Opioid receptors have been a target of pharmacological manipulation in alcohol use disorder (AUD) recovery protocols for many years. Aerobic exercise, a common adjunct in AUD recovery, is known to modulate opioid receptors (ORs) both during both acute and long term exposure. The three subtypes of ORs: mu (MOR), delta (DOR), and kappa (KOR) are all expressed on neurons in the mesocorticolimbic circuitry. Kappa-opioid receptors are expressed directly on dopamine (DA) neuron terminals in the nucleus accumbens (NAc). Mu and Delta ORs are expressed on cholinergic interneurons (CINs) and GABA neurons in the NAc. In alcohol dependent rodents, KORs are hypersensitized. It is theorized that this hypersensitization contributes to EtOH seeking behavior. In contrast, aerobic exercise desensitizes the KORs. Given the high degree of pharmacological overlap between opioid receptors, it is also hypothesized that EtOH and aerobic exercise may have effects on MORs and DORs as well. Here, it is investigated whether a routine of voluntary aerobic exercise decreases EtOH induced changes to KOR modulation of dopamine (DA) release in the nucleus accumbens (NAc) along with possible mechanisms through which this might occur. The responsiveness of MORs and DORs in EtOH dependence, and how aerobic exercise modulates those effects is also investigated. Exercise attenuated EtOH induced hypersensitization of KORs in the NAc. Exercise decreases expression of KORs, which may account for the changes in KOR sensitization. The MOR agonist DAMGO decreased DA reuptake ex vivo, but not signal amplitude while DOR agonist DPDPE had no effect on either reuptake or signal amplitude. Overall, dependent animals that were allowed to exercise, consumed less EtOH in a drinking in the dark model. These data suggest that exercise is a useful adjunct to AUD recovery protocols, and that its effects are likely mediated by KORs. The findings related to MORs and DORs suggest that MORs, but not DORs, may act through acetyl choline receptors to modulate DA reuptake in the NAc, however much more work is needed to characterize this effect.



College and Department

Life Sciences; Neuroscience



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alcohol, aerobic exercise, opioid receptor, cholinergic interneuron, nucleus accumbens