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Lu L, Hu N, Chen H, Wang S, Deng Y, Lin Z, Wang Z, Zhu X, Liu X, Liu L, Jiang L. Cisplatin-induced acute kidney injury increased brain 5-hydroxytryptamine levels partly due to the hippuric acid-induced upregulation of CYP2D4 expression and function in the brain of rats. Drug Metab Dispos 2025; 53:100068. [PMID: 40245581 DOI: 10.1016/j.dmd.2025.100068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 04/19/2025] Open
Abstract
Patients with acute kidney injury (AKI) are often associated with uremic encephalopathy, but its underlying mechanisms remain unclear. This study aimed to investigate how AKI induced neuropsychiatric disorders through cerebral 5-hydroxytryptamine (5-HT) dysregulation in cisplatin-induced AKI rats. Our findings demonstrated that AKI induced anxiety-like behaviors and increased cerebral 5-HT levels, which may be attributed to the upregulated CYP2D4 expression and activity. The intraventricular injection of quinine (CYP2D4 inhibitor) attenuated the elevated cortical 5-HT levels in AKI rats. Intraperitoneal administration of 5-methoxytryptamine (CYP2D4 substrate) also provoked anxiety-like behaviors and cerebral 5-HT accumulation, which were reversed by cotreatment with quinine. Hippuric acid (HA), as a classical uremic toxin, was severely accumulated in both the plasma and brain of AKI rats. In vitro experiments demonstrated that HA-induced reactive oxygen species (ROS) upregulated expression of CYP2D6 (over 70% homology with rat CYP2D4) via suppressing Nrf2/HO-1 pathway in SH-SY5Y cells. These effects were reversed by ROS scavenger N-acetylcysteine, Nrf2 activator sulforaphane, and HO-1 activator cobalt-protoporphyrin IX. Similarly, either Nrf2 inhibitor ML385 or HO-1 inhibitor zinc-protoporphyrin IX exerted up-regulatory effects on CYP2D6 expression. In vivo studies confirmed that HA treatment induced AKI-like behavioral abnormalities in rats, accompanied by increased cerebral 5-HT levels and CYP2D4 expression as well as induced production of ROS, decreased Nrf2 and HO-1 protein levels. Our findings elaborate a novel mechanism between kidney failure and neuropsychiatric complications. Specifically, cisplatin-induced AKI upregulates CYP2D4 expression via HA-mediated ROS release, subsequently promoting generation of cerebral 5-HT by CYP2D4 and revealing material basis of AKI-associated uremic encephalopathy. SIGNIFICANCE STATEMENT: This study revealed that the psychiatric disorders of cisplatin-induced acute kidney injury rats are partly attributed to the increased 5-hydroxytryptamine levels induced by brain CYP2D. The induction of CYP2D4 is mainly due to brain accumulation of hippuric acid via inactivation of Nrf2/HO-1 pathway by reactive oxygen species.
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Affiliation(s)
- Lingjue Lu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Nan Hu
- Department of Pharmacy, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Haoran Chen
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Siqian Wang
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ying Deng
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Zijin Lin
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Zhongyan Wang
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xinyue Zhu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaodong Liu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
| | - Li Liu
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
| | - Ling Jiang
- Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
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Bononi G, Lonzi C, Tuccinardi T, Minutolo F, Granchi C. The Benzoylpiperidine Fragment as a Privileged Structure in Medicinal Chemistry: A Comprehensive Review. Molecules 2024; 29:1930. [PMID: 38731421 PMCID: PMC11085656 DOI: 10.3390/molecules29091930] [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: 03/22/2024] [Revised: 04/08/2024] [Accepted: 04/22/2024] [Indexed: 05/13/2024] Open
Abstract
The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties. The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000. A specific section is focused on the synthetic strategies adopted to obtain this versatile chemical portion.
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Affiliation(s)
| | | | | | | | - Carlotta Granchi
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy; (G.B.); (C.L.); (T.T.); (F.M.)
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Chávez J, Alcántara-Alonso V, García-Luna C, Soberanes-Chávez P, Grammatopoulos D, de Gortari P. Hypothalamic TRH mediates anorectic effects of serotonin in rats. eNeuro 2022; 9:ENEURO.0077-22.2022. [PMID: 35545425 PMCID: PMC9159524 DOI: 10.1523/eneuro.0077-22.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/26/2022] [Accepted: 04/28/2022] [Indexed: 11/21/2022] Open
Abstract
Among the modulatory functions of thyrotropin-releasing hormone (TRH), an anorectic behavior in rodents is observed when centrally injected. Hypothalamic PVN neurons receive serotonergic inputs from dorsal raphe nucleus and express serotonin (5HT) receptors such as 5HT1A, 5HT2A/2C, 5HT6, which are involved in 5HT-induced feeding regulation. Rats subjected to dehydration-induced anorexia (DIA) model show increased PVN TRH mRNA expression, associated with their decreased food intake. We analyzed whether 5HT input is implicated in the enhanced PVN TRH transcription that anorectic rats exhibit, given that 5HT increases TRH expression and release when studied in vitro By using mHypoA-2/30 hypothalamic cell cultures, we found that 5HT stimulated TRH mRNA, pCREB and pERK1/2 levels. By inhibiting basal PKA or PKC activities or those induced by 5HT, pCREB or pERK1/2 content did not increase suggesting involvement of both kinases in their phosphorylation. 5HT effect on TRH mRNA was not affected by PKA inhibition, but it diminished in the presence of PKCi suggesting involvement of PKC in 5HT-induced TRH increased transcription. This likely involves 5HT2A/2C and the activation of alternative transduction pathways than those studied here. In agreement with the in vitro data, we found that injecting 5HT2A/2C antagonists into the PVN of DIA rats reversed the increased TRH expression of anorectic animals, as well as their decreased food intake; also, the agonist reduced food intake of hungry restricted animals along with elevated PVN TRH mRNA levels. Our results support that the anorectic effects of serotonin are mediated by PVN TRH in this model.Significance statementInteraction between brain peptides and neurotransmitters' pathways regulates feeding behavior, but when altered it could lead to the development of eating disorders, such as anorexia. An abnormal increased TRH expression in hypothalamic PVN results in dehydration-induced anorectic rats, associated to their low food intake. The role of neurotransmitters in that alteration is unknown, and since serotonin inhibits feeding and has receptors in PVN, we analyzed its participation in increasing TRH expression and reducing feeding in anorectic rats. By antagonizing PVN serotonin receptors in anorectic rats, we identify decreased TRH expression and increased feeding, suggesting that the anorectic effects of serotonin are mediated by PVN TRH. Elucidating brain networks involved in feeding regulation would help to design therapies for eating disorders.
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Affiliation(s)
- Jorge Chávez
- Molecular Neurophysiology laboratory, Department of Neuroscience, National Institute of Psychiatry "Ramón de la Fuente Muñiz", Mexico City, Mexico 14370
| | - Viridiana Alcántara-Alonso
- Molecular Neurophysiology laboratory, Department of Neuroscience, National Institute of Psychiatry "Ramón de la Fuente Muñiz", Mexico City, Mexico 14370
- Translational Medicine, Warwick Medical School, Coventry, United Kingdom CV4 7HL
| | - Cinthia García-Luna
- Molecular Neurophysiology laboratory, Department of Neuroscience, National Institute of Psychiatry "Ramón de la Fuente Muñiz", Mexico City, Mexico 14370
| | - Paulina Soberanes-Chávez
- Molecular Neurophysiology laboratory, Department of Neuroscience, National Institute of Psychiatry "Ramón de la Fuente Muñiz", Mexico City, Mexico 14370
| | - Dimitris Grammatopoulos
- Translational Medicine, Warwick Medical School, Coventry, United Kingdom CV4 7HL
- Institute of Precision Diagnostics and Translational Medicine, Division of Pathology, UHCW NHS Trust, Coventry, United Kingdom CV2 2DX
| | - Patricia de Gortari
- Molecular Neurophysiology laboratory, Department of Neuroscience, National Institute of Psychiatry "Ramón de la Fuente Muñiz", Mexico City, Mexico 14370.
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Oliva V, Lippi M, Paci R, Del Fabro L, Delvecchio G, Brambilla P, De Ronchi D, Fanelli G, Serretti A. Gastrointestinal side effects associated with antidepressant treatments in patients with major depressive disorder: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2021; 109:110266. [PMID: 33549697 DOI: 10.1016/j.pnpbp.2021.110266] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 01/28/2021] [Accepted: 01/31/2021] [Indexed: 12/25/2022]
Abstract
Gastrointestinal side effects (SEs) are frequently observed in patients with major depressive disorder (MDD) while taking antidepressants and may lead to treatment discontinuation. The aim of this meta-analysis is to provide quantitative measures on short-term rates of gastrointestinal SEs in MDD patients treated with second-generation antidepressants. An electronic search of the literature was conducted by using MEDLINE, ISI Web of Science - Web of Science Core Collection, and Cochrane Library databases. Eligible studies had to focus on the use of at least one of 15 antidepressants commonly used in MDD (i.e., agomelatine, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, mirtazapine, paroxetine, reboxetine, sertraline, venlafaxine, and vortioxetine) and report data on treatment-emergent gastrointestinal SEs (i.e. nausea/vomiting, diarrhoea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite and dry mouth) within 12 weeks of treatment. Overall, 304 studies were included in the meta-analyses. All the considered antidepressants showed higher rates of gastrointestinal SEs than placebo. Escitalopram and sertraline were shown to be the least tolerated antidepressants on the gastrointestinal tract, being associated with all the considered SEs with the exception of constipation and increased appetite, while mirtazapine was shown to be the antidepressant with fewer side effects on the gut, being only associated with increased appetite. In conclusion, commonly used antidepressants showed different profiles of gastrointestinal SEs, possibly related to their mechanisms of action. The specific tolerability profile of each compound should be considered by clinicians when prescribing antidepressants in order to improve adherence to treatment and increase positive outcomes in patients with MDD.
