TY - JOUR
T1 - The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task
T2 - Reversal with antidepressant drugs
AU - Randall, Patrick A.
AU - Lee, Christie A.
AU - Nunes, Eric J.
AU - Yohn, Samantha E.
AU - Nowak, Victoria
AU - Khan, Bilal
AU - Shah, Priya
AU - Pandit, Saagar
AU - Vemuri, V. Kiran
AU - Makriyannis, Alex
AU - Baqi, Younis
AU - Müller, Christa E.
AU - Correa, Merce
AU - Salamone, John D.
N1 - Funding Information:
The present research was supported by a grant to J. Salamone from NIH/NIMH (MH094966). In addition, J. Salamone has received grants from Merck-Serrono, Pfizer, and Roche, and Shire, which has been used to support other research that is not included in the present manuscript. J. Salamone has also been a consultant for Merz and Shire, and serves on the Advisory Board for Shire. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
PY - 2014/6/17
Y1 - 2014/6/17
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0099320
DO - 10.1371/journal.pone.0099320
M3 - Article
C2 - 24937131
AN - SCOPUS:84903281190
SN - 1932-6203
VL - 9
JO - PLoS One
JF - PLoS One
IS - 6
M1 - e99320
ER -