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Talaee N, Azadvar S, Khodadadi S, Abbasi N, Asli-Pashaki ZN, Mirabzadeh Y, Kholghi G, Akhondzadeh S, Vaseghi S. Comparing the effect of fluoxetine, escitalopram, and sertraline, on the level of BDNF and depression in preclinical and clinical studies: a systematic review. Eur J Clin Pharmacol 2024; 80:983-1016. [PMID: 38558317 DOI: 10.1007/s00228-024-03680-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024]
Abstract
Brain-derived neurotrophic factor (BDNF) dysfunction is one of the most important mechanisms underlying depression. It seems that selective serotonin reuptake inhibitors (SSRIs) improve depression via affecting BDNF level. In this systematic review, for the first time, we aimed to review the effect of three SSRIs including fluoxetine, escitalopram, and sertraline, on both depression and BDNF level in preclinical and clinical studies. PubMed electronic database was searched, and 193 articles were included in this study. After reviewing all manuscripts, only one important difference was found: subjects. We found that SSRIs induce different effects in animals vs. humans. Preclinical studies showed many controversial effects, while human studies showed only two effects: improvement of depression, with or without the improvement of BDNF. However, most studies used chronic SSRIs treatment, while acute SSRIs were not effectively used and evaluated. In conclusion, it seems that SSRIs are reliable antidepressants, and the improvement effect of SSRIs on depression is not dependent to BDNF level (at least in human studies).
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Affiliation(s)
- Nastaran Talaee
- Department of Psychology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Shataw Azadvar
- Department of Power Electronic, Faculty of Electrical Engineering, Sahand University of Technology, Tabriz, Iran
| | - Sanaz Khodadadi
- Student Research Committee, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nahal Abbasi
- Department of Health Psychology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Yasaman Mirabzadeh
- Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Gita Kholghi
- Department of Psychology, Faculty of Human Sciences, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Shahin Akhondzadeh
- Psychiatric Research Center, Department of Psychiatry, Faculty of Medicine, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Salar Vaseghi
- Cognitive Neuroscience Lab, Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, 1419815477, Iran.
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2
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Cubillos S, Engmann O, Brancato A. BDNF as a Mediator of Antidepressant Response: Recent Advances and Lifestyle Interactions. Int J Mol Sci 2022; 23:ijms232214445. [PMID: 36430921 PMCID: PMC9698349 DOI: 10.3390/ijms232214445] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/08/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022] Open
Abstract
Conventional antidepressants are widely employed in several psychiatric and neurologic disorders, yet the mechanisms underlying their delayed and partial therapeutic effects are only gradually being understood. This narrative review provides an up-to-date overview of the interplay between antidepressant treatment and Brain-Derived Neurotrophic Factor (BDNF) signaling. In addition, the impact of nutritional, environmental and physiological factors on BDNF and the antidepressant response is outlined. This review underlines the necessity to include information on lifestyle choices in testing and developing antidepressant treatments in the future.
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Affiliation(s)
- Susana Cubillos
- Institute for Biochemistry and Biophysics, Friedrich-Schiller-University Jena, 07745 Jena, Germany
| | - Olivia Engmann
- Institute for Biochemistry and Biophysics, Friedrich-Schiller-University Jena, 07745 Jena, Germany
- Correspondence:
| | - Anna Brancato
- Department of Sciences for Health Promotion and Mother and Child Care “G. D’Alessandro”, University of Palermo, 90127 Palermo, Italy
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Henn L, Zanta NC, Girardi CEN, Suchecki D. Chronic Escitalopram Treatment Does Not Alter the Effects of Neonatal Stress on Hippocampal BDNF Levels, 5-HT 1A Expression and Emotional Behaviour of Male and Female Adolescent Rats. Mol Neurobiol 2021; 58:926-943. [PMID: 33063280 DOI: 10.1007/s12035-020-02164-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 10/07/2020] [Indexed: 10/23/2022]
Abstract
Early life stress is considered a risk factor for the development of long-term psychiatric disorders. Maternal deprivation (MD) is a useful paradigm to understand the neurobiological underpinnings of early stress-induced changes in neurodevelopment trajectory. The goal of the present study was to examine the effects of a chronic treatment with escitalopram (ESC) on the hippocampal levels of BDNF and neuropeptide Y (NPY), expression of serotonin type 1A receptor (5-HT1A), plasma corticosterone levels and emotional behaviours in male and female adolescent rats submitted to MD at 9 days of life (group DEP9) and challenged with a brief and mild stress (saline injection (SAL)) at the end of MD. Whole litters were kept with mothers (CTL) or submitted to MD (DEP9). Within each group, pups were stress-challenged (CTL-SAL and DEP9-SAL) or not (CTL-NSAL and DEP9-NSAL). ESC or vehicle treatments began at weaning and lasted 24 days, when animals were sacrificed for determination of neurobiological variables or submitted to a battery of tests for evaluation of emotional behaviours. The results showed that BDNF levels were higher in SAL-challenged males and in DEP9-SAL females, whereas 5-HT1A receptor expression was reduced in DEP9 males and in SAL-challenged females. There were no changes in NPY or corticosterone levels. In the forced swim test, SAL-challenged males and DEP9 females displayed less immobility and ESC only increased social motivation in males. The results indicated that neonatal stress led to sex-dependent changes in neurobiology and behaviour and that chronic ESC treatment had minor effects on these parameters.
