 Japan
| | - Naofumi Taoka
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences; Hokkaido University; Sapporo 060-0812 Japan
| | - Fumiya Shinohara
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences; Hokkaido University; Sapporo 060-0812 Japan
| | - Masabumi Minami
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences; Hokkaido University; Sapporo 060-0812 Japan
| | - Katsuyuki Kaneda
- Department of Pharmacology; Graduate School of Pharmaceutical Sciences; Hokkaido University; Sapporo 060-0812 Japan
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Knapp CM, Ciraulo DA, Datta S. Mechanisms underlying sleep-wake disturbances in alcoholism: focus on the cholinergic pedunculopontine tegmentum. Behav Brain Res 2014; 274:291-301. [PMID: 25151622 DOI: 10.1016/j.bbr.2014.08.029] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 08/11/2014] [Accepted: 08/13/2014] [Indexed: 12/24/2022]
Abstract
Sleep-wake (S-W) disturbances are frequently associated with alcohol use disorders (AUD), occurring during periods of active drinking, withdrawal, and abstinence. These S-W disturbances can persist after months or even years of abstinence, suggesting that chronic alcohol consumption may have enduring negative effects on both homeostatic and circadian sleep processes. It is now generally accepted that S-W disturbances in alcohol-dependent individuals are a significant cause of relapse in drinking. Although significant progress has been made in identifying the socio-economic burden and health risks of alcohol addiction, the underlying neurobiological mechanisms that lead to S-W disorders in AUD are poorly understood. Marked progress has been made in understanding the basic neurobiological mechanisms of how different sleep stages are normally regulated. This review article in seeking to explain the neurobiological mechanisms underlying S-W disturbances associated with AUD, describes an evidence-based, easily testable, novel hypothesis that chronic alcohol consumption induces neuroadaptive changes in the cholinergic cell compartment of the pedunculopontine tegmentum (CCC-PPT). These changes include increases in N-methyl-d-aspartate (NMDA) and kainate receptor sensitivity and a decrease in gamma-aminobutyric acid (GABAB)-receptor sensitivity in the CCC-PPT. Together these changes are the primary pathophysiological mechanisms that underlie S-W disturbances in AUD. This review is targeted for both basic neuroscientists in alcohol addiction research and clinicians who are in search of new and more effective therapeutic interventions to treat and/or eliminate sleep disorders associated with AUD.
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Affiliation(s)
- Clifford M Knapp
- Laboratory of Sleep and Cognitive Neuroscience, Boston University Psychiatry Associates Clinical Studies Unit, Department of Psychiatry, Boston University School of Medicine, 85 East Newton Street, Boston, MA 02118, USA
| | - Domenic A Ciraulo
- Laboratory of Sleep and Cognitive Neuroscience, Boston University Psychiatry Associates Clinical Studies Unit, Department of Psychiatry, Boston University School of Medicine, 85 East Newton Street, Boston, MA 02118, USA
| | - Subimal Datta
- Laboratory of Sleep and Cognitive Neuroscience, Boston University Psychiatry Associates Clinical Studies Unit, Department of Psychiatry, Boston University School of Medicine, 85 East Newton Street, Boston, MA 02118, USA.
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Glucagon-like peptide-1 receptor activation in the nucleus accumbens core suppresses feeding by increasing glutamatergic AMPA/kainate signaling. J Neurosci 2014; 34:6985-92. [PMID: 24828651 DOI: 10.1523/jneurosci.0115-14.2014] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) activation in the nucleus accumbens (NAc) core is pharmacologically and physiologically relevant for regulating palatable food intake. Here, we assess whether GLP-1R signaling in the NAc core of rats modulates GABAergic medium spiny neurons (MSNs) through presynaptic-glutamatergic and/or presynaptic-dopaminergic signaling to control feeding. First, ex vivo fast-scan cyclic voltammetry showed that the GLP-1R agonist exendin-4 (Ex-4) does not alter dopamine release in the NAc core. Instead, support for a glutamatergic mechanism was provided by ex vivo electrophysiological analyses showing that Ex-4 activates presynaptic GLP-1Rs in the NAc core to increase the activity of MSNs via a glutamatergic, AMPA/kainate receptor-mediated mechanism, indicated by increased mEPSC frequency and decreased paired pulse ratio in core MSNs. Only a small, direct excitatory effect on MSNs by Ex-4 was observed, suggesting that the contribution of postsynaptic GLP-1R to MSN activity is minimal. The behavioral relevance of the electrophysiological data was confirmed by the finding that intracore injection of the AMPA/kainate receptor antagonist CNQX attenuated the ability of NAc core GLP-1R activation by Ex-4 microinjection to suppress food intake and body weight gain; in contrast, intracore NMDA receptor blockade by AP-5 did not inhibit the energy balance effects of NAc core Ex-4. Together, these data provide evidence for a novel glutamatergic, but not dopaminergic, mechanism by which NAc core GLP-1Rs promote negative energy balance.
