Mechanisms underlying the efficacy of exercise as an intervention for cocaine relapse: a focus on mGlu5 in the dorsal medial prefrontal cortex

Abstract

Rationale-Exercise shows promise as a treatment option for addiction, but in order to prevent relapse, it may need to be introduced early in the course of treatment. Objective-We propose that exercise, by upregulating dorsal medial prefrontal cortex (dmPFC)nucleus accumbens (NAc) transmission, offsets deficits in pathways targeting glutamate, BDNF, and dopamine during early abstinence, and in doing so, normalizes neuroadaptations that underlie relapse. Methods-We compared the effects of exercise (wheel-running, 2-hr/day) during early (days 1-7), late (days 8-14), and throughout abstinence (days 1-14) to sedentary conditions on cocaineseeking and gene expression in the dmPFC and NAc core of male rats tested following 24-hr/day extended-access cocaine (up to 96 infusions/day) or saline self-administration and protracted abstinence (15 days). Based on these data, we then used site-specific manipulation to determine whether dmPFC metabotropic glutamate receptor-5 (mGlu5) underlies the efficacy of exercise. Results-Exercise initiated during early, but not late abstinence, reduced cocaine-seeking; this effect was strongly associated with dmPFC Grm5 expression (gene encoding mGlu5), and modestly associated with dmPFC Grin1 and Bdnf-IV expression. Activation of mGlu5 in the dmPFC during early abstinence mimicked the efficacy of early-initiated exercise; however, inhibition of these receptors prior to the exercise sessions did not block its efficacy indicating that there may be redundancy in the mechanisms through which exercise reduces cocaine-seeking. Conclusion-These findings indicate that addiction treatments, including exercise, should be tailored for early versus late phases of abstinence since their effectiveness will vary over abstinence due to the dynamic nature of the underlying neuroadaptations.

Association between self-reported empathy and level of physical activity in healthy young adults

“…An earlier study proposed that self-reported cognitive empathy indicates a significant positive correlation with the local gray matter density in the cingulate cortex and dorsal medial prefrontal cortex 15) . Since there is a possibility that an increase in physical activity enhances neuronal plasticity in the brain regions mentioned above 16,17) , it is assumed that physical activity in healthy young adults is related to self-reported cognitive empathy. Also, there is a possibility that the genotype of the G protein coupled receptor family, including the arginine-vasopressin receptor 1a, modulates cognitive empathy 18,19) , therefore, we should investigate whether the individual differences of genotype have an influence on the relationship of physical activity with cognitive empathy or not.…”

Aerobic exercise as a promising nonpharmacological therapy for the treatment of substance use disorders

“…After 21 days of free access running wheel in a 24-hr two-bottle choice paradigm, adolescent female mice decreased ethanol consumption and preference (Gallego et al, 2015). Also, after cessation of voluntary exercise (running wheels), socially isolated adolescent rats increased ethanol consumption compared with controls (Lynch et al, 2019).…”

“…Exercise during cocaine withdrawal decreased cue‐induced cocaine‐seeking behavior and vulnerability to relapse (Zlebnik & Carroll, 2015a). Importantly, exercise during early cocaine withdrawal was found to reduce cocaine‐seeking behavior, but that effect was not obtained during later stages of withdrawal (Abel et al, 2019; Beiter et al, 2016). In addition, progesterone pretreatment (0.5 mg/kg subcutaneous) and aerobic exercise combined appear to be effective at reducing cocaine‐seeking behavior (Zlebnik et al, 2014).…”

“…Exercise also alters drug-induced impairment of neurogenesis, serotonergic and dopaminergic systems, integrity of bloodbrain barrier, and immune system, among others. However, the molecular/physiological mechanisms by which exercise induces all these changes remain undetermined (Abel et al, 2019;Mustroph et al, 2015;Ogbonmwan et al, 2015;Thanos et al, 2013). Clearly,…”

“…Several studies have shown that aerobic exercise alters cocaine‐induced molecular changes in the brain. Rodents exposed to cocaine with aerobic exercise exhibit increased prefrontal levels of extracellular signal‐regulated kinase signaling (ERK), BDNF, metabotropic receptor subunit gene GRM5, and N ‐methyl‐ d ‐aspartate (NMDA) receptor gene subunit Grin1, preventing drug‐seeking behavior (Abel et al., 2019; Lynch et al., 2010; Mustroph et al., 2015; Ogbonmwan et al., 2015; Smith et al., 2012; Thanos et al., 2013; Zlebnik & Carroll, 2015a). Similar results have been seen during involuntary exercise, where rats decreased cocaine consumption and BDNF levels in the NAc after resistance exercise (ladder climbing) (Strickland et al., 2016).…”