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Affiliation(s)
- Vincenzo Oliva
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Matteo Lippi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Riccardo Paci
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Lorenzo Del Fabro
- Department of Neurosciences and Mental Health, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Giuseppe Delvecchio
- Department of Neurosciences and Mental Health, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Paolo Brambilla
- Department of Neurosciences and Mental Health, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Diana De Ronchi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Giuseppe Fanelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Alessandro Serretti
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
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Vidot DC, Deo S, Daunert S, Joseph WL, de la Cruz-Munoz N, Messiah SE. A Preliminary Study on the Influence of Cannabis and Opioid Use on Weight Loss and Mental Health Biomarkers Post-weight Loss Surgery. Obes Surg 2020; 30:4331-4338. [PMID: 32860570 DOI: 10.1007/s11695-020-04828-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
PURPOSE A subpopulation of weight loss surgery (WLS) patients endorse cannabis and/or opioid use; however, impact on post-WLS anxiety and depression is unclear. This study examined the influence of the independent and combined use of cannabis and opioids on (1) depression and anxiety, (2) duodenum serotonin and cortisol, and (3) total percent weight loss. MATERIALS AND METHODS A cross-sectional analysis was conducted among patients (N = 18) who had biomarkers of serotonin and cortisol collected from the duodenum during WLS. Cannabis and opioid use was determined by self-reported lifetime, past-year, and past 30-day use. The Beck Anxiety Inventory and Depression Inventory-II assessed depression and anxiety symptoms. Total percent weight loss was calculated from pre-WLS and post-WLS weight (kg). Chi-squared analyses and t tests were conducted. RESULTS Over a quarter (27.8%) were cannabis-only users and 16.7% used a combination of cannabis and opioids. None reported using only opioids in this sample. Combination users presented with greater depressive symptoms (22.7%, p = 0.01) and greater total percent weight loss (34.1%, p = 0.04) than cannabis users (7.8, 23.2%, respectively). Cannabis users had greater serotonin (p = 0.02) and cortisol (p = 0.01) levels than combination users and never users. CONCLUSIONS Cannabis users had greater cortisol levels than never users and combination users. Combination users had greater weight loss and depression symptoms than cannabis users. Future studies should consider a larger sample size, utilization of a cohort design to address causality, and examination of the type, dose, and route of cannabis and opioid administration to further understand the impact of the combined use of cannabis and opioids post-WLS.
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Affiliation(s)
- Denise C Vidot
- School of Nursing and Health Studies, University of Miami, Coral Gables, FL, USA. .,Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Sapna Deo
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sylvia Daunert
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Willie L Joseph
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Sarah E Messiah
- University of Texas Health Science Center School of Public Health, Dallas Campus, Dallas, TX, USA.,Center for Pediatric Population Health, UT Health School of Public Health and Children's Health System of Texas, Dallas, TX, USA
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Paolacci S, Kiani AK, Manara E, Beccari T, Ceccarini MR, Stuppia L, Chiurazzi P, Dalla Ragione L, Bertelli M. Genetic contributions to the etiology of anorexia nervosa: New perspectives in molecular diagnosis and treatment. Mol Genet Genomic Med 2020; 8:e1244. [PMID: 32368866 PMCID: PMC7336737 DOI: 10.1002/mgg3.1244] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 03/19/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Anorexia nervosa is a multifactorial eating disorder that manifests with self-starvation, extreme anxiety, hyperactivity, and amenorrhea. Long-term effects include organ failure, disability, and in extreme cases, even death. METHODS Through a literature search, here we summarize what is known about the molecular etiology of anorexia nervosa and propose genetic testing for this condition. RESULTS Anorexia nervosa often has a familial background and shows strong heritability. Various genetic studies along with genome-wide association studies have identified several genetic loci involved in molecular pathways that might lead to anorexia. CONCLUSION Anorexia nervosa is an eating disorder with a strong genetic component that contributes to its etiology. Various genetic approaches might help in the molecular diagnosis of this disease and in devising novel therapeutic options.
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Affiliation(s)
| | | | | | - Tommaso Beccari
- Department of Pharmaceutical SciencesUniversity of PerugiaPerugiaItaly
| | | | - Liborio Stuppia
- Department of Psychological, Health and Territorial SciencesSchool of Medicine and Health Sciences"G. d'Annunzio" UniversityChietiItaly
| | - Pietro Chiurazzi
- Istituto di Medicina GenomicaUniversità Cattolica del Sacro CuoreRomeItaly
- UOC Genetica MedicaFondazione Policlinico Universitario “A. Gemelli” IRCCSRomeItaly
| | - Laura Dalla Ragione
- Center for the Treatment of Eating DisordersResidenza Palazzo FrancisciTodiPerugiaItaly
| | - Matteo Bertelli
- MAGI'S LABRoveretoTrentoItaly
- MAGI EUREGIOBolzanoItaly
- EBTNA‐LABRoveretoTrentoItaly
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Abstract
AbstractEating disorders (EDs) are one of the most severe and complex mental health problems facing researchers and clinicians today. The effective prevention and treatment of these conditions is therefore of paramount importance. However, at present our treatments fall short: generally demonstrating only poor to moderate efficacy, and often completely ineffective for severe or chronic cases. A possible reason for this is that the current theories underlying these treatments are flawed. In this paper, we review and evaluate several prominent theoretical explanations associated with current frontline and promising treatments for ED. In doing so, we identify fundamental problems within the construction of current ED explanations and their implications for treatment. In response to these findings, we propose several strategies for the construction of future ED explanations which we believe have the power to ameliorate these problems and potentially help to develop more efficacious treatment downstream.
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PET imaging of the mouse brain reveals a dynamic regulation of SERT density in a chronic stress model. Transl Psychiatry 2019; 9:80. [PMID: 30745564 PMCID: PMC6370816 DOI: 10.1038/s41398-019-0416-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 12/08/2018] [Accepted: 01/17/2019] [Indexed: 01/15/2023] Open
Abstract
The serotonin transporter (SERT, Slc6a4) plays an important role in the regulation of serotonergic neurotransmission and its aberrant expression has been linked to several psychiatric conditions. While SERT density has been proven to be amenable to in vivo quantitative evaluation by positron emission tomography (PET) in humans, this approach is in its infancy for rodents. Here we set out to evaluate the feasibility of using small-animal PET employing [11C]DASB ([11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) as a radiotracer to measure SERT density in designated areas of the mouse brain. Using Slc6a4+/+, Slc6a4+/-, and Slc6a4-/- mice as a genetic model of different SERT expression levels, we showed the feasibility of SERT imaging in the mouse brain with [11C]DASB-PET. The PET analysis was complemented by an evaluation of SERT protein expression using western blot, which revealed a highly significant correlation between in vivo and ex vivo measurements. [11C]DASB-PET was then applied to the examination of dynamic changes of SERT levels in different brain areas in the chronic corticosterone mouse model of chronic stress. The observed significant reduction in SERT density in corticosterone-treated mice was independently validated by and correlated with western blot analysis. This is the first demonstration of a quantitative in vivo evaluation of SERT density in subregions of the mouse brain using [11C]DASB-PET. The evidenced decrease in SERT density in response to chronic corticosterone treatment adds a new dimension to the complex involvement of SERT in the pathophysiology of stress-induced mental illnesses.
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Kabasakalian A, Ferretti CJ, Hollander E. Oxytocin and Prader-Willi Syndrome. Curr Top Behav Neurosci 2018; 35:529-557. [PMID: 28956320 DOI: 10.1007/7854_2017_28] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In the chapter, we explore the relationship between the peptide hormone, oxytocin (OT), and behavioral and metabolic disturbances observed in the genetic disorder Prader-Willi Syndrome (PWS). Phenotypic and genotypic characteristics of PWS are described, as are the potential implications of an abnormal OT system with respect to neural development including the possible effects of OT dysfunction on interactions with other regulatory mediators, including neurotransmitters, neuromodulators, and hormones. The major behavioral characteristics are explored in the context of OT dysfunction, including hyperphagia, impulsivity, anxiety and emotion dysregulation, sensory processing and interoception, repetitive and restrictive behaviors, and dysfunctional social cognition. Behavioral overlaps with autistic spectrum disorders are discussed. The implications of OT dysfunction on the mechanisms of reward and satiety and their possible role in informing behavioral characteristics are also discussed. Treatment implications and future directions for investigation are considered.
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Affiliation(s)
- Anahid Kabasakalian
- Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA
| | - Casara J Ferretti
- Ferkauf Graduate School of Psychology, Yeshiva University, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Eric Hollander
- Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.
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Das UN. Is There a Role for Bioactive Lipids in the Pathobiology of Diabetes Mellitus? Front Endocrinol (Lausanne) 2017; 8:182. [PMID: 28824543 PMCID: PMC5539435 DOI: 10.3389/fendo.2017.00182] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 07/10/2017] [Indexed: 12/12/2022] Open
Abstract
Inflammation, decreased levels of circulating endothelial nitric oxide (eNO) and brain-derived neurotrophic factor (BDNF), altered activity of hypothalamic neurotransmitters (including serotonin and vagal tone) and gut hormones, increased concentrations of free radicals, and imbalance in the levels of bioactive lipids and their pro- and anti-inflammatory metabolites have been suggested to play a role in diabetes mellitus (DM). Type 1 diabetes mellitus (type 1 DM) is due to autoimmune destruction of pancreatic β cells because of enhanced production of IL-6 and tumor necrosis factor-α (TNF-α) and other pro-inflammatory cytokines released by immunocytes infiltrating the pancreas in response to unknown exogenous and endogenous toxin(s). On the other hand, type 2 DM is due to increased peripheral insulin resistance secondary to enhanced production of IL-6 and TNF-α in response to high-fat and/or calorie-rich diet (rich in saturated and trans fats). Type 2 DM is also associated with significant alterations in the production and action of hypothalamic neurotransmitters, eNO, BDNF, free radicals, gut hormones, and vagus nerve activity. Thus, type 1 DM is because of excess production of pro-inflammatory cytokines close to β cells, whereas type 2 DM is due to excess of pro-inflammatory cytokines in the systemic circulation. Hence, methods designed to suppress excess production of pro-inflammatory cytokines may form a new approach to prevent both type 1 and type 2 DM. Roux-en-Y gastric bypass and similar surgeries ameliorate type 2 DM, partly by restoring to normal: gut hormones, hypothalamic neurotransmitters, eNO, vagal activity, gut microbiota, bioactive lipids, BDNF production in the gut and hypothalamus, concentrations of cytokines and free radicals that results in resetting glucose-stimulated insulin production by pancreatic β cells. Our recent studies suggested that bioactive lipids, such as arachidonic acid, eicosapentaneoic acid, and docosahexaenoic acid (which are unsaturated fatty acids) and their anti-inflammatory metabolites: lipoxin A4, resolvins, protectins, and maresins, may have antidiabetic actions. These bioactive lipids have anti-inflammatory actions, enhance eNO, BDNF production, restore hypothalamic dysfunction, enhance vagal tone, modulate production and action of ghrelin, leptin and adiponectin, and influence gut microbiota that may explain their antidiabetic action. These pieces of evidence suggest that methods designed to selectively deliver bioactive lipids to pancreatic β cells, gut, liver, and muscle may prevent type 1 and type 2 DM.