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Shinohara F, Kihara Y, Ide S, Minami M, Kaneda K. Critical role of cholinergic transmission from the laterodorsal tegmental nucleus to the ventral tegmental area in cocaine-induced place preference. Neuropharmacology 2014; 79:573-9. [PMID: 24467849 DOI: 10.1016/j.neuropharm.2014.01.019] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 01/07/2014] [Accepted: 01/11/2014] [Indexed: 02/06/2023]
Abstract
Conditioned place preference (CPP) is widely used to investigate the rewarding properties of cocaine. Various brain regions and neurotransmitters are involved in developing cocaine CPP. However, the contribution of cholinergic transmission in the ventral tegmental area (VTA) to cocaine CPP remains largely unexplored. Here, we examined the role of cholinergic input arising from the laterodorsal tegmental nucleus (LDT) to the VTA in the acquisition and expression of cocaine CPP in rats. Intra-LDT injection of carbachol, which hyperpolarizes LDT neurons, and of NMDA and AMPA receptor antagonists before cocaine conditioning blocked and attenuated cocaine CPP, respectively, indicating the necessity of LDT activity for acquiring the CPP. Additionally, intra-VTA injection of scopolamine or mecamylamine before cocaine conditioning also attenuated cocaine CPP, demonstrating the contribution of cholinergic transmission via muscarinic and nicotinic acetylcholine receptors in CPP acquisition. Furthermore, intra-VTA injection of scopolamine or mecamylamine immediately before the test attenuated cocaine CPP, indicating that cholinergic signaling is also associated with the expression of CPP. These results suggest that cholinergic transmission from the LDT to the VTA is critically involved in both acquiring and retrieving cocaine-associated memories in cocaine CPP.
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Affiliation(s)
- Fumiya Shinohara
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Yukari Kihara
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Soichiro Ide
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Masabumi Minami
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Katsuyuki Kaneda
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
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Steidl S, Wang H, Wise RA. Lesions of cholinergic pedunculopontine tegmental nucleus neurons fail to affect cocaine or heroin self-administration or conditioned place preference in rats. PLoS One 2014; 9:e84412. [PMID: 24465410 PMCID: PMC3897371 DOI: 10.1371/journal.pone.0084412] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 11/22/2013] [Indexed: 11/18/2022] Open
Abstract
Cholinergic input to the ventral tegmental area (VTA) is known to contribute to reward. Although it is known that the pedunculopontine tegmental nucleus (PPTg) provides an important source of excitatory input to the dopamine system, the specific role of PPTg cholinergic input to the VTA in cocaine reward has not been previously determined. We used a diphtheria toxin conjugated to urotensin-II (Dtx::UII), the endogenous ligand for urotensin-II receptors expressed by PPTg cholinergic but not glutamatergic or GABAergic cells, to lesion cholinergic PPTg neurons. Dtx::UII toxin infusion resulted in the loss of 95.78 (±0.65)% of PPTg cholinergic cells but did not significantly alter either cocaine or heroin self-administration or the development of cocaine or heroin conditioned place preferences. Thus, cholinergic cells originating in PPTg do not appear to be critical for the rewarding effects of cocaine or of heroin.