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Affiliation(s)
- Lorena Henn
- Departamento de Psicobiologia, Universidade Federal de São Paulo, Rua Napoleão de Barros, 925, 1° andar, São Paulo, SP, 04024-002, Brazil
| | - Natália C Zanta
- Departamento de Psicobiologia, Universidade Federal de São Paulo, Rua Napoleão de Barros, 925, 1° andar, São Paulo, SP, 04024-002, Brazil
| | - Carlos Eduardo N Girardi
- Departamento de Psicobiologia, Universidade Federal de São Paulo, Rua Napoleão de Barros, 925, 1° andar, São Paulo, SP, 04024-002, Brazil
| | - Deborah Suchecki
- Departamento de Psicobiologia, Universidade Federal de São Paulo, Rua Napoleão de Barros, 925, 1° andar, São Paulo, SP, 04024-002, Brazil.
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Presby RE, Rotolo RA, Hurley EM, Ferrigno SM, Murphy CE, McMullen HP, Desai PA, Zorda EM, Kuperwasser FB, Carratala-Ros C, Correa M, Salamone JD. Sex differences in lever pressing and running wheel tasks of effort-based choice behavior in rats: Suppression of high effort activity by the serotonin transport inhibitor fluoxetine. Pharmacol Biochem Behav 2021; 202:173115. [PMID: 33493546 DOI: 10.1016/j.pbb.2021.173115] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/18/2020] [Accepted: 01/13/2021] [Indexed: 12/25/2022]
Abstract
Selective serotonin transport (SERT) inhibitors such as fluoxetine are the most commonly prescribed treatments for depression. Although efficacious for many symptoms of depression, motivational impairments such as psychomotor retardation, anergia, fatigue and amotivation are relatively resistant to treatment with SERT inhibitors, and these drugs have been reported to exacerbate motivational deficits in some people. In order to study motivational dysfunctions in animal models, procedures have been developed to measure effort-related decision making, which offer animals a choice between high effort actions leading to highly valued reinforcers, or low effort/low reward options. In the present studies, male and female rats were tested on two different tests of effort-based choice: a fixed ratio 5 (FR5)/chow feeding choice procedure and a running wheel (RW)/chow feeding choice task. The baseline pattern of choice differed across tasks for males and females, with males pressing the lever more than females on the operant task, and females running more than males on the RW task. Administration of the SERT inhibitor and antidepressant fluoxetine suppressed the higher effort activity on each task (lever pressing and wheel running) in both males and females. The serotonin receptor mediating the suppressive effects of fluoxetine is uncertain, because serotonin antagonists with different patterns of receptor selectivity failed to reverse the effects of fluoxetine. Nevertheless, these studies uncovered important sex differences, and demonstrated that the suppressive effects of fluoxetine on high effort activities are not limited to tasks involving food reinforced behavior or appetite suppressive effects. It is possible that this line of research will contribute to an understanding of the neurochemical factors regulating selection of voluntary physical activity vs. sedentary behaviors, which could be relevant for understanding the role of physical activity in psychiatric disorders.
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Affiliation(s)
- Rose E Presby
- Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA
| | - Renee A Rotolo
- Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA
| | - Erin M Hurley
- Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA
| | - Sarah M Ferrigno
- Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA
| | - Cayla E Murphy
- Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA
| | - Haley P McMullen
- Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA
| | - Pranally A Desai
- Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA
| | - Emma M Zorda
- Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA
| | - Felicita B Kuperwasser
- Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA
| | - Carla Carratala-Ros
- Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA; Area de Psicobiologia, Universitat Jaume I, Castelló, Spain
| | - Merce Correa
- Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA; Area de Psicobiologia, Universitat Jaume I, Castelló, Spain
| | - John D Salamone
- Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA.
