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.
Highlights
Motivation is a complex process that involves multiple behavioral functions and neural circuits [1,2,3,4]
The adenosine A2A antagonist MSX-3 was synthesized in the laboratory of Christa Muller (University of Bonn, Bonn, Germany) and was dissolved in 0.9% saline solution and pH adjusted with 1N NaOH to a final pH of 7.4
Repeated measures ANOVA revealed a significant effect of treatment on total lever presses (F[4,12] = 4.950, p,0.05) in high responders, and planned comparisons revealed that both 1.0 and 2.0 mg/kg doses of MSX-3 were significantly higher than TBZ alone
Summary
Motivation is a complex process that involves multiple behavioral functions and neural circuits [1,2,3,4]. In the last few years, there has been growing interest in the neural circuitry underlying effort-based processes, both in animals [2,5,9,10,11,12,13,14,15] and humans [16,17,18,19,20]. Forebrain circuits regulating exertion of effort and effort-related choice behavior involve several structures, including basolateral amygdala and prefrontal/anterior cingulate cortex [10,14,21], ventral pallidum [13,22], and nucleus accumbens [5,15,23,24,25,26]
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