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Affiliation(s)
- Stephan Steidl
- Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland, United States of America
- * E-mail:
| | - Huiling Wang
- Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland, United States of America
| | - Roy A. Wise
- Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health/Department of Health and Human Services, Baltimore, Maryland, United States of America
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Mietlicki-Baase EG, Ortinski PI, Rupprecht LE, Olivos DR, Alhadeff AL, Pierce RC, Hayes MR. The food intake-suppressive effects of glucagon-like peptide-1 receptor signaling in the ventral tegmental area are mediated by AMPA/kainate receptors. Am J Physiol Endocrinol Metab 2013; 305:E1367-74. [PMID: 24105414 PMCID: PMC3882373 DOI: 10.1152/ajpendo.00413.2013] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) activation in the ventral tegmental area (VTA) is physiologically relevant for the control of palatable food intake. Here, we tested whether the food intake-suppressive effects of VTA GLP-1R activation are mediated by glutamatergic signaling within the VTA. Intra-VTA injections of the GLP-1R agonist exendin-4 (Ex-4) reduced palatable high-fat food intake in rats primarily by reducing meal size; these effects were mediated in part via glutamatergic AMPA/kainate but not NMDA receptor signaling. Additional behavioral data indicated that GLP-1R expressed specifically within the VTA can partially mediate the intake- and body weight-suppressive effects of systemically administered Ex-4, offering the intriguing possibility that this receptor population may be clinically relevant for food intake control. Intra-VTA Ex-4 rapidly increased tyrosine hydroxylase levels within the VTA, suggesting that GLP-1R activation modulates VTA dopaminergic signaling. Further evidence for this hypothesis was provided by electrophysiological data showing that Ex-4 increased the frequency of AMPA-mediated currents and reduced the paired/pulse ratio in VTA dopamine neurons. Together, these data provide novel mechanisms by which GLP-1R agonists in the mesolimbic reward system control for palatable food intake.
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Bossert JM, Marchant NJ, Calu DJ, Shaham Y. The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology (Berl) 2013; 229:453-76. [PMID: 23685858 PMCID: PMC3770775 DOI: 10.1007/s00213-013-3120-y] [Citation(s) in RCA: 359] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 04/13/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND RATIONALE Results from many clinical studies suggest that drug relapse and craving are often provoked by acute exposure to the self-administered drug or related drugs, drug-associated cues or contexts, or certain stressors. During the last two decades, this clinical scenario has been studied in laboratory animals by using the reinstatement model. In this model, reinstatement of drug seeking by drug priming, drug cues or contexts, or certain stressors is assessed following drug self-administration training and subsequent extinction of the drug-reinforced responding. OBJECTIVE In this review, we first summarize recent (2009-present) neurobiological findings from studies using the reinstatement model. We then discuss emerging research topics, including the impact of interfering with putative reconsolidation processes on cue- and context-induced reinstatement of drug seeking, and similarities and differences in mechanisms of reinstatement across drug classes. We conclude by discussing results from recent human studies that were inspired by results from rat studies using the reinstatement model. CONCLUSIONS Main conclusions from the studies reviewed highlight: (1) the ventral subiculum and lateral hypothalamus as emerging brain areas important for reinstatement of drug seeking, (2) the existence of differences in brain mechanisms controlling reinstatement of drug seeking across drug classes, (3) the utility of the reinstatement model for assessing the effect of reconsolidation-related manipulations on cue-induced drug seeking, and (4) the encouraging pharmacological concordance between results from rat studies using the reinstatement model and human laboratory studies on cue- and stress-induced drug craving.
