PT  - JOURNAL ARTICLE
AU  - Nunes, Eric J.
AU  - Randall, Patrick A.
AU  - Hart, Evan E.
AU  - Freeland, Charlotte
AU  - Yohn, Samantha E.
AU  - Baqi, Younis
AU  - Müller, Christa E.
AU  - López-Cruz, Laura
AU  - Correa, Mercè
AU  - Salamone, John D.
TI  - Effort-Related Motivational Effects of the VMAT-2 Inhibitor Tetrabenazine: Implications for Animal Models of the Motivational Symptoms of Depression
AID  - 10.1523/JNEUROSCI.2730-13.2013
DP  - 2013 Dec 04
TA  - The Journal of Neuroscience
PG  - 19120--19130
VI  - 33
IP  - 49
4099  - http://www.jneurosci.org/content/33/49/19120.short
4100  - http://www.jneurosci.org/content/33/49/19120.full
SO  - J. Neurosci.2013 Dec 04; 33
AB  - 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.