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Affiliation(s)
- Undurti N. Das
- BioScience Research Centre, Department of Medicine, Gayatri Vidya Parishad Hospital, GVP College of Engineering Campus, Visakhapatnam, India
- UND Life Sciences, Battle Ground, WA, United States
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Hinderberger P, Rullmann M, Drabe M, Luthardt J, Becker GA, Blüher M, Regenthal R, Sabri O, Hesse S. The effect of serum BDNF levels on central serotonin transporter availability in obese versus non-obese adults: A [(11)C]DASB positron emission tomography study. Neuropharmacology 2016; 110:530-536. [PMID: 27108933 DOI: 10.1016/j.neuropharm.2016.04.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 02/26/2016] [Accepted: 04/20/2016] [Indexed: 01/09/2023]
Abstract
BACKGROUND Serotonin (5-HT) and its neurotrophic support system, specifically brain-derived neurotrophic factor (BDNF), are thought to modulate energy homeostasis and susceptibility to obesity. Moreover, a polymorphism (5-HTTLPR) in the serotonin reuptake transporter (5-HTT) gene impairs its transcription, thereby altering serotonergic tone and potentially contributing to such susceptibility. This study aims to investigate the effect of BDNF, biallelic 5-HTTLPR, and central in-vivo 5-HTT availability in highly obese versus non-obese subjects using positron emission tomography (PET) and 5-HTT selective [(11)C]DASB. METHODS Thirty-eight subjects, 24 obese, otherwise mentally and physically healthy, and 14 non-obese healthy controls were included in this study. Parametric images of binding potential were generated from PET data. Central 5-HTT availability, 5-HTTLPR genotype, and serum BDNF concentrations were analyzed, first in a volume of interest, then in a voxel-wise manner. RESULTS Overall, our results showed an absence of a linear correlation between BDNF, in-vivo central 5-HTT availability, and body mass index (BMI). 5-HTTLPR genotyping revealed BDNF and hippocampal 5-HTT availability to be negatively correlated (r = -0.57, p = 0.007) in long allelic homozygotes. However, obese subjects exhibited opposing effects of BDNF levels on 5-HTT availability in the nucleus accumbens (NAcc) relative to our non-obese controls. CONCLUSIONS Our data did not confirm an overall correlation between serum BDNF, in-vivo central 5-HTT availability, 5-HTTLPR, and BMI. However, there is evidence that serotonergic tone linked to BDNF, specifically in the NAcc, is involved in the pathophysiology of obesity, although this needs further exploration over a wide range of reward-related eating behaviors.
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Affiliation(s)
- Philipp Hinderberger
- Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany; Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany
| | - Michael Rullmann
- Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany; Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany
| | - Mandy Drabe
- Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany
| | - Julia Luthardt
- Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany
| | | | - Matthias Blüher
- Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany
| | - Ralf Regenthal
- Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany
| | - Osama Sabri
- Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany; Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany
| | - Swen Hesse
- Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany; Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany.
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Gaber TJ, Dingerkus VLS, Crockett MJ, Bubenzer-Busch S, Helmbold K, Sánchez CL, Dahmen B, Herpertz-Dahlmann B, Zepf FD. Studying the effects of dietary body weight-adjusted acute tryptophan depletion on punishment-related behavioral inhibition. Food Nutr Res 2015; 59:28443. [PMID: 26268708 PMCID: PMC4534625 DOI: 10.3402/fnr.v59.28443] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/22/2015] [Accepted: 06/23/2015] [Indexed: 12/15/2022] Open
Abstract
Background Alterations in serotonergic (5-HT) neurotransmission are thought to play a decisive role in affective disorders and impulse control. Objective This study aims to reproduce and extend previous findings on the effects of acute tryptophan depletion (ATD) and subsequently diminished central 5-HT synthesis in a reinforced categorization task using a refined body weight–adjusted depletion protocol. Design Twenty-four young healthy adults (12 females, mean age [SD]=25.3 [2.1] years) were subjected to a double-blind within-subject crossover design. Each subject was administered both an ATD challenge and a balanced amino acid load (BAL) in two separate sessions in randomized order. Punishment-related behavioral inhibition was assessed using a forced choice go/no-go task that incorporated a variable payoff schedule. Results Administration of ATD resulted in significant reductions in TRP measured in peripheral blood samples, indicating reductions of TRP influx across the blood–brain barrier and related brain 5-HT synthesis. Overall accuracy and response time performance were improved after ATD administration. The ability to adjust behavioral responses to aversive outcome magnitudes and behavioral adjustments following error contingent punishment remained intact after decreased brain 5-HT synthesis. A previously observed dissociation effect of ATD on punishment-induced inhibition was not observed. Conclusions Our results suggest that neurodietary challenges with ATD Moja–De have no detrimental effects on task performance and punishment-related inhibition in healthy adults.
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Affiliation(s)
- Tilman J Gaber
- Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.,JARA Translational Brain Medicine, Aachen & Jülich, Germany
| | - Vita L S Dingerkus
- Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany
| | - Molly J Crockett
- Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom
| | - Sarah Bubenzer-Busch
- Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.,JARA Translational Brain Medicine, Aachen & Jülich, Germany
| | - Katrin Helmbold
- Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.,JARA Translational Brain Medicine, Aachen & Jülich, Germany
| | - Cristina L Sánchez
- Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.,JARA Translational Brain Medicine, Aachen & Jülich, Germany
| | - Brigitte Dahmen
- Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.,JARA Translational Brain Medicine, Aachen & Jülich, Germany
| | - Beate Herpertz-Dahlmann
- Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.,JARA Translational Brain Medicine, Aachen & Jülich, Germany
| | - Florian D Zepf
- Clinic for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.,JARA Translational Brain Medicine, Aachen & Jülich, Germany.,Institute for Neuroscience and Medicine, Jülich Research Centre, Jülich, Germany.,Department of Child and Adolescent Psychiatry, School of Psychiatry and Clinical Neurosciences & School of Paediatrics and Child Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, Australia.,Specialised Child and Adolescent Mental Health Services (CAMHS), Department of Health in Western Australia, Perth, WA, Australia;
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Higgins GA, Fletcher PJ. Therapeutic Potential of 5-HT2C Receptor Agonists for Addictive Disorders. ACS Chem Neurosci 2015; 6:1071-88. [PMID: 25870913 DOI: 10.1021/acschemneuro.5b00025] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) has long been associated with the control of a variety of motivated behaviors, including feeding. Much of the evidence linking 5-HT and feeding behavior was obtained from studies of the effects of the 5-HT releaser (dex)fenfluramine in laboratory animals and humans. Recently, the selective 5-HT2C receptor agonist lorcaserin received FDA approval for the treatment of obesity. This review examines evidence to support the use of selective 5-HT2C receptor agonists as treatments for conditions beyond obesity, including substance abuse (particularly nicotine, psychostimulant, and alcohol dependence), obsessive compulsive, and excessive gambling disorder. Following a brief survey of the early literature supporting a role for 5-HT in modulating food and drug reinforcement, we propose that intrinsic differences between SSRI and serotonin releasers may have underestimated the value of serotonin-based pharmacotherapeutics to treat clinical forms of addictive behavior beyond obesity. We then highlight the critical involvement of the 5-HT2C receptor in mediating the effect of (dex)fenfluramine on feeding and body weight gain and the evidence that 5-HT2C receptor agonists reduce measures of drug reward and impulsivity. A recent report of lorcaserin efficacy in a smoking cessation trial further strengthens the idea that 5-HT2C receptor agonists may have potential as a treatment for addiction. This review was prepared as a contribution to the proceedings of the 11th International Society for Serotonin Research Meeting held in Hermanus, South Africa, July 9-12, 2014.
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Affiliation(s)
- Guy A. Higgins
- InterVivo Solutions Inc., 120 Carlton Street, Toronto, ON M5A
4K2, Canada
- Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Paul J. Fletcher
- Section of Biopsychology
and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada
- Departments of Psychiatry & Psychology, University of Toronto, Toronto, ON M5T 1R8, Canada
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Farr OM, Tsoukas MA, Mantzoros CS. Leptin and the brain: influences on brain development, cognitive functioning and psychiatric disorders. Metabolism 2015; 64:114-30. [PMID: 25092133 DOI: 10.1016/j.metabol.2014.07.004] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 06/16/2014] [Accepted: 07/05/2014] [Indexed: 12/20/2022]
Abstract
Receptors of leptin, the prototypical adipokine, are expressed throughout the cortex and several other areas of the brain. Although typically studied for its role in energy intake and expenditure, leptin plays a critical role in many other neurocognitive processes and interacts with various other hormones and neurotransmitters to perform these functions. Here, we review the literature on how leptin influences brain development, neural degradation, Alzheimer's disease, psychiatric disorders, and more complicated cognitive functioning and feeding behaviors. We also discuss modulators of leptin and the leptin receptor as they relate to normal cognitive functioning and may mediate some of the actions of leptin in the brain. Although we are beginning to better understand the critical role leptin plays in normal cognitive functioning, there is much to be discovered.
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Affiliation(s)
- Olivia M Farr
- Division of Endocrinology, Boston VA Healthcare System/Harvard Medical School, Boston, MA 02215.
| | - Michael A Tsoukas
- Division of Endocrinology, Boston VA Healthcare System/Harvard Medical School, Boston, MA 02215
| | - Christos S Mantzoros
- Division of Endocrinology, Boston VA Healthcare System/Harvard Medical School, Boston, MA 02215
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15
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van Gestel MA, Kostrzewa E, Adan RAH, Janhunen SK. Pharmacological manipulations in animal models of anorexia and binge eating in relation to humans. Br J Pharmacol 2014; 171:4767-84. [PMID: 24866852 PMCID: PMC4209941 DOI: 10.1111/bph.12789] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 03/07/2014] [Accepted: 05/16/2014] [Indexed: 12/22/2022] Open
Abstract
Eating disorders, such as anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorders (BED), are described as abnormal eating habits that usually involve insufficient or excessive food intake. Animal models have been developed that provide insight into certain aspects of eating disorders. Several drugs have been found efficacious in these animal models and some of them have eventually proven useful in the treatment of eating disorders. This review will cover the role of monoaminergic neurotransmitters in eating disorders and their pharmacological manipulations in animal models and humans. Dopamine, 5-HT (serotonin) and noradrenaline in hypothalamic and striatal regions regulate food intake by affecting hunger and satiety and by affecting rewarding and motivational aspects of feeding. Reduced neurotransmission by dopamine, 5-HT and noradrenaline and compensatory changes, at least in dopamine D2 and 5-HT(2C/2A) receptors, have been related to the pathophysiology of AN in humans and animal models. Also, in disorders and animal models of BN and BED, monoaminergic neurotransmission is down-regulated but receptor level changes are different from those seen in AN. A hypofunctional dopamine system or overactive α2-adrenoceptors may contribute to an attenuated response to (palatable) food and result in hedonic binge eating. Evidence for the efficacy of monoaminergic treatments for AN is limited, while more support exists for the treatment of BN or BED with monoaminergic drugs.
