title: The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs.
abstract: Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of the effort-related deficits observed in depressed patients.
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Randall
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.
authors.forename: Christie A
authors.initials: CA
authors.lastname: Lee
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nunes
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.
authors.forename: Samantha E
authors.initials: SE
authors.lastname: Yohn
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.
authors.forename: Victoria
authors.initials: V
authors.lastname: Nowak
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.
authors.forename: Bilal
authors.initials: B
authors.lastname: Khan
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.
authors.forename: Priya
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.
authors.forename: Saagar
authors.initials: S
authors.lastname: Pandit
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States of America.
authors.forename: V Kiran
authors.initials: VK
authors.lastname: Vemuri
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Makriyannis
authors.affiliation: Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie, Universität Bonn, Bonn, Germany; Department of Chemistry, Faculty of Science, Sultan Qaboos University, Muscat, Oman.
authors.forename: Younis
authors.initials: Y
authors.lastname: Baqi
authors.affiliation: Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie, Universität Bonn, Bonn, Germany.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America; Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, Castelló, Spain.
authors.forename: Merce
authors.initials: M
authors.lastname: Correa
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.
authors.forename: John D
authors.initials: JD
authors.lastname: Salamone
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D001577:Benzophenones / Q000494:pharmacology; D016642:Bupropion / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002755:Choice Behavior / Q000187:drug effects*; D003863:Depression / Q000139:chemically induced / Q000188:drug therapy*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005247:Feeding Behavior / Q000187:drug effects*; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012457:Salicylamides / Q000494:pharmacology; D012642:Selegiline / Q000494:pharmacology; D013747:Tetrabenazine / Q000494:pharmacology*; D000077867:Tolcapone; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors*; D014970:Xanthines / Q000494:pharmacology
chemical_list: C529765:AM4113; D000928:Antidepressive Agents; D001552:Benzazepines; D001577:Benzophenones; D063387:Cannabinoid Receptor Antagonists; D018492:Dopamine Antagonists; C113602:MSX 3 compound; D009596:Nitrophenols; D011720:Pyrazoles; D012457:Salicylamides; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D014970:Xanthines; D016642:Bupropion; C058081:ecopipam; D012642:Selegiline; D000077867:Tolcapone; C045989:eticlopride; D013747:Tetrabenazine