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Affiliation(s)
- Jennifer M Bossert
- Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA,
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Mietlicki-Baase EG, Rupprecht LE, Olivos DR, Zimmer DJ, Alter MD, Pierce RC, Schmidt HD, Hayes MR. Amylin receptor signaling in the ventral tegmental area is physiologically relevant for the control of food intake. Neuropsychopharmacology 2013; 38:1685-97. [PMID: 23474592 PMCID: PMC3717548 DOI: 10.1038/npp.2013.66] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Revised: 02/12/2013] [Accepted: 03/01/2013] [Indexed: 11/09/2022]
Abstract
The ability of amylin, a pancreatic β-cell-derived neuropeptide, to promote negative energy balance has been ascribed to neural activation at the area postrema. However, despite amylin binding throughout the brain, the possible role of amylin signaling at other nuclei in the control of food intake has been largely neglected. We show that mRNA for all components of the amylin receptor complex is expressed in the ventral tegmental area (VTA), a mesolimbic structure mediating food intake and reward. Direct activation of VTA amylin receptors reduces the intake of chow and palatable sucrose solution in rats. This effect is mediated by reductions in meal size and is not due to nausea/malaise or prolonged suppression of locomotor activity. VTA amylin receptor activation also reduces sucrose self-administration on a progressive ratio schedule. Finally, antagonist studies provide novel evidence that VTA amylin receptor blockade increases food intake and attenuates the intake-suppressive effects of a peripherally administered amylin analog, suggesting that amylin receptor signaling in the VTA is physiologically relevant for food intake control and potentially clinically relevant for the treatment of obesity.
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Affiliation(s)
- Elizabeth G Mietlicki-Baase
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - Laura E Rupprecht
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Diana R Olivos
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Derek J Zimmer
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Mark D Alter
- Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - R Christopher Pierce
- Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Heath D Schmidt
- Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Matthew R Hayes
- Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Kurosawa R, Taoka N, Shinohara F, Minami M, Kaneda K. Cocaine exposure enhances excitatory synaptic drive to cholinergic neurons in the laterodorsal tegmental nucleus. Eur J Neurosci 2013; 38:3027-35. [PMID: 23822660 DOI: 10.1111/ejn.12296] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 05/24/2013] [Accepted: 06/07/2013] [Indexed: 12/15/2022]
Abstract
Accumulating evidence indicates that the laterodorsal tegmental nucleus (LDT) is associated with reward processing and addiction. The cholinergic projection from the LDT to the ventral tegmental area is essential for a large dopamine release in the nucleus accumbens, which is critically involved in the reinforcing effects of addictive drugs, including cocaine. In contrast to the large number of studies on plasticity induced after cocaine exposure in the mesocorticolimbic dopaminergic system, it remains unknown whether LDT cholinergic neurons exhibit plastic changes following cocaine administration. To address this issue, we performed ex vivo whole-cell recordings in LDT cholinergic neurons obtained from rats following cocaine administration. Neurons obtained from 1 day after 5-day cocaine-treated rats showed significantly smaller paired-pulse ratios of evoked EPSCs and higher miniature EPSC frequencies than those from saline-treated rats, indicating an induction of presynaptic plasticity of increased glutamate release. This plasticity seemed to recover after a 5-day withdrawal from repeated cocaine exposure, and required NMDA receptor stimulation and nitric oxide production. Additionally, pharmacological suppression of activity of the medial prefrontal cortex inhibited the presynaptic plasticity in the LDT. On the other hand, AMPA/NMDA ratios were not different between saline- and cocaine-treated groups, revealing an absence of postsynaptic plasticity. These findings provide the first direct evidence of cocaine-induced synaptic plasticity in LDT cholinergic neurons and suggest that the presynaptic plasticity enhances the activity of LDT cholinergic neurons, contributing to the expression of cocaine-induced addictive behaviors through the dysregulation of the mesocorticolimbic system.
