Treadmill exercise training inhibits morphine CPP by reversing morphine effects on GABA neurotransmission in D2-MSNs of the accumbens-pallidal pathway in male mice.

Relapse is a major challenge in the treatment of drug addiction, and exercise has been shown to decrease relapse to drug seeking in animal models. However, the neural circuitry mechanisms by which exercise inhibits morphine relapse remain unclear. In this study, we report that 4-week treadmill training prevented morphine conditioned place preference (CPP) expression during abstinence by acting through the nucleus accumbens (NAc)-ventral pallidum (VP) pathway. We found that neuronal excitability was reduced in D2-dopamine receptor-expressing medium spiny neurons (D2-MSNs) following repeated exposure to morphine and forced abstinence. Enhancing the excitability of NAc D2-MSNs via treadmill training decreased the expression of morphine CPP. We also found that the effects of treadmill training were mediated by decreasing enkephalin levels and that restoring opioid modulation of GABA neurotransmission in the VP, which increased neurotransmitter release from NAc D2-MSNs to VP, decreased morphine CPP. Our findings suggest the inhibitory effect of exercise on morphine CPP is mediated by reversing morphine-induced neuroadaptations in the NAc-to-VP pathway.