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Affiliation(s)
- M A van Gestel
- Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center UtrechtUtrecht, The Netherlands
| | - E Kostrzewa
- Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center UtrechtUtrecht, The Netherlands
| | - R A H Adan
- Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center UtrechtUtrecht, The Netherlands
| | - S K Janhunen
- Orion Corporation Orion Pharma, Research and Development, CNS ResearchTurku, Finland
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16
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Lee JS, Lee HS. Reciprocal connections between CART-immunoreactive, hypothalamic paraventricular neurons and serotonergic dorsal raphe cells in the rat: Light microscopic study. Brain Res 2014; 1560:46-59. [DOI: 10.1016/j.brainres.2014.03.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 02/13/2014] [Accepted: 03/07/2014] [Indexed: 10/25/2022]
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17
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Rondanelli M, Opizzi A, Faliva M, Bucci M, Perna S. Relationship between the absorption of 5-hydroxytryptophan from an integrated diet, by means of Griffonia simplicifolia extract, and the effect on satiety in overweight females after oral spray administration. Eat Weight Disord 2012; 17:e22-8. [PMID: 22142813 DOI: 10.3275/8165] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The management of overweight may include the use of dietary supplements targeted to counter the feeling of hunger. A randomized, double-blind, placebo-controlled trial has been performed in 20 overweight females. These subjects were randomly assigned to supplement their diet with either an extract from Griffonia Simplicifolia (10 subjects) or a placebo (10 matched subjects) for 4-weeks, in conjunction with a personalised reduced calorie diet. The main aim of this study was to evaluate the efficacy, by the assessment of 24-h urinary 5-hydroxyindoleacetic acid levels (5-HIAA), of 1-month administration of a dietary supplement containing 5-hydroxytryptophan (5-HTP) from botanical extracts in healthy, overweight females. Secondary endpoints were the assessment of sensation of appetite (by Haber score), body composition, and severity of binge eating. The supplemented group had a significant increase of 24-h urinary 5-HIAA levels (p<0.001), and a decrease in Haber score (p<0.001) while the placebo group did not show significant changes. With regard to changes in body composition, statistically significant differences between the treatment groups were found for the mean change in BMI, suprailiac skinfold thicknesses, arm circumference and hip circumference. Other parameters were found to be similar in the treated and in the placebo groups. In conclusion, this study shows that the 5-hydroxytryptophan present in the Griffonia extract, administered via spray to the oral cavity, is adequately absorbed, as confirmed by the increase in 24-h urinary 5-HIAA, and that the supplementation of the diet of overweight women with 5-hydroxytryptophan increases the feeling of satiety associated with a decrease in BMI.
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Affiliation(s)
- M Rondanelli
- Department of Applied Health Sciences, Section of Human Nutrition and Dietetics, Faculty of Medicine, University of Pavia, Metabolic and Nutrition Unit, Azienda di Servizi alla Persona, Italy.
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18
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Tarantino G, Savastano S, Capone D, Colao A. Spleen: A new role for an old player? World J Gastroenterol 2011; 17:3776-3784. [PMID: 21987619 PMCID: PMC3181438 DOI: 10.3748/wjg.v17.i33.3776] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2010] [Revised: 12/13/2010] [Accepted: 12/20/2010] [Indexed: 02/06/2023] Open
Abstract
The spleen could be considered a neglected organ. To date, it has been deemed an ancillary organ in portal hypertension or an organ localization in lymphoproliferative diseases, even though it has had significant attention in infectious diseases for some time. Now, it is thought to be central in regulating the immune system, a metabolic asset and involved in endocrine function with regard to nonalcoholic fatty liver disease. The main mechanisms involved in this complex network will be critically discussed in this article.
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19
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Mahendran R. Acute Manic Relapse with Dexfenfluramine. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2011; 9:44. [PMID: 23431324 PMCID: PMC3568654 DOI: 10.9758/cpn.2011.9.1.44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Accepted: 01/19/2011] [Indexed: 12/02/2022]
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20
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Cannabidiol inhibits the hyperphagia induced by cannabinoid-1 or serotonin-1A receptor agonists. Pharmacol Biochem Behav 2011; 98:268-72. [DOI: 10.1016/j.pbb.2011.01.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2010] [Revised: 12/01/2010] [Accepted: 01/08/2011] [Indexed: 11/24/2022]
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21
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Kelemen LE, Atkinson EJ, de Andrade M, Pankratz VS, Cunningham JM, Wang A, Hilker CA, Couch FJ, Sellers TA, Vachon CM. Linkage analysis of obesity phenotypes in pre- and post-menopausal women from a United States mid-western population. BMC MEDICAL GENETICS 2010; 11:156. [PMID: 21062459 PMCID: PMC2992490 DOI: 10.1186/1471-2350-11-156] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Accepted: 11/09/2010] [Indexed: 12/28/2022]
Abstract
Background Obesity has a strong genetic influence, with some variants showing stronger associations among women than men. Women are also more likely to distribute weight in the abdomen following menopause. We investigated whether genetic loci link with obesity-related phenotypes differently by menopausal status. Methods We performed univariate and bivariate linkage analysis for the phenotypes of body mass index (BMI), waist (W) and hip (H) circumferences (WC, HC), and WH ratio (WHR) separately among 172 pre-menopausal and 405 post-menopausal women from 90 multigenerational families using a genome scan with 403 microsatellite markers. Bivariate analysis used pair-wise combinations of obesity phenotypes to detect linkage at loci with pleiotropic effects for genetically correlated traits. BMI was adjusted in models of WC, HC and WHR. Results Pre-menopausal women, compared to post-menopausal women, had higher heritability for BMI (h2 = 94% versus h2 = 39%, respectively) and for HC (h2 = 99% versus h2 = 43%, respectively), and lower heritability for WC (h2 = 29% versus h2 = 61%, respectively) and for WHR (h2 = 39% versus h2 = 57%, respectively). Among pre-menopausal women, the strongest evidence for linkage was for the combination of BMI and HC traits at 3p26 (bivariate LOD = 3.65) and at 13q13-q14 (bivariate LOD = 3.59). Among post-menopausal women, the highest level of evidence for genetic linkage was for HC at 4p15.3 (univariate LOD = 2.70) and 14q13 (univariate LOD = 2.51). WC was not clearly linked to any locus. Conclusions These results support a genetic basis for fat deposition that differs by menopausal status, and suggest that the same loci encode genes that influence general obesity (BMI) and HC, specifically, among pre-menopausal women. However, lower heritability among pre-menopausal women for WC and WHR suggests that pre-menopausal waist girth may be influenced to a greater extent by controllable environmental factors than post-menopausal waist girth. Possibly, targeted interventions for weight control among pre-menopausal women may prevent or attenuate post-menopausal abdominal weight deposition.
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Affiliation(s)
- Linda E Kelemen
- Department of Population Health Research, Alberta Health Services-Cancer Care, Calgary, AB, Canada.
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22
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Ehrlich S, Franke L, Scherag S, Burghardt R, Schott R, Schneider N, Brockhaus S, Hein J, Uebelhack R, Lehmkuhl U. The 5-HTTLPR polymorphism, platelet serotonin transporter activity and platelet serotonin content in underweight and weight-recovered females with anorexia nervosa. Eur Arch Psychiatry Clin Neurosci 2010; 260:483-90. [PMID: 19957188 DOI: 10.1007/s00406-009-0092-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2009] [Accepted: 11/16/2009] [Indexed: 01/28/2023]
Abstract
Serotonin (5-HT) pathways play an important role in the pathophysiology of anorexia nervosa (AN). In this study, we investigated functional characteristics of the platelet 5-HT transporter and platelet 5-HT content in AN patients at various stages of their illness in comparison to healthy control woman (HCW) controlling for the 5-HTTLPR deletion/insertion polymorphism and other confounding variables. Fasting blood samples of 58 acutely underweight AN patients (acAN, BMI = 15.2 ± 1.4), 26 AN patients of the initial acAN sample after short-term/partial weight restoration (BMI = 17.3 ± 0.9), 36 weight-recovered AN patients (recAN, BMI = 20.7 ± 2.2) and 58 HCW (BMI = 21.6 ± 2.0) were assessed for kinetic characteristics of platelet 5-HT uptake (V (max), K (m)) and platelet 5-HT content. Plasma leptin served as an indicator of malnutrition. Mean V (max) and K (m) values were significantly higher in recAN subjects in comparison to HCW (2.05 ± 0.62 vs. 1.66 ± 0.40 nmol 5-HT/10(9) platelets min and 432 ± 215 vs. 315 ± 136 nmol, respectively) but there were no differences in platelet 5-HT content (464.8 ± 210.6 vs. 472.0 ± 162.2 ng 5-HT/10(9) platelets). 5-HT parameters in acAN patients and HCW were similar. 5-HTTLPR variants were not related to 5-HT platelet variables. In the longitudinal part of the study we found significantly increased 5-HT content but unchanged 5-HT uptake in AN patients after short-term/partial weight restoration. Our results highlight the importance of malnutrition for the interpretation of abnormalities in neurotransmitter systems in AN. Changes in platelet 5-HT transporter activity were related to the stage of the illness but not to 5-HTTLPR genotype. Increased V (max) and K (m) in recovered AN patients might mirror adaptive modulations of the 5-HT system.
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Affiliation(s)
- Stefan Ehrlich
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Charité, Universitätsmedizin Berlin, CVK, Berlin, Germany.
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Long-term consequences of early maternal deprivation in serotonergic activity and HPA function in adult rat. Neurosci Lett 2010; 480:7-11. [PMID: 20435091 DOI: 10.1016/j.neulet.2010.04.054] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2009] [Revised: 04/03/2010] [Accepted: 04/22/2010] [Indexed: 02/07/2023]
Abstract
Increasing body of evidence indicates that early life stressful events may induce permanent alterations in neurodevelopment, which in turn, could lead to the development of psychopathologies in adulthood. In particular, maternal deprivation (MD) for 24h in rats has been associated with several abnormalities in brain and behaviour during adulthood, relevant to the neurobiological substrate of anxiety disorders. The aim of the present study was to clarify the long-term effects of MD, on hypothalamo-pituitary-adrenal (HPA) axis activity and serotonergic (5-HT) function, in adulthood, subjects that have not been yet thoroughly investigated. For this purpose, Wistar rat pups were deprived from their mothers for a 24-h single period at postnatal day 9 (pnd 9) and were examined when aged 69-90 days. Plasma corticosterone and ACTH levels along with the animal's behaviour in an open field were used as indices of stress. Moreover, serotonergic activity was estimated in hypothalamus and hippocampus, key structures in the coordination of neuroendocrine and behavioural responses to stress. Interestingly, in adulthood, MD rats compared to controls, displayed decreased body weight, increased serotonergic activity and "anxiety" related behaviour, as well as elevated plasma corticosterone and ACTH levels. The findings of this study showed that MD results in long-term modifications in HPA axis and serotonergic activity indicating a clear relationship between early life stressful events and the development of anxiety-like disorders later in adulthood.