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Affiliation(s)
- Ryo Kurosawa
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Naofumi Taoka
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Fumiya Shinohara
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Masabumi Minami
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| | - Katsuyuki Kaneda
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
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Off the beaten path: drug addiction and the pontine laterodorsal tegmentum. ISRN NEUROSCIENCE 2013; 2013:604847. [PMID: 24959564 PMCID: PMC4045562 DOI: 10.1155/2013/604847] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Accepted: 05/29/2013] [Indexed: 02/01/2023]
Abstract
Drug addiction is a multileveled behavior controlled by interactions among many diverse neuronal groups involving several neurotransmitter systems. The involvement of brainstem-sourced, cholinergic neurotransmission in the development of addiction and in the persistent physiological processes that drive this maladaptive behavior has not been widely investigated. The major cholinergic input to neurons in the midbrain which are instrumental in assessment of reward and assignment of salience to stimuli, including drugs of abuse, sources from acetylcholine- (ACh-) containing pontine neurons of the laterodorsal tegmentum (LDT). Excitatory LDT input, likely cholinergic, is critical in allowing behaviorally relevant neuronal firing patterns within midbrain reward circuitry. Via this control, the LDT is positioned to be importantly involved in development of compulsive, addictive patterns of behavior. The goal of this review is to present the anatomical, physiological, and behavioral evidence suggesting a role of the LDT in the neurobiology underlying addiction to drugs of abuse. Although focus is directed on the evidence supporting a vital participation of the cholinergic neurons of the LDT, data indicating a contribution of noncholinergic LDT neurons to processes underlying addiction are also reviewed. While sparse, available information of actions of drugs of abuse on LDT cells and the output of these neurons as well as their influence on addiction-related behavior are also presented. Taken together, data from studies presented in this review strongly support the position that the LDT is a major player in the neurobiology of drug addiction. Accordingly, the LDT may serve as a future treatment target for efficacious pharmaceutical combat of drug addiction.
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Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 2013; 226:687-98. [PMID: 22411428 PMCID: PMC3649073 DOI: 10.1007/s00213-012-2681-5] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2011] [Accepted: 02/24/2012] [Indexed: 02/04/2023]
Abstract
RATIONALE Glutamate and orexin/hypocretin systems are involved in Pavlovian cue-triggered drug seeking. OBJECTIVES Here, we asked whether orexin and glutamate interact within ventral tegmental area (VTA) to promote reinstatement of extinguished cocaine seeking in a rat self-administration paradigm. METHODS/RESULTS We first found that bilateral VTA microinjections of the orexin 1 receptor (OX1R) antagonist SB-334867 (SB) or a cocktail of the AMPA and NMDA glutamate receptor antagonists CNQX/AP-5 reduced reinstatement of cocaine seeking elicited by cues. In contrast, neither of these microinjections nor systemic SB reduced cocaine-primed reinstatement. Additionally, unilateral VTA OX1R blockade combined with contralateral VTA glutamate blockade attenuated cue-induced reinstatement, indicating that VTA orexin and glutamate are simultaneously necessary for cue-induced reinstatement. We further probed the receptor specificity of glutamate actions in VTA, finding that CNQX, but not AP-5, dose-dependently attenuated cue-induced reinstatement, indicating that AMPA but not NMDA receptor transmission is required for this type of cocaine seeking. Given the necessary roles of both OX1 and AMPA receptors in VTA for cue-induced cocaine seeking, we hypothesized that these signaling pathways interact during this behavior. We found that PEPA, a positive allosteric modulator of AMPA receptors, completely reversed the SB-induced attenuation of reinstatement behavior. Intra-VTA PEPA alone did not alter cue-induced reinstatement, indicating that potentiating AMPA activity with this drug specifically compensates for OX1R blockade, rather than simply inducing or enhancing reinstatement itself. CONCLUSIONS These findings show that cue-induced, but not cocaine-primed, reinstatement of cocaine seeking is dependent upon orexin and AMPA receptor interactions in VTA.
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50
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Lima RH, Radiske A, Köhler CA, Gonzalez MC, Bevilaqua LR, Rossato JI, Medina JH, Cammarota M. Nicotine modulates the long-lasting storage of fear memory. Learn Mem 2013; 20:120-4. [PMID: 23418390 DOI: 10.1101/lm.029900.112] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Late post-training activation of the ventral tegmental area (VTA)-hippocampus dopaminergic loop controls the entry of information into long-term memory (LTM). Nicotinic acetylcholine receptors (nAChR) modulate VTA function, but their involvement in LTM storage is unknown. Using pharmacological and behavioral tools, we found that α7-nAChR-mediated cholinergic interactions between the pedunculopontine tegmental nucleus and the medial prefrontal cortex modulate the duration of fear-motivated memories, maybe by regulating the activation state of VTA-hippocampus dopamine connections.
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Affiliation(s)
- Ramón H Lima
- Laboratory of Behavioral Neurobiology, Biomedical Research Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, Brazil
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