title: Effort-related motivational effects of the VMAT-2 inhibitor tetrabenazine: implications for animal models of the motivational symptoms of depression.
abstract: Motivated behaviors are often characterized by a high degree of behavioral activation, and work output and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with major depression and other disorders often show effort-related motivational symptoms such as anergia, psychomotor retardation, and fatigue. It has been suggested that tasks measuring effort-related choice behavior could 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) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, because of its selective inhibition of VMAT-2, it preferentially depletes dopamine (DA). Rats were assessed using a concurrent fixed-ratio 5/chow feeding choice task that is known to be sensitive to dopaminergic manipulations. Tetrabenazine shifted response choice in rats, producing a dose-related decrease in lever pressing and a concomitant increase in chow intake. However, it did not alter food intake or preference in parallel free-feeding choice studies. The effects of tetrabenazine on effort-related choice were reversed by the adenosine A2A antagonist MSX-3 and the antidepressant bupropion. A behaviorally active dose of tetrabenazine decreased extracellular DA in nucleus accumbens and increased expression of DARPP-32 in accumbens medium spiny neurons in a pattern indicative of reduced transmission at both D1 and D2 DA receptors. These experiments demonstrate that tetrabenazine, which is used in animal models to produce depression-like effects, can alter effort-related choice behavior. These studies have implications for the development of animal models of the motivational symptoms of depression and related disorders.
authors.affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut 06269-1020, Universität Bonn, Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie, 53121 Bonn, Germany, and Àrea de Psicobiologia, Campus de Riu Sec, Universitat Jaume I, 12071 Castelló, Spain.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nunes
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Randall
authors.forename: Evan E
authors.initials: EE
authors.lastname: Hart
authors.forename: Charlotte
authors.initials: C
authors.lastname: Freeland
authors.forename: Samantha E
authors.initials: SE
authors.lastname: Yohn
authors.forename: Younis
authors.initials: Y
authors.lastname: Baqi
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Laura
authors.initials: L
authors.lastname: López-Cruz
authors.forename: Mercè
authors.initials: M
authors.lastname: Correa
authors.forename: John D
authors.initials: JD
authors.lastname: Salamone
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D016642:Bupropion / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003863:Depression / Q000523:psychology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D017551:Microdialysis; D009042:Motivation / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000378:metabolism; D013747:Tetrabenazine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors*; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D018759:Adrenergic Uptake Inhibitors; D018687:Antidepressive Agents, Second-Generation; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004745:Enkephalins; C113602:MSX 3 compound; C497930:Ppp1r1b protein, rat; D016760:Proto-Oncogene Proteins c-fos; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D014970:Xanthines; D016642:Bupropion; D013373:Substance P; D004298:Dopamine; D013747:Tetrabenazine
keywords: DAT inhibitor; basal ganglia; decision making; motivation; negative symptoms; vigor