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Seo HJ, Jung YE, Woo YS, Jun TY, Chae JH, Bahk WM. Effect of augmented atypical antipsychotics on weight change in patients with major depressive disorder in a naturalistic setting. Hum Psychopharmacol 2009; 24:135-43. [PMID: 19156709 DOI: 10.1002/hup.1001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
OBJECTIVE The extent of weight changes in depressed patients who use atypical antipsychotics (AAP) as augmentation could not be easily predicted due to weight related symptoms of depression and the interaction with antidepressants which have weight reducing effects. METHODS Patients were treated with either antidepressants augmented with AAP for more than 2 weeks (AAP group, n = 100) or only with antidepressants (non-AAP group, n = 172) during the admission between 2002 and 2006, and the differences in weight were analyzed. RESULTS Mean weight gains of AAP group were significantly higher than those of non-AAP group (2.98 +/- 1.87 kg vs. 1.70 +/- 1.85 kg, p = 0.001). When stratified by antidepressants, the significant difference between the two groups was shown among the subjects who had taken serotonin reuptake inhibitors (SSRIs), but not mirtazapine and venlafaxine (3.42 +/- 2.01 kg vs. 1.48 +/- 1.79 kg, p < 0.001). Comparing among different combinations in AAP group showed that subjects treated with SSRIs and olanzapine had the greatest weight gain (4.21 +/- 1.90 kg), significantly higher than that of the other subgroups (p < 0.001). CONCLUSIONS Our findings suggest that AAP used in patients with depression could severely aggravate preexisting weight-related problems of antidepressants use and the possibility that the combined use with specific antidepressants could have a unique effect on weight by drug-drug interactions.
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Affiliation(s)
- Ho-Jun Seo
- Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Wöckel L, Zepf FD, Koch S, Meyer-Keitel AE, Schmidt MH. Serotonin-induced decrease of intracellular Ca(2+) release in platelets of bulimic patients normalizes during treatment. J Neural Transm (Vienna) 2008; 116:89-95. [PMID: 19082524 DOI: 10.1007/s00702-008-0163-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2008] [Accepted: 11/18/2008] [Indexed: 12/01/2022]
Abstract
Numerous symptoms related to eating disorders have been shown to be influenced by serotonergic (5-HT) functioning, with the 5-HT(2A) receptor subtype being one of the most relevant involved in the pathophysiology of bulimia nervosa (BN). In line with this, Ca(2+) mobilization as mediated by 5-HT(2) receptors in platelets was shown to serve as a peripheral model for central nervous 5-HT functioning. Here, the 5-HT-induced intracellular Ca(2+) mobilization in platelets was measured in 13 female normal weight bulimic patients (14-18 years) upon admission and at the end of inpatient treatment. Findings were compared to 21 age-matched healthy female adolescents. 5-HT-induced Ca(2+) release was significantly decreased in bulimic patients upon admission and normalized during inpatient treatment. Antidepressive medication caused a significant improvement. The data provide further evidence that altered 5-HT(2) receptor functioning is involved in the pathophysiological underpinnings in BN.
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Affiliation(s)
- Lars Wöckel
- Department of Child and Adolescent Psychiatry and Psychotherapy, RWTH Aachen University, Neuenhofer Weg 21, 52074, Aachen, Germany.
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Saunders CL, Chiodini BD, Sham P, Lewis CM, Abkevich V, Adeyemo AA, de Andrade M, Arya R, Berenson GS, Blangero J, Boehnke M, Borecki IB, Chagnon YC, Chen W, Comuzzie AG, Deng HW, Duggirala R, Feitosa MF, Froguel P, Hanson RL, Hebebrand J, Huezo-Dias P, Kissebah AH, Li W, Luke A, Martin LJ, Nash M, Ohman M, Palmer LJ, Peltonen L, Perola M, Price RA, Redline S, Srinivasan SR, Stern MP, Stone S, Stringham H, Turner S, Wijmenga C, Collier DA. Meta-analysis of genome-wide linkage studies in BMI and obesity. Obesity (Silver Spring) 2007; 15:2263-75. [PMID: 17890495 DOI: 10.1038/oby.2007.269] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
OBJECTIVE The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. RESEARCH METHODS AND PROCEDURES We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. RESULTS Bins at chromosome 13q13.2- q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1-qter and 12p11.21-q23 (p < 0.01). CONCLUSION Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.
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Affiliation(s)
- Catherine L Saunders
- King's College London, Guy's, King's & St. Thomas' School of Medicine, London, United Kingdom
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Sookoian S, Gemma C, García SI, Gianotti TF, Dieuzeide G, Roussos A, Tonietti M, Trifone L, Kanevsky D, González CD, Pirola CJ. Short allele of serotonin transporter gene promoter is a risk factor for obesity in adolescents. Obesity (Silver Spring) 2007; 15:271-6. [PMID: 17299098 DOI: 10.1038/oby.2007.519] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Obesity and hypertension are increasing medical problems in adolescents. Serotonin transporter (5-HTT) is involved in mood and eating disturbances. Encoded by the gene SLC6A4, the promoter shows functional insertion/deletion alleles: long (L) and short (S). Because individuals who are carriers for the short version are known to be at risk for higher levels of anxiety, we hypothesized that this variant may be associated with overweight. Data and blood samples were collected from 172 adolescents out of a cross-sectional, population-based study of 934 high school students. To replicate the findings, we also included 119 outpatients from the Nutrition and Diabetes Section of the Children's County Hospital. We found that the S allele was associated with overweight (BMI > 85th percentile), being a risk factor for overweight independently of sex, age, and hypertension [odds ratio (OR): 1.85; 95% confidence interval (CI): 1.13, 3.05; p < 0.02]. Additionally, in the outpatient study, compared with the homozygous LL subjects, S allele carriers showed a higher BMI z-score (1.47 +/- 1.09 vs. 0.51 +/- 1.4; p < 0.002) and were more frequent in overweight children. In conclusion, the S allele of the SLC6A4 promoter variant is associated with overweight being an independent genetic risk factor for obesity.
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Affiliation(s)
- Silvia Sookoian
- Molecular Cardiology, Institute of Medical Research, A Lanari, University of Buenos Aires, Buenos Aires, Argentina
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Antonatos S, Galanopoulou P. Effects of mu-CPP and mesulergine on dietary choices in deprived rats: possible mechanisms of their action. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:112-9. [PMID: 16242827 DOI: 10.1016/j.pnpbp.2005.08.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/26/2005] [Indexed: 10/25/2022]
Abstract
Although it has been well established that compounds that stimulate 5-HT(2C) and/or 5-HT(1B) receptors induce hypophagia by promoting satiety process, the relative role of these receptor subtypes in dietary choices remains to be fully determined. m-CPP is considered a useful probe of 5-HT(2C) receptor function in vivo and its administration reduces food intake and appetite in humans and rats. Conversely, the non-selective 5-HT(2C) receptor antagonist mesulergine elicits feeding in rats. Food intake and dietary choices were measured in a food-deprivation experimental protocol employing male Wistar rats. Animals were given access for a 4-h period to a pair of isocaloric diets. These two diets were enriched in protein or carbohydrate proportions, respectively, but fat content was held constant. The mixed 5-HT(2C/1B) receptor agonist, m-CPP, led to a dose-dependent hypophagia, due to substantial reduction in carbohydrate consumption while protein intake was spared (0.62, 1.25 and 2.50 mg/kg i.p., respectively). The non-selective 5-HT(2C) receptor antagonist and also D2 agonist, mesulergine, on its own produced a significant dose-dependent increase in both protein and carbohydrate diets (1.0 and 3.0 mg/kg i.p., respectively). Combined treatment with m-CPP, at its maximum effective dose, and mesulergine dose-dependently reversed m-CPP-induced hypophagia, during the 4-h test period. In order to clarify the effects of mesulergine on dietary choices since it is simultaneously a dopamine agonist besides its antiserotonergic properties, the D2 agonist apomorphine was also used. Apomorphine caused a dose-dependent increase in protein intake while carbohydrate and total food intake remained nearly unchanged (0.5 and 1.0 mg/kg i.p., respectively). It is concluded that the mesulergine-induced hyperphagic response on both diets is the expression of a dual mode of action, due to its 5-HT(2C) antagonist activity together with D2 agonist properties. The results further indicate that the activation of hypothalamic 5-HT(2C) receptors may be involved in both protein sparing and carbohydrate suppressing effects of 5-HT (m-CPP-like effect), whereas an important role in increase of protein consumption seems to have the dopaminergic system probably through D2 receptors (apomorphine-like and mesulergine-like effects, respectively).
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Affiliation(s)
- Spyridon Antonatos
- Department of Experimental Pharmacology, Medical School, University of Athens, 75, M. Asias, str, Athens 11527, Goudi, Greece.
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Kaye WH, Frank GK, Bailer UF, Henry SE. Neurobiology of anorexia nervosa: clinical implications of alterations of the function of serotonin and other neuronal systems. Int J Eat Disord 2005; 37 Suppl:S15-9; discussion S20-1. [PMID: 15852312 DOI: 10.1002/eat.20109] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Recent evidence suggests that genetic and neurobiologically mediated mechanisms contribute to the etiology of anorexia nervosa (AN). Serotonin neuronal systems, in particular, may create vulnerabilities related to pathological feeding, anxiety and obsessions, and extremes of impulse control, that make individuals susceptible to developing an eating disorder, perhaps in combination with environmental stressors.
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Affiliation(s)
- Walter H Kaye
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
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Herbeth B, Aubry E, Fumeron F, Aubert R, Cailotto F, Siest G, Visvikis-Siest S. Polymorphism of the 5-HT2A receptor gene and food intakes in children and adolescents: the Stanislas Family Study. Am J Clin Nutr 2005; 82:467-70. [PMID: 16087994 DOI: 10.1093/ajcn.82.2.467] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Serotonin (5-hydroxytryptamine; 5-HT) is a key mediator in the control of food intake and is probably involved in the etiology of anorexia nervosa. An association between a polymorphism of the 5-HT receptor (5-HT2A) gene promoter (-1438G/A) and anorexia nervosa has been reported. OBJECTIVE We investigated the relation between the -1438G/A polymorphism of the 5-HT(2A) gene and the energy and macronutrient intakes of children and adolescents. DESIGN This cross-sectional study included 370 children and adolescents aged 10-20 y (176 boys and 194 girls from 251 families) drawn from the Stanislas Family Study. Energy and macronutrient intakes were assessed by using 3-d food records. The -1438G/A polymorphism was analyzed by polymerase chain reaction and then by Hpa II digestion. RESULTS In the overall group, after adjustment for age, sex, weight, height, and family correlation, the A allele was significantly associated with lower energy (P for trend = 0.045) and with total, monounsaturated, and saturated fat intakes expressed in g/d (P for trend = 0.007, 0.005, and 0.006, respectively). Subjects with the GA genotype had intermediate values. In addition, genotype x sex and genotype x age interactions were not significant. CONCLUSIONS The 5-HT2A gene polymorphism in the promoter region is associated with energy and fat intakes in young people. This could be explained by the role of the serotonergic system as a determinant of food intakes and eating behavior.
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Affiliation(s)
- Bernard Herbeth
- From INSERM U525, Epidemiologic and Molecular Genetics of Cardiovascular Diseases, Faculté de Pharmacie, Nancy, France, and the Centre de Médecine Préventive, Vandoeuvre-lès-Nancy, France.
