Cocaine-Enhanced Enkephalin Gates Plasticity of Distinct Striatal Synapses and Facilitates Cue-Induced Cocaine-Seeking During Abstinence

Background: Cocaine seeking after abstinence is associated with increased ventral pallidum (VP) activity. This increase appears to involve an opioid peptide that suppresses GABA release from D2 receptor-expressing medium spiny neurons (D2-MSNs) to the VP, but its identity is unclear. We previously found that cocaine abstinence increases enkephalin mRNA expression in D2-MSNs and that exogenous enkephalin inhibits GABA release from these neurons. We therefore hypothesized that cocaine-enhanced enkephalin release from D2-MSNs suppresses GABA release into the VP, which disinhibits VP neurons and promotes cocaine seeking. Methods: To examine how enkephalin alters striatal circuit plasticity and cocaine seeking following abstinence, we performed ex vivo electrophysiology and cocaine self-administration in mice lacking enkephalin selectively from D2-MSNs (D2-PenkKO). Recordings were obtained from the primary D2-MSNs targets : VP neurons and D1 receptor-expressing MSNs (D1-MSNs). Results: Following cocaine abstinence, GABA release from D2-MSNs to VP neurons was reduced in controls, but not D2-PenkKOs. In contrast, cocaine abstinence did not alter GABA release to D1-MSNs. Optogenetically evoked GABA release from D2-MSNs inhibited VP neuron firing in saline-abstinent controls and D2-PenkKOs, but not cocaine-abstinent controls. Female, but not male, D2-PenkKOs self-administered less cocaine in early acquisition and exhibited blunted cue-induced cocaine seeking after abstinence. Conclusion: Abstinence from cocaine self-administration increases D2-MSN enkephalin expression, leading to auto-inhibition of GABA release onto VP neurons, but not D1-MSNs, thereby selectively disinhibiting VP neuron activity. These findings identify enkephalin as a key mediator of cocaine abstinence-induced striatopallidal circuit plasticity and suggest that this plasticity contributes to cocaine seeking following abstinence.