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Abstract
OBJECTIVE Genetic and environmental factors interact in the development of major depressive disorder (MDD). While neurobiological correlates have only partially been elucidated, altered levels of calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) in animal models and in the cerebrospinal fluid of depressed patients were reported, suggesting that CGRP may be involved in the pathophysiology and/or be a trait marker of MDD. However, changes in CGRP brain levels resulting from interactions between genetic and environmental risk factors and the response to antidepressant treatment have not been explored. METHODS We therefore superimposed maternal separation (MS) onto a genetic rat model (Flinders-sensitive and -resistant lines, FSL/FRL) of depression, treated these rats with antidepressants (escitalopram and nortriptyline) and measured CGRP-LI in selected brain regions. RESULTS CGRP was elevated in the frontal cortex, hippocampus and amygdala (but not in the hypothalamus) of FSL rats. However, MS did not significantly alter levels of this peptide. Likewise, there were no significant interactions between the genetic and environmental factors. Most importantly, neither escitalopram nor nortriptyline significantly altered brain CGRP levels. CONCLUSION Our data demonstrate that increased brain levels of CGRP are present in a well-established rat model of depression. Given that antidepressants have virtually no effect on the brain level of this peptide, our study indicates that further research is needed to evaluate the functional role of CGRP in the FSL model for depression.
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Mul JD. Voluntary exercise and depression-like behavior in rodents: are we running in the right direction? J Mol Endocrinol 2018; 60:R77-R95. [PMID: 29330149 DOI: 10.1530/jme-17-0165] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 01/11/2018] [Indexed: 12/18/2022]
Abstract
Acute or chronic exposure to stress can increase the risk to develop major depressive disorder, a severe, recurrent and common psychiatric condition. Depression places an enormous social and financial burden on modern society. Although many depressed patients are treated with antidepressants, their efficacy is only modest, underscoring the necessity to develop clinically effective pharmaceutical or behavioral treatments. Exercise training produces beneficial effects on stress-related mental disorders, indicative of clinical potential. The pro-resilient and antidepressant effects of exercise training have been documented for several decades. Nonetheless, the underlying molecular mechanisms and the brain circuitries involved remain poorly understood. Preclinical investigations using voluntary wheel running, a frequently used rodent model that mimics aspects of human exercise training, have started to shed light on the molecular adaptations, signaling pathways and brain nuclei underlying the beneficial effects of exercise training on stress-related behavior. In this review, I highlight several neurotransmitter systems that are putative mediators of the beneficial effects of exercise training on mental health, and review recent rodent studies that utilized voluntary wheel running to promote our understanding of exercise training-induced central adaptations. Advancements in our mechanistic understanding of how exercise training induces beneficial neuronal adaptations will provide a framework for the development of new strategies to treat stress-associated mental illnesses.
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Affiliation(s)
- Joram D Mul
- Department of Endocrinology and MetabolismAcademic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- Laboratory of EndocrinologyDepartment of Clinical Chemistry, University of Amsterdam, Amsterdam, the Netherlands
- Netherlands Institute for NeuroscienceRoyal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, the Netherlands
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7
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Bains RS, Wells S, Sillito RR, Armstrong JD, Cater HL, Banks G, Nolan PM. Assessing mouse behaviour throughout the light/dark cycle using automated in-cage analysis tools. J Neurosci Methods 2017; 300:37-47. [PMID: 28456660 PMCID: PMC5909039 DOI: 10.1016/j.jneumeth.2017.04.014] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/21/2017] [Accepted: 04/22/2017] [Indexed: 12/15/2022]
Abstract
Automated assessment of mouse home-cage behaviour is robust and reliable. Analysis over multiple light/dark cycles improves ability to classify behaviours. Combined RFID and video analysis enables home-cage analysis in group housed animals. An important factor in reducing variability in mouse test outcomes has been to develop assays that can be used for continuous automated home cage assessment. Our experience has shown that this has been most evidenced in long-term assessment of wheel-running activity in mice. Historically, wheel-running in mice and other rodents have been used as a robust assay to determine, with precision, the inherent period of circadian rhythms in mice. Furthermore, this assay has been instrumental in dissecting the molecular genetic basis of mammalian circadian rhythms. In teasing out the elements of this test that have determined its robustness – automated assessment of an unforced behaviour in the home cage over long time intervals – we and others have been investigating whether similar test apparatus could be used to accurately discriminate differences in distinct behavioural parameters in mice. Firstly, using these systems, we explored behaviours in a number of mouse inbred strains to determine whether we could extract biologically meaningful differences. Secondly, we tested a number of relevant mutant lines to determine how discriminative these parameters were. Our findings show that, when compared to conventional out-of-cage phenotyping, a far deeper understanding of mouse mutant phenotype can be established by monitoring behaviour in the home cage over one or more light:dark cycles.
