Preference for Exercise vs. More Sedentary Reinforcers: Validation of an Animal Model of Tetrabenazine-Induced Anergia.

Carla Carratalá-Ros,Laura López-Cruz,Patricia Ibáñez-Marín,John D Salamone,Mercè Correa,Andrea Martínez-Verdú,Noemí Sanmiguel

doi:10.3389/fnbeh.2019.00289

Carla Carratalá-Ros, Laura López-Cruz + Show 5 more

Open Access

https://doi.org/10.3389/fnbeh.2019.00289

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Abstract

Physical activities can have intrinsic motivational or reinforcing properties. The choice to engage in voluntary physical activity is undertaken in relation to the selection of other alternatives, such as sedentary behaviors, drugs, or food intake. The mesolimbic dopamine (DA) system plays a critical role in behavioral activation or exertion of effort, and DA antagonism or depletion induces anergia in effort-based decision-making tasks. However, little is known about the neural mechanisms underlying the decision-making processes that establish preferences for sedentary vs. activity-based reinforcers. In the present work with male CD1 mice, we evaluated the effect of tetrabenazine (TBZ), a DA-depleting agent, on a three-choice T-maze task developed to assess preference between reinforcers with different behavioral activation requirements and sensory properties [i.e., a running wheel (RW) vs. sweet pellets or a neutral nonsocial odor]. We also studied the effects of TBZ on the forced swim test (FST), which measures climbing and swimming in a stressful setting, and on anxiety tests [dark-light (DL) box and elevated plus maze (EPM)]. In the three-choice task, TBZ reduced time running in the wheel but increased time spent consuming sucrose, thus indicating reduced activation but relatively intact sucrose reinforcement. The effect of TBZ was not mimicked by motivational manipulations that change the value of the reinforcers, such as making the RW aversive or harder to move, food-restricting the animals, inducing a binge-like eating pattern, or introducing social odors. In the FST, TBZ decreased time climbing (most active behavior) and increased immobility but did not affect anxiety in the DL or EPM. These results indicate that the three-choice T-maze task could be useful for assessing DA modulation of preferences for exercise based on activation and effort requirements, differentiating those effects from changes in preference produced by altering physical requirements, food restriction state, and stress during testing.

Highlights

Motivated behavior is characterized by a high degree of behavioral activation, as demonstrated by the speed, vigor, or persistence seen in the instigation and maintenance of instrumental responding (Salamone and Correa, 2002, 2012; Robbins and Everitt, 2007; Mai et al, 2012; McGinty et al, 2013; Floresco, 2015)
TBZ acts by inhibiting the vesicular monoamine transporter-type 2 (VMAT-2), which leads to a blockade of vesicular storage and a depletion of monoamines, with its greatest effects at low doses being on striatal DA in rats and mice (Pettibone et al, 1984; Nunes et al, 2013; López-Cruz et al, 2018)
We explored the impact of a broad range of TBZ doses that have been demonstrated to deplete accumbens DA in mice (López-Cruz et al, 2018), comparing its impact on different measures of behavioral activation induced by stressful conditions (FST) or by spontaneous preference for physical activity in the T-maze choice task

Summary

Introduction

Motivated behavior is characterized by a high degree of behavioral activation, as demonstrated by the speed, vigor, or persistence seen in the instigation and maintenance of instrumental responding (Salamone and Correa, 2002, 2012; Robbins and Everitt, 2007; Mai et al, 2012; McGinty et al, 2013; Floresco, 2015). Diverse tasks have been used in rodents for evaluating behavioral activation and effort-related decision making, including tasks that give animals the option of vigorously working (lever pressing or climbing a barrier) to obtain access to more highly valued reinforcers vs approaching and consuming a less preferred reinforcer (Cousins et al, 1994; Salamone and Correa, 2002; Salamone et al, 2016; Mott et al, 2009; Mai et al, 2012; Pardo et al, 2012, 2015; Randall et al, 2012; Sommer et al, 2014; Yohn et al, 2015a, 2016b; Correa et al, 2018; SanMiguel et al, 2019) In these tasks, conditions that alter DA transmission, such as administration of DA antagonists or tetrabenazine (TBZ), can alter behavioral activation and reduce selection of high-effort choices in rats (Nunes et al, 2013; Randall et al, 2014; Hosking et al, 2015; Pardo et al, 2015; Yohn et al, 2015a, 2016a,b; Contreras-Mora et al, 2018; Rotolo et al, 2019). TBZ administered chronically in a mouse model of Huntington’s disease (Wang et al, 2010) improved motor deficits but increased depression-like measures in the forced swim test (FST)

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