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

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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-h/day) during early (days 1–7), late (days 8–14), and throughout abstinence (days 1–14) to sedentary conditions on cocaine-seeking and gene expression in the dmPFC and NAc core of male rats tested following 24-h/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 receptor5 (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.

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Funding

This research was supported by NIDA R01 grants DA039093 and DA024716 (WJL).

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Authors and Affiliations

  1. Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, USA

    Jean M. Abel, Tanseli Nesil, Anousheh Bakhti-Suroosh & Wendy J. Lynch

  2. Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA

    Patrick A. Grant

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  1. Jean M. Abel
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  2. Tanseli Nesil
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  3. Anousheh Bakhti-Suroosh
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  4. Patrick A. Grant
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Correspondence to Wendy J. Lynch.

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Abel, J.M., Nesil, T., Bakhti-Suroosh, A. et al. Mechanisms underlying the efficacy of exercise as an intervention for cocaine relapse: a focus on mGlu5 in the dorsal medial prefrontal cortex. Psychopharmacology 236, 2155–2171 (2019). https://doi.org/10.1007/s00213-019-05208-0

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