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Herbeth B, Aubry E, Fumeron F, Aubert R, Cailotto F, Siest G, Visvikis-Siest S. Polymorphism of the 5-HT2A receptor gene and food intakes in children and adolescents: the Stanislas Family Study. Am J Clin Nutr 2005. [DOI: 10.1093/ajcn/82.2.467] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Affiliation(s)
- Bernard Herbeth
- From INSERM U525, Epidemiologic and Molecular Genetics of Cardiovascular Diseases, Faculté de Pharmacie, Nancy, France (BH, EA, FC, GS, and SV); INSERM U695, Genetics of Type 2 Diabetes and of its Vascular Complications, Faculté Xavier Bichat, Paris, France (FF and RA), and the Centre de Médecine Préventive, Vandoeuvre-le’s-Nancy, France (GS)
| | - Eléonore Aubry
- From INSERM U525, Epidemiologic and Molecular Genetics of Cardiovascular Diseases, Faculté de Pharmacie, Nancy, France (BH, EA, FC, GS, and SV); INSERM U695, Genetics of Type 2 Diabetes and of its Vascular Complications, Faculté Xavier Bichat, Paris, France (FF and RA), and the Centre de Médecine Préventive, Vandoeuvre-le’s-Nancy, France (GS)
| | - Frédéric Fumeron
- From INSERM U525, Epidemiologic and Molecular Genetics of Cardiovascular Diseases, Faculté de Pharmacie, Nancy, France (BH, EA, FC, GS, and SV); INSERM U695, Genetics of Type 2 Diabetes and of its Vascular Complications, Faculté Xavier Bichat, Paris, France (FF and RA), and the Centre de Médecine Préventive, Vandoeuvre-le’s-Nancy, France (GS)
| | - Roberte Aubert
- From INSERM U525, Epidemiologic and Molecular Genetics of Cardiovascular Diseases, Faculté de Pharmacie, Nancy, France (BH, EA, FC, GS, and SV); INSERM U695, Genetics of Type 2 Diabetes and of its Vascular Complications, Faculté Xavier Bichat, Paris, France (FF and RA), and the Centre de Médecine Préventive, Vandoeuvre-le’s-Nancy, France (GS)
| | - Frédéric Cailotto
- From INSERM U525, Epidemiologic and Molecular Genetics of Cardiovascular Diseases, Faculté de Pharmacie, Nancy, France (BH, EA, FC, GS, and SV); INSERM U695, Genetics of Type 2 Diabetes and of its Vascular Complications, Faculté Xavier Bichat, Paris, France (FF and RA), and the Centre de Médecine Préventive, Vandoeuvre-le’s-Nancy, France (GS)
| | - Gérard Siest
- From INSERM U525, Epidemiologic and Molecular Genetics of Cardiovascular Diseases, Faculté de Pharmacie, Nancy, France (BH, EA, FC, GS, and SV); INSERM U695, Genetics of Type 2 Diabetes and of its Vascular Complications, Faculté Xavier Bichat, Paris, France (FF and RA), and the Centre de Médecine Préventive, Vandoeuvre-le’s-Nancy, France (GS)
| | - Sophie Visvikis-Siest
- From INSERM U525, Epidemiologic and Molecular Genetics of Cardiovascular Diseases, Faculté de Pharmacie, Nancy, France (BH, EA, FC, GS, and SV); INSERM U695, Genetics of Type 2 Diabetes and of its Vascular Complications, Faculté Xavier Bichat, Paris, France (FF and RA), and the Centre de Médecine Préventive, Vandoeuvre-le’s-Nancy, France (GS)
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Ginawi OT, Al-Majed AA, Al-Suwailem AK. Ondansetron, a selective 5-HT3 antagonist, antagonizes methamphetamine-induced anorexia in mice. Pharmacol Res 2005; 51:255-9. [PMID: 15661576 DOI: 10.1016/j.phrs.2004.09.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/09/2004] [Indexed: 11/27/2022]
Abstract
Effects of some selective serotonergic (5-HT) antagonists on methamphetamine-induced anorexia were investigated in male mice. The least possible dose of methamphetamine alone that caused significant anorectic activity was 11 micromolkg(-1), i.p. (2 mgkg(-1)). Various doses of some selective serotonergic receptor antagonists were administered half an hour before the above mentioned dose of methamphetamine. Methiothepin potentiated, whereas NAN-190, methysergide, mianserin and ondansetron antagonized methamphetamine-induced anorectic activity. The least possible doses of these antagonists which modified methamphetamine-induced anorexia were as follows: methiothepin (1.1 micromolkg(-1), i.p.), NAN-190 (4.2 micromolkg(-1), i.p.), methysergide (2.1 micromolkg(-1), i.p.), mianserin (3.3 micromolkg(-1), i.p.) and ondansetron (0.003 micromolkg(-1), i.p.). The serotonergic antagonists at the above mentioned doses did not modify the food intake of animals not treated with methamphetamine, except for methiothepin, which produced a significant reduction, and mianserin, which produced a significant increase in food intake. The results of the present study indicated that the anorectic activity induced by methamphetamine is related to the interactions of methamphetamine with 5-HT receptor. Since a very small dose (0.003 micromolkg(-1)) of ondansetron (the 5-HT(3) antagonist), as compared with the other antagonists used in this study, antagonized the anorexia induced by methamphetamine, the 5-HT(3) receptor is likely to be the site for this interaction.
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Affiliation(s)
- O T Ginawi
- Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
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Salli U, Reddy AP, Salli N, Lu NZ, Kuo HC, Pau FKY, Wolf DP, Bethea CL. Serotonin neurons derived from rhesus monkey embryonic stem cells: similarities to CNS serotonin neurons. Exp Neurol 2004; 188:351-64. [PMID: 15246835 DOI: 10.1016/j.expneurol.2004.04.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2003] [Revised: 04/01/2004] [Accepted: 04/15/2004] [Indexed: 11/24/2022]
Abstract
We sought an in vitro primate model for serotonin neurons. Rhesus monkey embryonic stem (ES) cell colonies were isolated and differentiated into embryoid bodies (EBs), then transferred to serum-free medium with 1% insulin-transferrin-selenium for 7 days to induce neural precursor cell (NPC) formation. NPCs were cultured in medium with 1% N-2 neural supplement and human fibroblast growth factor 2 (FGF2, 10 ng/ml) for 7 days to stimulate cell proliferation. Lastly, NPCs were dispersed into single cells and cultured without FGF2 for another 7 days to obtain terminal differentiation. Terminal cells were characterized for neuronal and serotonergic markers. Over 95% of the NPCs were immunopositive for nestin and Musashi1. Terminally differentiated cells appeared in both small and large morphologies. Most (>95%) of the mature cells (both small and large) were immunopositive for neuron-specific nuclear protein (NeuN), synaptophysin, microtubule-associated protein (MAP2C), Tau-1, neurofilament 160 (NF-160), beta-tubulin (TujIII), tryptophan hydroxylase (TPH), serotonin, the serotonin reuptake transporter (SERT), estrogen receptor-beta (ERbeta), and progestin receptor (PR), but not estrogen receptor-alpha (ERalpha). Less than 2-3% of cells were positive for tyrosine hydroxylase (TH). Reverse transcriptase polymerase chain reaction (RT-PCR) detected mRNA transcripts for TPH-1, TPH-2, SERT, 5-HT1A-autoreceptor, ERbeta, and PR in the differentiated population. A low level of expression of ERalpha mRNA was also detected. Quantitative RT-PCR indicated that the relative abundance of TPH-2 mRNA was greater than TPH-1 mRNA. Serotonin as measured by ELISA increased 3-fold in the mature stage compared to the selection and expansion stages. In summary, a remarkably high percentage of cells derived from monkey ES cells exhibited neuronal plus serotonergic markers as well as nuclear steroid receptors similar to primate CNS serotonin neurons, suggesting that these cells may serve as a useful primate model for serotonergic neurons.
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Affiliation(s)
- Ugur Salli
- Division of Reproductive Sciences, Oregon National Primate Research Center, Beaverton 97006, USA
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Ramacciotti CE, Coli E, Paoli R, Marazziti D, Dell'Osso L. Serotonergic activity measured by platelet [3H]paroxetine binding in patients with eating disorders. Psychiatry Res 2003; 118:33-8. [PMID: 12759159 DOI: 10.1016/s0165-1781(03)00059-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Most of the evidence from pharmacological studies supports the hypothesis of a serotonergic (5-HT) dysregulation in eating disorders (ED), though a specific alteration related to the major ED subtypes, anorexia (AN) and bulimia nervosa (BN), has not been identified yet, possibly because of changes over time in ED nosology. The aim of the present study was to verify whether differences in serotonergic activity, measured by platelet [3H]paroxetine binding, would validate current ED classification. Platelet [3H]paroxetine binding was investigated in 26 patients with eating disorders diagnosed in accord with DSM-IV criteria (AN, n=11; BN, n=15) and 26 normal weight controls of comparable age; ED symptomatology was assessed by the Diagnostic Schedule for Eating Disorders. ED patients had significantly lower B(max) values than controls (288.5+/-109.2 vs. 1396.8+/-251.3 fmol/mg), whereas the K(d) was not significantly altered (0.12+/-0.13 and 0.12+/-0.05 nM, respectively). Among patients, differences in B(max) were related neither to DSM-IV subtypes nor to clinical variables such as presence of binge-eating, purging, impulsive behaviors, or symptoms of depression. Although ED patients share a dysregulation in serotonergic activity, DSM-IV subtype classification was not validated by [3H]paroxetine binding, and hence does not correspond to a specific 5-HT profile.
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Affiliation(s)
- Carla E Ramacciotti
- Department of Psychiatry, Pharmacology, Neurobiology and Biotechnologies, Section of Psychiatry, University of Pisa, Italy.
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Malina A, Gaskill J, McConaha C, Frank GK, LaVia M, Scholar L, Kaye WH. Olanzapine treatment of anorexia nervosa: a retrospective study. Int J Eat Disord 2003; 33:234-7. [PMID: 12616591 DOI: 10.1002/eat.10122] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Recent reports raise the possibility that olanzapine, which commonly causes weight gain in non-eating-disordered subjects, assisted weight gain and mood during refeeding in anorexia nervosa (AN) patients. METHODS Eighteen AN subjects who engaged in open treatment with olanzapine were retrospectively questioned about their response. RESULTS Subjects reported a significant reduction in anxiety, difficulty eating, and core eating disorder symptoms after taking olanzapine. DISCUSSION These data lend support to the possibility that olanzapine may be useful in AN patients. CONCLUSION A controlled trial is necessary to prove that olanzapine is efficacious.
