, Volume 236, Issue 7, pp 2155–2171 | Cite as

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

  • Jean M. Abel
  • Tanseli Nesil
  • Anousheh Bakhti-Suroosh
  • Patrick A. Grant
  • Wendy J. LynchEmail author
Original Investigation



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.


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.


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.


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.


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.


Bdnf-IV Cocaine Exercise Grm5 mGlu5 dmPFC Relapse 


Funding information

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

Compliance with ethical standards

Competing interests

The authors declare no competing interests.

Correspondence and requests for materials should be addressed to

Supplementary material

213_2019_5208_MOESM1_ESM.docx (135 kb)
ESM 1 (DOCX 134 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Psychiatry and Neurobehavioral SciencesUniversity of VirginiaCharlottesvilleUSA
  2. 2.Department of Biochemistry and Molecular GeneticsUniversity of VirginiaCharlottesvilleUSA

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