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

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 decisionmaking 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.

Impact of Fluoxetine on Behavioral Invigoration of Appetitive and Aversively Motivated Responses: Interaction With Dopamine Depletion

“…These results obtained from animal studies are consistent with clinical data showing a reduced selection of high effort alternatives in depressed people tested on tasks of effort-based choice (Treadway et al, 2012;Chong et al, 2016). Administration of the vesicular monoamine transporter (VMAT-2) inhibitor tetrabenazine (TBZ), which blocks the monoamine storage and leads to a striatal DA depletion at low doses in primates (Pettibone et al, 1984), rats (Nunes et al, 2013;Podurgiel et al, 2015Podurgiel et al, , 2016Yohn et al, 2015b), and mice (López-Cruz et al, 2018;Carratalá-Ros et al, 2020) has been used to induce effort-related motivational impairments in rodents (Nunes et al, 2014;Yohn et al, 2015bYohn et al, , 2016bCorrea et al, 2018;López-Cruz et al, 2018;Rotolo et al, 2019;Carratalá-Ros et al, 2020). This drug is used in the treatment of Huntington's disease and has been reported to produce depressive symptoms including fatigue in people (Frank, 2009;Guay, 2010).…”

“…This drug is used in the treatment of Huntington's disease and has been reported to produce depressive symptoms including fatigue in people (Frank, 2009;Guay, 2010). Recently, we have also demonstrated that TBZ induces depressive symptoms in the forced swim test (FST); mice show less vigorous scaping behaviors and increase immobility (Carratalá-Ros et al, 2020).…”

“…Thus, some studies have focused upon different tasks involving effort-based decision-making that offer rodents the possibility of choosing between high-effort instrumental actions leading to more valued reinforcers or to choose the low-effort options leading to less valued reinforcers. Conditions associated with depression, including stress (Shafiei et al, 2012;Floresco, 2016, 2019) and pro-inflammatory cytokines (Nunes et al, 2014;Goldsmith et al, 2016;Yohn et al, 2016a), as well as dopamine (DA) receptor antagonism (Pardo et al, 2012(Pardo et al, , 2015Yohn et al, 2015a;Correa et al, 2016;Yang et al, 2020) or DA depletion (Nunes et al, 2013;Randall et al, 2014;Yohn et al, 2015b;López-Cruz et al, 2018;Rotolo et al, 2019;Carratalá-Ros et al, 2020) can affect effort-related decision-making and bias animals towards the low effort options. These results obtained from animal studies are consistent with clinical data showing a reduced selection of high effort alternatives in depressed people tested on tasks of effort-based choice (Treadway et al, 2012;Chong et al, 2016).…”

“…Willingness to do effort can also be studied in a recreational context in which there is no stress from which to escape, and no work required to obtain a meal. Thus, voluntary vigorous wheel running was used in a recently developed T-maze choice task as the high effort/highly preferred option (Correa et al, 2016;López-Cruz et al, 2018;Carratalá-Ros et al, 2020).…”

Sedentary time is related to deficits in response inhibition among adults with overweight and obesity: An accelerometry and event‐related brain potentials study

“…On the neurofunctional level, administration of methylphenidate (a drug used to manage symptoms of ADHD with dual action on dopamine and norepinephrine pathways) increased neural activation in brain regions supporting response inhibition (cingulate gyrus, medial frontal gyrus, temporal and frontal gyri; Kasparbauer et al, 2015). These findings suggest that modulation of the DA2 receptor activity may have a shared influence over the preference for sedentary activity (Carratalá-Ros et al, 2020;Correa et al, 2020;López-Cruz et al, 2018) and impulsivity (Costa et al, 2013;Kasparbauer et al, 2015;Nandam et al, 2013;Weber et al, 2016). However, the role of sedentary behavior in the regulation of dopamine availability in humans remains unexplored.…”