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Affiliation(s)
- Amanda Malina
- Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
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Wang GJ, Volkow ND, Thanos PK, Fowler JS. Positron Emission Tomographic Evidence of Similarity Between Obesity and Drug Addiction. Psychiatr Ann 2003. [DOI: 10.3928/0048-5713-20030201-06] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Strüder H. The serotonergic system: Implications for overtraining and exercise-induced eating disorders. Eur J Sport Sci 2003. [DOI: 10.1080/17461390300073106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Laviano A, Meguid MM, Gleason JR, Rossi-Fanelli F. VMN/LHA functional inhibition in tumor-bearing rats suggests hypothalamic involvement in cancer anorexia. Nutr Neurosci 2002; 5:443-56. [PMID: 12509074 DOI: 10.1080/1028415021000039202] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Food intake is mainly controlled in the hypothalamus via a series of functionally related nuclei, including the ventromedial nucleus of hypothalamus (VMN) and the lateral hypothalamic area (LHA). Since food intake is the product of meal number and meal size, we investigated the role of the VMN and LHA in influencing these feeding indices and in mediating cancer anorexia in tumor-bearing (TB) rats, via temporarily inhibiting VMN or LHA. Adult male Fischer-344 rats (n = 23) inoculated with 106 MCA sarcoma cells were studied. When anorexia developed, rats were randomly assigned to stereotaxically located bilateral intra-VMN or intra-LHA microinjections of the neuronal blocker colchicine (CX; n = 6 each group) or saline (n = 6 and n = 5, respectively). Non TB rats (NTB; n = 7) served as controls. Food intake and feeding indices were recorded by a computerized device. At onset of anorexia, a reduction of meal number occurred, leading to reduced food intake. After inhibition of VMN activity by CX, meal number significantly increased, so that food intake increased and almost normalized. In contrast, intra-LHA microinjection of either CX or saline resulted in reduction of meal size, leading to reduced food intake and death. Findings suggest that VMN and LHA influence meal number and meal size, respectively. Since cancer anorexia mainly results from an initial reduction of meal number and the inhibition of VMN led to an increase in meal number, the early effect of tumor growth on VMN activity may be an early step leading to reduced food intake.
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Affiliation(s)
- A Laviano
- Department of Clinical Medicine, University of Rome La Sapienza, viale dell'Università 37, 00185 Rome, Italy.
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Fessler DMT. Pseudoparadoxical impulsivity in restrictive anorexia nervosa: a consequence of the logic of scarcity. Int J Eat Disord 2002; 31:376-88. [PMID: 11948643 DOI: 10.1002/eat.10035] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE To explain an apparently paradoxical pattern wherein sufferers of restrictive anorexia nervosa exhibit both rigorous self-restraint and episodic impulsivity. METHOD The experimental, historical, and clinical literatures were examined for evidence of psychological and behavioral changes accompanying severe dietary constriction; such changes were noted and compared with those reported to occur in anorexics. RESULTS Increased impulsivity in association with dietary constriction is described in diverse literatures. A number of lines of evidence suggest that the serotonergic system mediates this change. DISCUSSION Many forms of impulsivity can be understood as having once constituted fitness-enhancing responses to resource scarcity. It is suggested that an evolved psychological mechanism calibrates the individual's sensitivity to risk in light of future prospects. Self-injurious behaviors are explicable as misfirings of such a mechanism. Similarly, excessive exercising by anorexics may reflect the misdirection of reward systems that normally encourage adaptive increases in ranging behavior under conditions of scarcity.
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Affiliation(s)
- Daniel M T Fessler
- Department of Anthropology, UCLA, Los Angeles, California 90095-1553, USA
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Celada P, Casanovas JM, Paez X, Artigas F. Control of serotonergic neurons in the dorsal raphe nucleus by the lateral hypothalamus. Brain Res 2002; 932:79-90. [PMID: 11911864 DOI: 10.1016/s0006-8993(02)02284-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Anatomical evidence indicates the presence of projections from the lateral hypothalamus to serotonergic (5-hydroxytryptamine, 5-HT) neurons of the dorsal raphe nucleus (DR). Using dual probe microdialysis and extracellular recordings in the DR, we show that the application of GABAergic agents in the lateral hypothalamus modulates the activity of 5-HT neurons in the DR. GABA and bicuculline or baclofen, applied in the lateral hypothalamus significantly reduced and increased, respectively, the 5-HT output in the DR. Likewise, the intrahypothalamic application of GABA and bicuculline reduced (14/20 neurons) and increased (8/12 neurons), respectively, the firing rate of 5-HT neurons in the DR. A smaller percentage of neurons, however, were excited by GABA (3/20) and inhibited by bicuculline (1/12). Application of tetrodotoxin in the lateral hypothalamus suppressed the local 5-HT output and reduced that in the DR. The 5-HT output in the DR increased transiently soon after darkness. The hypothalamic application of GABA attenuated and that of bicuculline potentiated this spontaneous change with an efficacy similar to that seen in light conditions. These results indicate that the lateral hypothalamus is involved in the control of 5-HT activity in the DR, possibly through excitatory (major) and inhibitory (minor) inputs.
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Affiliation(s)
- Pau Celada
- Department of Neurochemistry, Instituto de Investigaciones Biomédicas de Barcelona, CSIC (IDIBAPS), Rosselló 161, 08036 Barcelona, Spain
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Zippel U, Heidel E, Plagemann A, Davidowa H. Action of CCK and 5-HT on lateral hypothalamic neurons depends on early postnatal nutrition. Nutr Neurosci 2002; 4:143-52. [PMID: 11842882 DOI: 10.1080/1028415x.2001.11747358] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Wistar rats grown up during the early postnatal life (3-21 days after birth) in artificially built normal, small or large lifters developed a significantly different body weight. This difference persisted also during adulthood when they had free access to food and water. The influence of iontophoretically administered cholecystokinin (CCK8S), serotonin (5-HT) or co-ejection of both on firing of lateral hypothalamic neurons was investigated in adult, urethane anesthetized rats of the three groups. The responsiveness to CCK8S was significantly higher in large- and small-litter rats than in the normal control group. The differences were greater in males than in females. They resulted in the male large-litter group from an increase of excitatory responses, whereas in the male small-litter group the proportion of inhibitory responses was augmented. Co-administration of 5-HT generally reduced the neuronal responsiveness. Especially in the large-litter group excitatory responses were significantly reduced. It may be speculated that the availability of food in the early postnatal life influences the development of the hypothalamic regulatory network in such a way that it stabilizes the high or low food ingestion all the life. At least in males, a changed responsiveness and type of response to cholecystokinin of lateral hypothalamic neurons might be involved in this altered regulation.
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Affiliation(s)
- U Zippel
- Johannes-Mueller-Institute of Physiology, Faculty of Medicine, Charité, Humboldt University Berlin, Germany.
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Feitosa MF, Borecki IB, Rich SS, Arnett DK, Sholinsky P, Myers RH, Leppert M, Province MA. Quantitative-trait loci influencing body-mass index reside on chromosomes 7 and 13: the National Heart, Lung, and Blood Institute Family Heart Study. Am J Hum Genet 2002; 70:72-82. [PMID: 11713718 PMCID: PMC384905 DOI: 10.1086/338144] [Citation(s) in RCA: 112] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2001] [Accepted: 10/05/2001] [Indexed: 01/14/2023] Open
Abstract
Obesity is a risk factor for many chronic diseases, including glucose intolerance, lipid disorders, hypertension, and coronary heart disease. Even though the body-mass index (BMI) is a heterogeneous phenotype reflecting the amount of fat, lean mass, and body build, several studies have provided evidence of one or two major loci contributing to the variation in this complex trait. We sought to identify loci with potential influence on BMI in the data obtained from National Heart, Lung, and Blood Institute Family Heart Study. Two complementary samples were studied: (a) 1,184 subjects in 317 sibships, with 243 markers typed by the Utah Molecular Genetics Laboratory (UMGL) and (b) 3,027 subjects distributed among 401 three-generation families, with 404 markers typed by the Mammalian Genotyping Service (MGS). A genome scan using a variance-components-based linkage approach was performed for each sample, as well as for the combined sample, in which the markers from each analysis were placed on a common genetic map. There was strong evidence for linkage on chromosome 7q32.3 in each sample: the maximum multipoint LOD scores were 4.7 (P<10-5) at marker GATA43C11 and 3.2 (P=.00007) at marker D7S1804, for the MGS and UMGL samples, respectively. The linkage result is replicated by the consistent evidence from these two complementary subsets. Furthermore, the evidence for linkage was maintained in the combined sample, with a LOD score of 4.9 (P<10-5) for both markers, which map to the same location. This signal is very near the published location for the leptin gene, which is the most prominent candidate gene in this region. For the combined-sample analysis, evidence of linkage was also found on chromosome 13q14, with D13S257 (LOD score 3.2, P=.00006), and other, weaker signals (LOD scores 1.5-1.9) were found on chromosomes 1, 2, 3, 5, 6, 14, and 15.
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Affiliation(s)
- Mary F Feitosa
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
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Bethea CL, Lu NZ, Gundlah C, Streicher JM. Diverse actions of ovarian steroids in the serotonin neural system. Front Neuroendocrinol 2002; 23:41-100. [PMID: 11906203 DOI: 10.1006/frne.2001.0225] [Citation(s) in RCA: 364] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
All of the serotonin-producing neurons of the mammalian brain are located in 10 nuclei in the mid- and hindbrain regions. The cells of the rostal nuclei project to almost every area of the forebrain and regulate diverse neural processes from higher order functions in the prefrontal cortex such as integrative cognition and memory, to limbic system control of arousal and mood, to diencephalic functions such as pituitary hormone secretion, satiety, and sexual behavior. The more caudal serotonin neurons project to the spinal cord and interact with numerous autonomic and sensory systems. All of these neural functions are sensitive to the presence or absence of the ovarian hormones, estrogen and progesterone. We have shown that serotonin neurons in nonhuman primates contain estrogen receptor beta and progestin receptors. Thus, they are targets for ovarian steroids which in turn modify gene expression. Any change in serotoninergic neural function could be manifested by a change in any of the projection target systems and in this manner, serotonin neurons integrate steroid hormone information and partially transduce their action in the CNS. This article reviews the work conducted in this laboratory on the actions of estrogens and progestins in the serotonin neural system of nonhuman primates. Comparisons to results obtained in other laboratory animal models are made when available and limited clinical data are referenced. The ability of estrogens and progestins to alter the function of the serotonin neural system at various levels provides a cellular mechanism whereby ovarian hormones can impact cognition, mood or arousal, hormone secretion, pain, and other neural circuits.
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Affiliation(s)
- Cynthia L Bethea
- Division of Reproductive Sciences, Oregon Regional Primate Research Center, Beaverton 97006, USA.
