Partial reversal of the effort-related motivational effects of tetrabenazinewith the MAO-B inhibitor deprenyl (selegiline): Implications for treatingmotivational dysfunctions

Abstract

People with depression and Parkinsonism frequently show effort-related motivational symptoms, such as an-ergia, psychomotor retardation, and fatigue. Tasks that assess effort-related choice are being used as animalmodels of these motivational symptoms. The present studies characterized the ability of monoamine oxidase(MAO) inhibitors with varying selectivity profiles to reverse the low effort bias induced by the monoaminestorage inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans, and because of itsselective inhibition of VMAT-2, it preferentially depletes DA at low doses. Effort-based decision making is stu-died with tasks o ffering choices between high effort options leading to highly valued reinforcers vs. low effort/low reward options. Tetrabenazine shifted choice behavior, reducing selection of fixed ratio 5 lever pressing, butincreasing intake of the concurrently available but less preferred lab chow. These effects of 0.75 mg/kg tetra-benazine were attenuated by co-administration of the MAO-B inhibitor deprenyl (selegiline). The ability ofdeprenyl to reverse the effects of tetrabenazine was marked by an inverted-U shaped dose response curve, withthe middle dose (2.5 mg/kg) being effective. In contrast, neither the MAO-A selective antagonist moclobemidenor the nonselective drug pargyline reversed the effects of tetrabenazine, and moclobemide decreased leverpressing when administered alone. Deprenyl was originally developed as an antiparkinsonian drug, but it alsohas been shown to have antidepressant effects in humans and induce antidepressant-like effects in classicalrodent models of depression. These studies have implications for the potential use of MAO-B inhibitors astreatments for the motivational symptoms of depression and Parkinsonism