The VMAT-2 Inhibitor Tetrabenazine Affects Effort-Related Decision Making in a Progressive Ratio/Chow Feeding Choice Task: Reversal with Antidepressant Drugs

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.

Opioidergic and dopaminergic modulation of cost/benefit decision-making in Long Evans Rats

“…Experiment 1 demonstrated that the DA D 2 receptor antagonist haloperidol, at both doses tested, decreased the breakpoint, number of lever presses, number of reinforcers obtained, and increased intake of freely available laboratory chow. Our results are in line with previous work that has carefully described the role of DA mechanisms on this lever pressing and chow feeding task [52,53,58]. DA antagonism and striatal depletions by 6-OHDA or tetrabenazine have been shown to decrease measures of lever pressing while resulting in compensatory increases in chow intake.…”

Not All Antidepressants Are Created Equal: Differential Effects of Monoamine Uptake Inhibitors on Effort-Related Choice Behavior

“…The dose of 0.75 mg/kg TBZ and 15.0 mg/kg bupropion were based on previous work from our laboratory (Nunes et al, 2013a;Randall et al, 2014;Yohn et al, 2015). The subthreshold doses of 0.05 mg/kg ECO and HAL were based on previous research (Sink et al, 2008).…”

“…Across multiple paradigms, low doses of DA antagonists and accumbens DA depletions reduce the tendency to work for high reward options and increase selection of low reward choices Correa 2002, 2012;Salamone et al, 2003Salamone et al, , 2007Floresco et al, 2008;Mai et al, 2012;Randall et al, 2012;Hosking et al, 2015). Recent studies have shown that reduced selection of high-effort alternatives in rodents is induced by manipulations associated with depression, including stress (Shafiei et al, 2012), proinflammatory cytokine administration , and injections of the vesicular monoamine transporter-type 2 (VMAT-2) inhibitor tetrabenazine (TBZ; Nunes et al, 2013;Randall et al, 2014;Yohn et al, 2015). TBZ induces depressive symptoms including fatigue in humans (Frank 2010), and recent studies show that this drug shifts choice behavior from high effort to low effort options at doses that do not impair intake of or preference for solid foods or sucrose, hedonic reactivity to sucrose, reference memory, or discrimination of reward magnitude (Nunes et al, 2013;Randall et al, 2014;Pardo et al, 2015;Yohn et al, 2015).…”

“…Recent studies have shown that reduced selection of high-effort alternatives in rodents is induced by manipulations associated with depression, including stress (Shafiei et al, 2012), proinflammatory cytokine administration , and injections of the vesicular monoamine transporter-type 2 (VMAT-2) inhibitor tetrabenazine (TBZ; Nunes et al, 2013;Randall et al, 2014;Yohn et al, 2015). TBZ induces depressive symptoms including fatigue in humans (Frank 2010), and recent studies show that this drug shifts choice behavior from high effort to low effort options at doses that do not impair intake of or preference for solid foods or sucrose, hedonic reactivity to sucrose, reference memory, or discrimination of reward magnitude (Nunes et al, 2013;Randall et al, 2014;Pardo et al, 2015;Yohn et al, 2015). These results from animal studies are consistent with clinical data showing that patients with major depression show reduced selection of high effort alternatives in tests of effort-based decision making (Treadway et al, 2012).…”

“…Bupropion, a catecholamine reuptake blocker that elevates extracellular DA and norepinephrine (NE; Hudson et al, 2012;Randall et al, 2015), has been shown to reverse the effort related effects of TBZ (Nunes et al, 2013;Randall et al, 2014;Yohn et al, 2015).…”