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Affiliation(s)
- Rasneer S Bains
- Mary Lyon Centre, MRC Harwell Institute, Harwell Science Campus, Oxfordshire, UK
| | - Sara Wells
- Mary Lyon Centre, MRC Harwell Institute, Harwell Science Campus, Oxfordshire, UK
| | | | - J Douglas Armstrong
- Actual Analytics Ltd., Edinburgh, UK; School of Informatics, University of Edinburgh, Edinburgh, UK
| | - Heather L Cater
- Mary Lyon Centre, MRC Harwell Institute, Harwell Science Campus, Oxfordshire, UK
| | - Gareth Banks
- Mammalian Genetics Unit, MRC Harwell Institute, Harwell Science Campus, Oxfordshire, UK
| | - Patrick M Nolan
- Mammalian Genetics Unit, MRC Harwell Institute, Harwell Science Campus, Oxfordshire, UK.
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8
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Gómez-Galán M, Femenía T, Åberg E, Graae L, Van Eeckhaut A, Smolders I, Brené S, Lindskog M. Running Opposes the Effects of Social Isolation on Synaptic Plasticity and Transmission in a Rat Model of Depression. PLoS One 2016; 11:e0165071. [PMID: 27764188 PMCID: PMC5072675 DOI: 10.1371/journal.pone.0165071] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 10/05/2016] [Indexed: 12/19/2022] Open
Abstract
Stress, such as social isolation, is a well-known risk factor for depression, most probably in combination with predisposing genetic factors. Physical exercise on the other hand, is depicted as a wonder-treatment that makes you healthier, happier and live longer. However, the published results on the effects of exercise are ambiguous, especially when it comes to neuropsychiatric disorders. Here we combine a paradigm of social isolation with a genetic rat model of depression, the Flinders Sensitive Line (FSL), already known to have glutamatergic synaptic alterations. Compared to group-housed FSL rats, we found that social isolation further affects synaptic plasticity and increases basal synaptic transmission in hippocampal CA1 pyramidal neurons. These functional synaptic alterations co-exist with changes in hippocampal protein expression levels: social isolation in FSL rats reduce expression of the glial glutamate transporter GLT-1, and increase expression of the GluA2 AMPA-receptor subunit. We further show that physical exercise in form of voluntary running prevents the stress-induced synaptic effects but do not restore the endogenous mechanisms of depression already present in the FSL rat.
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Affiliation(s)
- Marta Gómez-Galán
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Teresa Femenía
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Elin Åberg
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Lisette Graae
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Ann Van Eeckhaut
- Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit, Brussel, Belgium
| | - Ilse Smolders
- Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit, Brussel, Belgium
| | - Stefan Brené
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Maria Lindskog
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- * E-mail:
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9
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Kondo MA, Gray LJ, Pelka GJ, Leang SK, Christodoulou J, Tam PPL, Hannan AJ. Affective dysfunction in a mouse model of Rett syndrome: Therapeutic effects of environmental stimulation and physical activity. Dev Neurobiol 2015; 76:209-24. [DOI: 10.1002/dneu.22308] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Revised: 03/24/2015] [Accepted: 05/22/2015] [Indexed: 01/06/2023]
Affiliation(s)
- Mari A. Kondo
- Florey Institute of Neuroscience and Mental Health; University of Melbourne; Parkville Victoria 3010 Australia
- Department of Anatomy and Neuroscience; University of Melbourne; Parkville Victoria 3010 Australia
| | - Laura J. Gray
- Florey Institute of Neuroscience and Mental Health; University of Melbourne; Parkville Victoria 3010 Australia
| | - Gregory J. Pelka
- Embryology Unit; Children's Medical Research Institute; Westmead New South Wales 2145 Australia
| | - Sook-Kwan Leang
- Florey Institute of Neuroscience and Mental Health; University of Melbourne; Parkville Victoria 3010 Australia
| | - John Christodoulou
- Western Sydney Genetics Program; Children's Hospital at Westmead; Westmead, New South Wales 2145 Australia
- Disciplines of Paediatrics and Child Health and Genetic Medicine; University of Sydney; Sydney New South Wales 2006 Australia
| | - Patrick P. L. Tam
- Embryology Unit; Children's Medical Research Institute; Westmead New South Wales 2145 Australia
- Sydney Medical School; University of Sydney; Sydney New South Wales 2006 Australia
| | - Anthony J. Hannan
