The dopamine depleting agent tetrabenazine alters effort-related decision making as assessed by mouse touchscreen procedures

Abstract

Rationale Effort-based decision-making tasks allow animals to choose between preferred reinforcers that require high effort to obtain vs. low-effort/low reward options. Mesolimbic dopamine (DA) and related neural systems regulate effort-based choice. Tetrabenazine (TBZ) is a vesicular monoamine transport type-2 inhibitor that blocks DA storage and depletes DA. In humans, TBZ induces motivational dysfunction and depression. TBZ has been shown reliably to induce a low-effort bias in rats, but there are fewer mouse studies. Objectives The present studies used touchscreen operant procedures (Bussey-Saksida chambers) to assess the effects of TBZ on effort-based choice in mice. Methods C57BL6 mice were trained to press an elevated lit panel on the touchscreen on a fixed ratio 1 schedule reinforced by strawberry milkshake, vs. approaching and consuming a concurrently available but less preferred food pellets (Bio-serv). Results TBZ (2.0–8.0 mg/kg IP) shifted choice, producing a dose-related decrease in panel pressing but an increase in pellet intake. In contrast, reinforcer devaluation by pre-feeding substantially decreased both panel pressing and pellet intake. In freefeeding choice tests, mice strongly preferred the milkshake vs. the pellets, and TBZ had no effect on milkshake intake or preference, indicating that the TBZ-induced low-effort bias was not due to changes in primary food motivation or preference. TBZ significantly decreased tissue levels of nucleus accumbens DA. Conclusion The DA depleting agent TBZ induced an effort-related motivational dysfunction in mice, which may have clinical relevance for assessing novel drug targets for their potential use as therapeutic agents in patients with motivation impairments.