Voluntary wheel running reduces voluntary consumption of ethanol in mice: identification of candidate genes through striatal gene expression profiling

Abstract

Hedonic substitution, where wheel running reduces voluntary ethanol consumption has been observed in prior studies. Here we replicate and expand on previous work showing that mice decrease voluntary ethanol consumption and preference when given access to a running wheel. While earlier work has been limited mainly to behavioral studies, here we assess the underlying molecular mechanisms that may account for this interaction. From four groups of female C57BL/6J mice (control, access to two-bottle choice ethanol, access to a running wheel, and access to both two-bottle choice ethanol and a running wheel), mRNA-sequencing of the striatum identified differential gene expression. Many genes in ethanol preference quantitative trait loci were differentially expressed due to running. Furthermore, we conducted Weighted Gene Co-expression Network Analysis and identified gene networks corresponding to each effect behavioral group. Candidate genes for mediating the behavioral interaction between ethanol consumption and wheel running include multiple potassium channel genes, Oprm1, Prkcg, Stxbp1, Crhr1, Gabra3, Slc6a13, Stx1b, Pomc, Rassf5, Polr2a, and Camta2. After observing an overlap of many genes and functional groups previously identified in studies of initial sensitivity to ethanol, we hypothesized that wheel running may induce a change in sensitivity, thereby affecting ethanol consumption. A behavioral study examining Loss of Righting Reflex to ethanol following exercise trended toward supporting this hypothesis. These data provide a rich resource for future studies that may better characterize the observed transcriptional changes in gene networks in response to ethanol consumption and wheel running.

Exercise as a Prevention for Substance Use Disorder: a Review of Sex Differences and Neurobiological Mechanisms

“…For example, continuous access to a wheel prior to and following each self-administration session prevents escalation of methamphetamine intake and decreases its reinforcing effects in male rats (9). Similar results have been obtained for the effects of concurrent wheel access on escalation of cocaine self-administration in adolescent female rats (44), and free-access alcohol consumption in female mice (38–39), indicating that exercise attenuates/blocks the development of features of substance use disorder. As in humans, however, effects on alcohol consumption in males are variable with results from one study showing decreased consumption (37), and another, showing no effect (39).…”

“…Recent studies also show that exercise can block drug use escalation (9,38–39,44). For example, continuous access to a wheel prior to and following each self-administration session prevents escalation of methamphetamine intake and decreases its reinforcing effects in male rats (9).…”

High motivation for exercise is associated with altered chromatin regulators of monoamine receptor gene expression in the striatum of selectively bred mice

“…Consistent with this idea is that mice do not need to run to acquire any necessary resources (food, mating, etc. When we compared our DEG list to another RNA-seq dataset comparing the effects of wheel running and alcohol consumption on striatal gene expression in C57BL/6J mice (Darlington et al 2016), we found no significant overlap (for effects of running, P = 0.304; alcohol, P = 0.602; and interaction, P = 0.813, hypergeometric tests). If running is rewarding, and we have uncovered pathways in the brain that are associated with high motivation for running reward, then our data may inform about molecular architecture of motivation in general, or in relation to other rewards.…”

Behavioral and neuronal interactions between exercise and alcohol: Sex and genetic differences

“…Numerous studies in rodents have provided evidence for an interaction between voluntary wheel running and alcohol consumption . In a recent review, Hallgreen et al pointed out that, “physical exercise is widely regarded as “medicine” for the prevention and treatment of myriad somatic health conditions.” However, the effectiveness of physical activity to treat AUDs remains understudied.…”

“…Several studies have investigated the effect of voluntary exercise on 2‐bottle choice (2BC) and 2‐hour limited access drinking in the dark (DID) alcohol paradigms using unlimited access to voluntary wheel running . In an early study, Crews et al used a typical 12 day 10% alcohol 2BC paradigm and reported no effect of voluntary wheel running on male C57BL/6J alcohol consumption (females were not tested).…”