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PLoS One. 2014 Jun 17;9(6):e99320. doi: 10.1371/journal.pone.0099320. eCollection 2014.

The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs.

Author information

1
Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.
2
Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States of America.
3
Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie, Universität Bonn, Bonn, Germany; Department of Chemistry, Faculty of Science, Sultan Qaboos University, Muscat, Oman.
4
Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie, Universität Bonn, Bonn, Germany.
5
Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America; Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, Castelló, Spain.

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.

PMID:
24937131
PMCID:
PMC4061002
DOI:
10.1371/journal.pone.0099320
[Indexed for MEDLINE]
Free PMC Article
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