- Florey Institute of Neuroscience and Mental Health; University of Melbourne; Parkville Victoria 3010 Australia
- Department of Anatomy and Neuroscience; University of Melbourne; Parkville Victoria 3010 Australia
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Possamai F, dos Santos J, Walber T, Marcon JC, dos Santos TS, Lino de Oliveira C. Influence of enrichment on behavioral and neurogenic effects of antidepressants in Wistar rats submitted to repeated forced swim test. Prog Neuropsychopharmacol Biol Psychiatry 2015; 58:15-21. [PMID: 25485962 DOI: 10.1016/j.pnpbp.2014.10.017] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 10/17/2014] [Accepted: 10/22/2014] [Indexed: 12/27/2022]
Abstract
Repeated forced swimming test (rFST) may detect gradual effects of antidepressants in adult rats. Antidepressants, as enrichment, affected behavior and neurogenesis in rats. However, the influence of enrichment on behavioral and neurogenic effects of antidepressants is unknown. Here, effects of antidepressants on rFST and hippocampal neurogenesis were investigated in rats under enriched conditions. Behaviors of male Wistar rats, housed from weaning in standard (SE) or enriched environment (EE), were registered during rFST. The rFST consisted of 15min of swimming (pretest) followed by 5min of swimming in the first (test), seventh (retest 1) and fourteenth (retest 2) days after pretest. One hour before the test, rats received an intraperitoneal injection of saline (1ml/kg), fluoxetine (2.5mg/kg) or imipramine (2.5 or 5mg/kg). These treatments were performed daily until the day of the retest 2. After retest 2, rats were euthanized for the identification of markers for neurogenesis in the hippocampus. Fluoxetine or imipramine decreased immobility in retests 1 and 2, as compared to saline. EE abolished these differences. In EE, fluoxetine or imipramine (5mg/kg) reduced immobility time in retest 2, as compared to the test. Independent of the housing conditions, fluoxetine and imipramine (5mg/kg) increased the ratio of immature neurons per progenitor cell in the hippocampus. In summary, antidepressants or enrichment counteracted the high immobility in rFST. Enrichment changed the effects of antidepressants in rFST depending on the type, and the dose of a substance but failed to change neurogenesis in control or antidepressant treated-rats. Effects of antidepressants and enrichment on rFST seemed neurogenesis-independent.
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Affiliation(s)
- Fernanda Possamai
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina-UFSC, Campus Trindade, Florianópolis, 88040-900 SC, Brazil
| | - Juliano dos Santos
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina-UFSC, Campus Trindade, Florianópolis, 88040-900 SC, Brazil
| | - Thais Walber
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina-UFSC, Campus Trindade, Florianópolis, 88040-900 SC, Brazil
| | - Juliana C Marcon
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina-UFSC, Campus Trindade, Florianópolis, 88040-900 SC, Brazil
| | - Tiago Souza dos Santos
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina-UFSC, Campus Trindade, Florianópolis, 88040-900 SC, Brazil
| | - Cilene Lino de Oliveira
- Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina-UFSC, Campus Trindade, Florianópolis, 88040-900 SC, Brazil.
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11
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Sierakowiak A, Mattsson A, Gómez-Galán M, Feminía T, Graae L, Aski SN, Damberg P, Lindskog M, Brené S, Åberg E. Hippocampal morphology in a rat model of depression: the effects of physical activity. Open Neuroimag J 2015; 9:1-6. [PMID: 25674191 PMCID: PMC4319211 DOI: 10.2174/1874440001509010001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 12/01/2014] [Accepted: 12/11/2014] [Indexed: 11/22/2022] Open
Abstract
Accumulating in vivo and ex vivo evidences show that humans suffering from depression have decreased hippocampal volume and altered spine density. Moreover, physical activity has an antidepressant effect in humans and in animal models, but to what extent physical activity can affect hippocampal volume and spine numbers in a model for depression is not known. In this study we analyzed whether physical activity affects hippocampal volume and spine density by analyzing a rodent genetic model of depression, Flinders Sensitive Line Rats (FSL), with Magnetic Resonance Imaging (MRI) and ex vivo Golgi staining. We found that physical activity in the form of voluntary wheel running during 5 weeks increased hippocampal volume. Moreover, runners also had larger numbers of thin spines in the dentate gyrus. Our findings support that voluntary wheel running, which is antidepressive in FSL rats, is associated with increased hippocampal volume and spine numbers.