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Abstract
The atypical antipsychotics have been shown to have superior efficacy compared with typical antipsychotics such as haloperidol, particularly in the treatment of negative symptoms of schizophrenia. Furthermore, they induce less extrapyramidal effects. However, following clinical use, marked bodyweight gain has been frequently observed with some of the atypical antipsychotic drugs. In order to examine and compare the frequency, amount and conditions of bodyweight gain during treatment with atypical antipsychotics, studies concerning bodyweight gain with these agents were identified through a MEDLINE search from 1966 to March 2000. Although comparison is limited by the different designs and recruitment procedures of the reviewed studies, the available data support the notion that the frequency as well as the amount of bodyweight gain is high in patients treated with olanzapine (average bodyweight gain 2.3 kg/month), clozapine (1.7 kg/month), quetiapine (1.8 kg/month), and possibly also zotepine (2.3 kg/month). Moderate changes in bodyweight have been observed in the treatment with risperidone (average bodyweight gain 1.0 kg/month). Ziprasidone seems to induce only slight bodyweight changes (0.8 kg/month). Bodyweight gain most frequently occurs in the first 12 weeks of treatment. Patients who were underweight at the beginning of treatment are at highest risk of gaining bodyweight. The underlying pathomechanism still remains largely unclear. The relative receptor affinities of the atypical antipsychotics for histamine H1 receptors as well as the ratio of their affinity for serotonin 5-HT2 and dopamine D2 receptors appear to be the most robust correlate of bodyweight gain. Furthermore, the induction of leptin secretion may have an important impact on bodyweight gain in patients treated with atypical antipsychotics. Although many questions concerning the pathogenesis of bodyweight gain remain unresolved, this adverse effect has to be taken into consideration when prescribing the atypical antipsychotics, particularly in view its affect on compliance during long term treatment and the long term effects of obesity on mortality and morbidity.
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Affiliation(s)
- T Wetterling
- Department of Psychiatry and Psychotherapy I, Johann Wolfgang Goethe University, Frankfurt, Germany.
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Coscina DV, Currie PJ, Bishop C, Parker GC, Rollins BL, King BM. Posterodorsal amygdala lesions reduce feeding stimulated by 8-OH-DPAT. Brain Res 2000; 883:243-9. [PMID: 11074055 DOI: 10.1016/s0006-8993(00)02918-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Injections of the serotonin (5-HT)(1A) agonist, 8-hydroxy-2(di-n-propylamino)tetralin, (8-OH-DPAT), either systemically or into the midbrain raphe nuclei, elicit food intake in otherwise satiated rats. Lesions of the paraventricular nucleus of the hypothalamus are well known for producing long-term overeating, but past research has excluded this site as a potential locus for short-term 8-OH-DPAT feeding effects. More recent work shows that small lesions of the posterodorsal amygdala (PDA) elicit overeating in their own right. Since this and related regions of the amygdala receive 5-HT innervations from the dorsal raphe nucleus (DRN), we determined if PDA lesions might alter feeding after injecting 8-OH-DPAT into this midbrain region. Adult female rats received either bilateral electrolytic lesions of the PDA or sham lesions. After recording weight gains for over 1 month, all rats were implanted with DRN cannulae, then randomly tested every 3-4 days for 1 h intake of standard lab chow after 0, 0.4, 0.8 or 1.6 nmol injections of 8-OH-DPAT. Additional 90 min measures of intake were also made after 0 vs. 250 microg (760 nmol) 8-OH-DPAT s.c. At the two highest DRN doses tested, lesioned rats showed 50% less intake compared to shams. A similar profile emerged after the single s.c. dose. These results suggest that the PDA may be an important locus at which reduced release of endogenous 5-HT stimulates feeding. Alternatively, the PDA may represent part of a larger brain circuit whose integrity is necessary for eliciting intake in response to a variety of feeding stimuli.
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Affiliation(s)
- D V Coscina
- Department of Psychology, Wayne State University, 71 W. Warren Ave., Detroit, MI 48202, USA.
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Meguid MM, Fetissov SO, Varma M, Sato T, Zhang L, Laviano A, Rossi-Fanelli F. Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition 2000; 16:843-57. [PMID: 11054589 DOI: 10.1016/s0899-9007(00)00449-4] [Citation(s) in RCA: 299] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Because daily food intake is the product of the size of a meal and the frequency of meals ingested, the characteristic of meal size to meal number during a 24-h light-dark cycle constitutes an identifiable pattern specific to normal states and obesity and that occurs during early cancer anorexia. An understanding of simultaneous changes in meal size and meal number (constituting a change in feeding patterns) as opposed to an understanding of only food intake provides a more insightful dynamic picture reflecting integrated behavior. We have correlated this to simultaneous changes in dopamine and serotonin concentrations and to their postsynaptic receptors, focusing simultaneously on two discrete hypothalamic food-intake-related nuclei, in response to the ingestion of food. The relation between concentrations of dopamine and serotonin limited to the lateral hypothalamic area (LHA) and the ventromedial nucleus (VMN) as they relate to the influence of meal size and meal number during the hyperphagia of obesity and anorexia of cancer as measured in our experiments are discussed. Based on these data, conceptual models are proposed concerning: 1) an "afferent-efferent neurotransmitter unit," with facilitatory or inhibitory neuropeptide properties to generate an appropriate neuroendocrine and neuronal response that ultimately modifies food intake; 2) initiation and termination of a meal, thereby determining the number and size of a meal under normal conditions; and 3) a schema integrating the onset mechanism of cancer anorexia. Nicotine is used as a tool to further explore the relation of meal size to meal number, with a focus on simultaneous changes in dopamine and serotonin concentrations in the LHA and VMN with the onset of acute anorexia of nicotine infusion and acute hyperphagia of nicotine cessation. Data concerning the role of sex-related hormones on dopamine and serotonin with regard to the LHA and VMN in relation to the modulation of food intake are also presented.
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Affiliation(s)
- M M Meguid
- Neuroscience Program, Surgical Metabolism and Nutrition Laboratory, Department of Surgery, University Hospital, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
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Aubert R, Betoulle D, Herbeth B, Siest G, Fumeron F. 5-HT2A receptor gene polymorphism is associated with food and alcohol intake in obese people. Int J Obes (Lond) 2000; 24:920-4. [PMID: 10918541 DOI: 10.1038/sj.ijo.0801253] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE To test the association between a polymorphism of the 5-HT2A receptor gene, -1438G/A, and energy and nutrients intake, including alcohol. SUBJECTS Two hundred and seventy six unrelated overweight subjects (180 women, 96 men) were recruited from the Nutrition Department of Bichat Hospital in Paris on the basis of 120% of ideal body weight (body mass index, BMI=33.3+/-4.8 kg/m2). A second overweight sample (31 women, 49 men) was drawn from the Stanislas Family Study, composed of volunteers for a free health examination in Nancy (BMI=29.6+/-3.1 kg/m2). MEASUREMENTS Energy and nutrients intake were assessed using the diet history method in Paris and the 3-day record method in Nancy. We analyzed the polymorphism by PCR followed by MspI digestion. Statistical differences between genotypes were assessed by using the non-parametric Kruskal-Wallis test. RESULTS In the whole overweight population, the A allele was associated with lower energy intake 10. 3+/-2.8, 9.9+/-2.8, 9.3+/-2.9 MJ/day for GG, GA and AA genotypes respectively (P<0.05). This association was significant in the patient sample from Paris and in the overweight male volunteers from Nancy. Allele A-related lowering in energy intake was due to a trend to lower intakes in all the main nutrients. The A allele was also associated with a lower alcohol consumption: 18.4+/-19.7, 15.3+/-21. 2 and 12.3+/-17.5 g/day for GG, GA and AA genotypes, respectively (P<0.05). CONCLUSIONS These data indicate that a gene polymorphism may influence food and alcohol intake in overweight humans. This could be explained by the role of the serotonergic system as a determinant of food intake.
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Affiliation(s)
- R Aubert
- Human Nutrition Laboratory, Xavier Bichat Medicine School, BP416, 75870 Paris Cedex 18, France
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Laviano A, Cangiano C, Fava A, Muscaritoli M, Mulieri G, Rossi Fanelli F. Peripherally injected IL-1 induces anorexia and increases brain tryptophan concentrations. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2000; 467:105-8. [PMID: 10721046 DOI: 10.1007/978-1-4615-4709-9_15] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Interleukin-1 is an anorexigenic cytokine, and is involved in the pathogenesis of cancer anorexia. Interleukin-1 induced anorexia is mediated by direct action within the hypothalamus, and by peripheral mechanism(s) yet to be determined. Here we present evidence showing that in an animal model the peripheral injection of interleukin-1 is followed by a significant rise in brain tryptophan concentrations. Tryptophan is the precursor of the neurotransmitter serotonin, known to mediate the onset of satiety under normal and pathological conditions. By inference, we conclude that interleukin-1 induced anorexia is mediated by at least two different mechanism: i) interleukin-1 direct action within the hypothalamus; ii) increased brain serotonergic activity, secondary to interleukin-1 induced increased brain availability of the serotonin precursor, tryptophan.
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Affiliation(s)
- A Laviano
- Department of Clinical Medicine, University La Sapienza, Rome, Italy
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Abstract
Two females with severe anorexia nervosa were treated with olanzapine in open trials. Olanzapine was tried because it has caused weight gain in other patient groups. Both anorexic patients had a chronic illness and had failed multiple other treatments. Olanzapine administration was associated with weight gain and maintenance as well as reduced agitation and resistance to treatment. These case histories support further exploration of this class of drugs in anorexia nervosa.
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Affiliation(s)
- M C La Via
- Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Harvey BH, Bouwer CD. Neuropharmacology of paradoxic weight gain with selective serotonin reuptake inhibitors. Clin Neuropharmacol 2000; 23:90-7. [PMID: 10803799 DOI: 10.1097/00002826-200003000-00006] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
It has been suggested that weight gain associated with tricyclic antidepressants (TCA) reflect actions on dopamine (DA) and histamine receptors. However, a definitive cause is purely assumptive given the nonselective pharmacology of these agents. The selective serotonin reuptake inhibitors (SSRIs), as well as agents like dexfenfluramine (DFF), have emphasized the pivotal role of serotonin (5HT) in reducing carbohydrate (CHO) intake, and have provided a more selective tool with which to study appetite regulation. It would be expected that all SSRIs should exert a similar anorectic action. However, recent reports provide evidence to the contrary. Despite their claimed selectivity, SSRIs still interact, either directly or indirectly, with various critical neurotransmitter systems. In addition, although the anorectic action of fluoxetine (FLX) is well recognized, long-term follow-up studies in depressed patients and in obese nondepressed patients reveal that its weight-reducing effects are transient, even leading to a gain in body weight. Similarly, paroxetine (PRX) and citalopram (CTP) have also been associated with weight gain. These latter observations are unexpected because PRX and CTP are highly potent and selective SSRIs. A neuropharmacologic rationale for the apparent paradoxic effects of SSRIs on appetite not a review of neuronal regulation of appetite is presented in this article. As with the regulation of feeding, paradoxic weight gain observed with SSRIs appears to rest on the interaction of 5HT with multiple mechanisms, with the extent of weight gain observed being dependent on subtle, yet important pharmacologic differences within the group. Finally, the neurobiology of depressive illness itself, and of recovery from it, is a major contributing factor to individual response to these drugs.
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Affiliation(s)
- B H Harvey
- Department of Pharmacology, Potchefstroom University for Christian Higher Education, South Africa
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