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 A 2A 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 D 1 and D 2 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.Key words: decision making; vigor; motivation; negative symptoms; basal ganglia; DAT inhibitor IntroductionTo survive, organisms must overcome obstacles separating them from motivational stimuli and make effort-related decisions based upon cost/benefit analyses Correa, 2002, 2012). There is considerable interest in characterizing the neural circuitry underlying effort-based processes in animals (Salamone et al., 1997 Walton et al., 2003; Cagniard et al., 2006;Floresco and Ghods-Sharifi, 2007; Hauber and Sommer, 2009;Salamone and Correa, 2012; Nunes et al., 2013a;Pasquereau and Turner, 2013) and humans (Croxson et al., 2009;Kurniawan et al., 2010; Wardle et al., 2011;Treadway et al., 2012a). Effort-based decision making is studied with tasks offering choices between high effort options leading to highly valued reinforcers versus low effort/low reward options. In animal studies, such tasks include operant procedures offering choices between responding on ratio schedules for preferred reinforcers versus approaching and consuming a less preferred food (Salamone et al., , 2002, a T-maze barrier crossing task Mott et al., 2009;, and effort discounting Bardgett et al., 2009). Considerable research has focused on the ...

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“…The same pattern of results has been observed in different effort-choice tasks using D2 antagonists combined with the non-selective (A1/A2A) antagonists caffeine and theophylline . These agents restored totally or partially the shift on the choice behavior from the low effort/low reward option to the high effort/high reward option induced by a DA antagonist or DA depletor in concurrent choice tasks Nunes et al, 2013;. Consistent with these results, A2A KO mice were protected from the anergia-like effects induced by the DA D2 antagonist haloperidol .…”

“…Adenosine receptors and DA receptors interact at the cellular level Salamone et al, 2010;Santerre et al, 2012;Nunes et al, 2013).…”

“…Some of these studies have also focused on the effects of this interaction at the intracellular level (Santerre et al, 2012;Nunes et al, 2013;Svenningson et al, 1999).…”

“…Enkephalinergic MSNs predominantly express dopamine D2 and A2A receptors, while dynorphinergic MSNs, which also express the peptide substance P, predominantly express dopamine D1 receptors and adenosine receptors of the A1 subtype . DARPP-32 is phosphorylated after activation of D1-A1 or D2-A2A receptors and can be used as an index of DA activation (Svenningsson et al, 1997(Svenningsson et al, , 2004Nunes et al, 2013). DARPP-32 function depends on its relative state of phosphorylation at two main regulatory sites, threonine 34 and 75 (Thr34 and Thr75).…”

“…In this sense, adenosine A2A agonists have been shown to induce effects that resemble those produced by DA antagonists or DA depletions, inducing anergia-like effects in an effort-based decision making task , whereas selective adenosine antagonists of A2A receptors (and to a much lesser extent of A1 receptors), have been shown to attenuate anergia-like effects induced by DA antagonists or depletors Nunes et al, 2013;Yohn et al, 2015). In this regard, a selective A2A receptor antagonist MSX-3 reversed the anergia-like effects induced by a DA depletor agent (tetrabenazine, TBZ) in concurrent operant /chow feeding choice tasks and in a T-maze barrier task (Nunes et al, 2013;Yohn et al, 2015). The same pattern of results has been observed in different effort-choice tasks using D2 antagonists combined with the non-selective (A1/A2A) antagonists caffeine and theophylline .…”