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Affiliation(s)
- Adam Sierakowiak
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Sweden
| | - Anna Mattsson
- Department of Neuroscience, Karolinska Institutet, Sweden
| | | | - Teresa Feminía
- Department of Neuroscience, Karolinska Institutet, Sweden
| | - Lisette Graae
- Department of Neuroscience, Karolinska Institutet, Sweden
| | - Sahar Nikkhou Aski
- Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Sweden
| | - Peter Damberg
- Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Sweden
| | - Mia Lindskog
- Department of Neuroscience, Karolinska Institutet, Sweden
| | - Stefan Brené
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Sweden
| | - Elin Åberg
- AstraZeneca Translational Science Centre, Personalised Healthcare & Biomarkers, AstraZeneca R&D Innovative Medicines, Solna, Sweden and Department of Clinical Neuroscience, Science for Life Laboratory, Karolinska Institutet, Sweden
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12
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Bogdanova OV, Kanekar S, D'Anci KE, Renshaw PF. Factors influencing behavior in the forced swim test. Physiol Behav 2013; 118:227-39. [PMID: 23685235 DOI: 10.1016/j.physbeh.2013.05.012] [Citation(s) in RCA: 302] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Revised: 03/31/2013] [Accepted: 05/06/2013] [Indexed: 12/19/2022]
Abstract
The forced swim test (FST) is a behavioral test in rodents which was developed in 1978 by Porsolt and colleagues as a model for predicting the clinical efficacy of antidepressant drugs. A modified version of the FST added the classification of active behaviors into swimming and climbing, in order to facilitate the differentiation between serotonergic and noradrenergic classes of antidepressant drugs. The FST is now widely used in basic research and the pharmaceutical screening of potential antidepressant treatments. It is also one of the most commonly used tests to assess depressive-like behavior in animal models. Despite the simplicity and sensitivity of the FST procedure, important differences even in baseline immobility rates have been reported between different groups, which complicate the comparison of results across studies. In spite of several methodological papers and reviews published on the FST, the need still exists for clarification of factors which can influence the procedure. While most recent reviews have focused on antidepressant effects observed with the FST, this one considers the methodological aspects of the procedure, aiming to summarize issues beyond antidepressant action in the FST. The previously published literature is analyzed for factors which are known to influence animal behavior in the FST. These include biological factors, such as strain, age, body weight, gender and individual differences between animals; influence of preconditioning before the FST: handling, social isolation or enriched environment, food manipulations, various kinds of stress, endocrine manipulations and surgery; schedule and routes of treatment, dosage and type of the drugs as well as experimental design and laboratory environmental effects. Consideration of these factors in planning experiments may result in more consistent FST results.
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Affiliation(s)
- Olena V Bogdanova
- Brain Institute, University of Utah, 383 Colorow Drive, Salt Lake City, UT84108, USA.
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L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc Natl Acad Sci U S A 2013; 110:4804-9. [PMID: 23382250 DOI: 10.1073/pnas.1216100110] [Citation(s) in RCA: 210] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a well-tolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-ĸB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-ĸB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.
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Renoir T, Pang TYC, Zajac MS, Chan G, Du X, Leang L, Chevarin C, Lanfumey L, Hannan AJ. Treatment of depressive-like behaviour in Huntington's disease mice by chronic sertraline and exercise. Br J Pharmacol 2012; 165:1375-89. [PMID: 21718306 DOI: 10.1111/j.1476-5381.2011.01567.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND PURPOSE Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. Women are more prone to develop depression and such susceptibility might be related to 5-hydroxytryptaminergic (serotonergic) dysregulation. EXPERIMENTAL APPROACH We performed tests of depression-related behaviours on female R6/1 HD mice that had been chronically treated with sertraline or provided with running-wheels. Functional assessments of 5-HT(1A) and 5-HT(2A) receptors were performed by measuring behavioural and physiological responses following administration of specific agonists, in combination with analysis of hippocampal gene expression. Finally we assessed the effect of exercise on hippocampal cell proliferation. KEY RESULTS Female HD mice recorded increased immobility time in the forced-swimming test, reduced saccharin preference and a hyperthermic response to stress compared with wild-type animals. These alterations were improved by chronic sertraline treatment. Wheel-running also resulted in similar improvements with the exception of saccharin preference but failed to correct the hippocampal cell proliferation deficits displayed by HD mice. The benefits of sertraline treatment and exercise involved altered 5-HT(1A) autoreceptor function, as demonstrated by modulation of the exaggerated 8-OH-DPAT-induced hypothermia exhibited by female HD mice. On the other hand, sertraline treatment was unable to restore the reduced 5-HT(1A) and 5-HT(2) heteroceptor function observed in HD animals. CONCLUSIONS AND IMPLICATIONS We report for the first time a crucial role for 5-HT(1A) autoreceptor function in mediating the sex-specific depressive-like phenotype of female R6/1 HD mice. Our data further support a differential effect of chronic sertraline treatment and exercise on hippocampal cell proliferation despite common behavioural benefits.
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Affiliation(s)
- Thibault Renoir
- Howard Florey Institute, Florey Neuroscience Institutes, University of Melbourne, Parkville, Victoria, Australia.
