title: Mouse psychosocial stress reduces motivation and cognitive function in operant reward tests: A model for reward pathology with effects of agomelatine.
abstract: A major domain of depression is decreased motivation for reward. Translational automated tests can be applied in humans and animals to study operant reward behaviour, aetio-pathophysiology underlying deficits therein, and effects of antidepressant treatment. Three inter-related experiments were conducted to investigate depression-relevant effects of chronic psychosocial stress on operant behaviour in mice. (A) Non-manipulated mice were trained on a complex reversal learning (CRL) test with sucrose reinforcement; relative to vehicle (VEH), acute antidepressant agomelatine (AGO, 25mg/kg p.o.) increased reversals. (B) Mice underwent chronic social defeat (CSD) or control handling (CON) on days 1-15, and were administered AGO or VEH on days 10-22. In a progressive ratio schedule motivation test for sucrose on day 15, CSD mice made fewer responses; AGO tended to reverse this effect. In a CRL test on day 22, CSD mice completed fewer reversals; AGO tended to increase reversals in CSD mice associated with an adaptive increase in perseveration. (C) Mice with continuous operant access to water and saccharin solution in the home cage were exposed to CSD or CON; CSD mice made fewer responses for saccharin and water and drank less saccharin in the active period, and drank more water in the inactive period. In a separate CSD cohort, repeated AGO was without effect on these home cage operant and consummatory changes. Overall, this study demonstrates that psychosocial stress in mice leads to depression-relevant decreases in motivation and cognition in operant reward tests; partial reversal of these deficits by AGO provides evidence for predictive validity.
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Zurich, Switzerland.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bergamini
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Flurin
authors.initials: F
authors.lastname: Cathomas
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Auer
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Sigrist
authors.affiliation: Neuroscience Center, University and ETH Zurich, Zurich, Switzerland; Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland.
authors.forename: Erich
authors.initials: E
authors.lastname: Seifritz
authors.affiliation: Department of Life Sciences, University of Roehampton, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Patterson
authors.affiliation: Institut de Recherches Internationales Servier (IRIS), Suresnes, France.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gabriel
authors.affiliation: Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Zurich, Switzerland. Electronic address: christopher.pryce@bli.uzh.ch.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pryce
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D057205:Automation, Laboratory; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D003216:Conditioning, Operant / Q000187:drug effects*; D019422:Dietary Sucrose; D004291:Dominance-Subordination; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008550:Melatonin / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009042:Motivation / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D012193:Reversal Learning / Q000187:drug effects; D012201:Reward; D012439:Saccharin; D012702:Serotonin Antagonists / Q000494:pharmacology; D013315:Stress, Psychological / Q000188:drug therapy*; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000928:Antidepressive Agents; D019422:Dietary Sucrose; D007211:Indoles; D008550:Melatonin; D011725:Pyridines; D044405:Receptor, Serotonin, 5-HT2C; D012439:Saccharin; D012702:Serotonin Antagonists; C000599853:5-hydroxytryptamine2C receptor, mouse; C533966:S32006; C084711:agomelatine; D009281:Naphthalenes
keywords: Agomelatine; Animal model; Circadian rhythm; Decreased motivation; Depression; Operant