The dopamine depleting agent tetrabenazine alters effort-related decision making as assessed by mouse touchscreen proced
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ORIGINAL INVESTIGATION
The dopamine depleting agent tetrabenazine alters effort-related decision making as assessed by mouse touchscreen procedures Jen-Hau Yang 1 & Rose E. Presby 1 & Renee A. Rotolo 1 & Taina Quiles 1 & Kevin Okifo 1 & Emma Zorda 1 & Roslyn Holly Fitch 1 & Mercè Correa 1,2 & John D. Salamone 1 Received: 14 April 2020 / Accepted: 1 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Motivation . Dopamine . Schizophrenia . Bussey-Saksida chambers . Panel pressing . Preference test
Introduction Motivated behaviors are directed towards or away from particular stimuli, but they also are characterized by a high degree of behavioral activation, vigor, speed, and persistence (Salamone and Correa 2002, 2012). To overcome obstacles separating them from significant stimuli, organisms frequently make effort-related decisions based upon cost/benefit analyses. Motivational deficits such as anergia, psychomotor retardation, apathy, fatigue, and low-effort bias are a major group
* John D. Salamone [email protected] 1
Behavioral Neuroscience Division, Department of Psychological Sciences, University of Connecticut, Storrs, CT, USA
2
Area de Psicobiologia, Universitat Jaume I, Castelló, Spain
of symptoms commonly seen in major depression, schizophrenia
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