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Novak CM, Burghardt PR, Levine JA. The use of a running wheel to measure activity in rodents: relationship to energy balance, general activity, and reward. Neurosci Biobehav Rev 2012; 36:1001-1014. [PMID: 22230703 DOI: 10.1016/j.neubiorev.2011.12.012] [Citation(s) in RCA: 225] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Revised: 12/07/2011] [Accepted: 12/22/2011] [Indexed: 12/21/2022]
Abstract
Running wheels are commonly employed to measure rodent physical activity in a variety of contexts, including studies of energy balance and obesity. There is no consensus on the nature of wheel-running activity or its underlying causes, however. Here, we will begin by systematically reviewing how running wheel availability affects physical activity and other aspects of energy balance in laboratory rodents. While wheel running and physical activity in the absence of a wheel commonly correlate in a general sense, in many specific aspects the two do not correspond. In fact, the presence of running wheels alters several aspects of energy balance, including body weight and composition, food intake, and energy expenditure of activity. We contend that wheel-running activity should be considered a behavior in and of itself, reflecting several underlying behavioral processes in addition to a rodent's general, spontaneous activity. These behavioral processes include defensive behavior, predatory aggression, and depression- and anxiety-like behaviors. As it relates to energy balance, wheel running engages several brain systems-including those related to the stress response, mood, and reward, and those responsive to growth factors-that influence energy balance indirectly. We contend that wheel-running behavior represents factors in addition to rodents' tendency to be physically active, engaging additional neural and physiological mechanisms which can then independently alter energy balance and behavior. Given the impact of wheel-running behavior on numerous overlapping systems that influence behavior and physiology, this review outlines the need for careful design and interpretation of studies that utilize running wheels as a means for exercise or as a measurement of general physical activity.
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Affiliation(s)
- Colleen M Novak
- Department of Biological Sciences, Kent State University, PO Box 5190, 222 Cunningham Hall, Kent, OH 44242, United States
| | | | - James A Levine
- Mayo Clinic, Endocrine Research Unit, Rochester, MN 55905, United States
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Mikrouli E, Wörtwein G, Soylu R, Mathé AA, Petersén Å. Increased numbers of orexin/hypocretin neurons in a genetic rat depression model. Neuropeptides 2011; 45:401-6. [PMID: 21871662 DOI: 10.1016/j.npep.2011.07.010] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Revised: 07/11/2011] [Accepted: 07/30/2011] [Indexed: 11/28/2022]
Abstract
The Flinders Sensitive Line (FSL) rat is a genetic animal model of depression that displays characteristics similar to those of depressed patients including lower body weight, decreased appetite and reduced REM sleep latency. Hypothalamic neuropeptides such as orexin/hypocretin, melanin-concentrating hormone (MCH) and cocaine and amphetamine regulated transcript (CART), that are involved in the regulation of both energy metabolism and sleep, have recently been implicated also in depression. We therefore hypothesized that alterations in these neuropeptide systems may play a role in the development of the FSL phenotype with both depressive like behavior, metabolic abnormalities and sleep disturbances. In this study, we first confirmed that the FSL rats displayed increased immobility in the Porsolt forced swim test compared to their control strain, the Flinders Resistant Line (FRL), which is indicative of depressive-like behavior. We then examined the number of orexin-, MCH- and CART-immunopositive neurons in the hypothalamus using stereological analyses. We found that the total number of orexin-positive neurons was higher in the hypothalamus of female FSL rats compared to female FRL rats, whereas no changes in the MCH or CART populations could be detected between the strains. Chronic treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram reduced immobility only in the FRL rats where it also increased the number of MCH positive neurons compared to untreated rats. These findings support the view that orexin may be involved in depression and strengthen the notion that the "depressed" brain responds differently to pharmacological interventions than the normal brain.
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Affiliation(s)
- Elli Mikrouli
- Translational Neuroendocrine Research Unit, BMC D11, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden
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Hansson AC, Rimondini R, Heilig M, Mathé AA, Sommer WH. Dissociation of antidepressant-like activity of escitalopram and nortriptyline on behaviour and hippocampal BDNF expression in female rats. J Psychopharmacol 2011; 25:1378-87. [PMID: 21262856 DOI: 10.1177/0269881110393049] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A major hypothesis of depression postulates that a dysregulation of the neurotrophin systems is directly involved in the pathophysiology of depression, and that restoration of such deficits may underlie the therapeutic efficacy of antidepressant treatment. One key finding supporting this hypothesis is upregulation of brain derived neurotrophic factor (BDNF) in the hippocampus after antidepressant treatment. Here, we further test the hypothesis of BDNF involvement in antidepressant action in a genetic rat model of depression after chronic oral treatment with escitalopram, nortriptyline or placebo. Active treatments had significant behavioural antidepressant-like actions in female rats of the Flinders Sensitive Line (FSL) and non-selected Sprague Dawley (SD) rats, while Flinders Resistant Line (FRL) rats were unaffected. Escitalopram, but not nortriptyline, markedly reduced BDNF mRNA levels in the dentate gyrus of FSL rats. The BDNF downregulation was common to the four major promoters of the gene. Treatments did not affect BDNF expression in FRL or SD strains. We conclude that the antidepressant effects of escitalopram and nortriptyline, two common drugs with different pharmacological profiles, appear to be unrelated to the regulation of hippocampal BDNF expression in female rats. These results indicate that the tropic hypothesis of depression has limitations and emphasize the need for validated disease models of depression to assess potential treatment targets.
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Affiliation(s)
- Anita C Hansson
- Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA
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Escitalopram modulates neuron-remodelling proteins in a rat gene-environment interaction model of depression as revealed by proteomics. Part I: genetic background. Int J Neuropsychopharmacol 2011; 14:796-833. [PMID: 21054914 DOI: 10.1017/s1461145710001318] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The wide-scale analysis of protein expression provides a powerful strategy for the molecular exploration of complex pathophysiological mechanisms, such as the response to antidepressants. Using a 2D proteomic approach we investigated the Flinders Sensitive Line (FSL), a genetically selected rat model of depression, and the control Flinders Resistant Line (FRL). To evaluate gene-environment interactions, FSL and FRL pups were separated from their mothers for 3 h (maternal separation, MS), as early-life trauma is considered an important antecedent of depression. All groups were treated with either escitalopram (Esc) admixed to food (25 mg/kg.d) or vehicle for 1 month. At the week 3, forced swim tests were performed. Protein extracts from prefrontal/frontal cortex and hippocampus were separated by 2D electrophoresis. Proteins displaying statistically significant differences in expression levels were identified by mass spectrometry. Immobility time values in the forced swim test were higher in FSL rats and reduced by antidepressant treatment. Moreover, the Esc-induced reduction in immobility time was not detected in MS rats. The impact of genetic background in response to Esc was specifically investigated here. Bioinformatics analyses highlighted gene ontology terms showing tighter associations with the modulated proteins. Esc modulated protein belonging to cytoskeleton organization in FSL; carbohydrate metabolism and intracellular transport in FRL. Proteins differently modulated in the two strains after MS and Esc play a role in cytoskeleton organization, vesicle-mediated transport, apoptosis regulation and macromolecule catabolism. These findings suggest pathways involved in neuronal remodelling as molecular correlates of response to antidepressants in a model of vulnerability.
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Chourbaji S, Brandwein C, Gass P. Altering BDNF expression by genetics and/or environment: impact for emotional and depression-like behaviour in laboratory mice. Neurosci Biobehav Rev 2010; 35:599-611. [PMID: 20621121 DOI: 10.1016/j.neubiorev.2010.07.003] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2010] [Revised: 07/01/2010] [Accepted: 07/02/2010] [Indexed: 10/19/2022]
Abstract
According to the "neurotrophin hypothesis", brain-derived neurotrophic factor (BDNF) is an important candidate gene in depression. Moreover, environmental stress is known to represent a risk factor in the pathophysiology and treatment of this disease. To elucidate, whether changes of BDNF availability signify cause or consequence of depressive-like alterations, it is essential to look for endophenotypes under distinct genetic conditions (e.g. altered BDNF expression). Furthermore it is crucial to examine environment-driven BDNF regulation and its effect on depressive-linked features. Consequently, gene × environment studies investigating prospective genetic mouse models of depression in different environmental contexts become increasingly important. The present review summarizes recent findings in BDNF-mutant mice, which have been controversially discussed as models of depression and anxiety. It furthermore illustrates the potential of environment to serve as naturalistic stressor with the potential to modulate the phenotype in wildtype and mutant mice. Moreover, environment may exert protective effects by regulating BDNF levels as attributed to "environmental enrichment". The effect of this beneficial condition will also be discussed with regard to probable "curative/therapeutic" approaches.
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Affiliation(s)
- Sabine Chourbaji
- Central Institute of Mental Health Mannheim (ZI), University of Heidelberg, Germany.
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Abstract
This paper is the 31st consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2008 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).
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Affiliation(s)
- Richard J Bodnar
- Department of Psychology and Neuropsychology Doctoral Sub-Program, Queens College, City University of New York, 65-30 Kissena Blvd, Flushing, NY 11367, United States.
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