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

striatal slices from control mice, but not from D2-PenkKO mice. Application of exogenous met-enkephalin inhibited GABA release in D2-PenkKO slices but not in cocaine-abstinent controls, because GABA release was already suppressed in control mice. Optogenetically-evoked GABA release from D2-MSNs inhibited VP excitability in saline-abstinent controls and D2-PenkKOs but not in cocaine-abstinent controls. Additionally, cocaine abstinence suppressed spontaneous firing in control VP neurons, potentially due to adaptive depolarization of their action potential threshold. Our data strongly implicate cocaine-induced autocrine release of enkephalin from D2-MSNs as a key mechanism for GABA plasticity that drives increased VP neuron excitability during cocaine abstinence. Significance Statement: GABA release from striatal D2 receptor-expressing medium spiny neurons (d2-MSNs) to the ventral pallidum restrains reward seeking. Following abstinence from long-term cocaine intake, however, GABA release becomes suppressed by an opioidergic mechanism, a form of synaptic plasticity implicated in increased cocaine seeking. The identity and source of the opioid peptide mediating this inhibition have remained unclear. Here, we show that enkephalin produced by D2-MSNs acts in an autocrine manner to reduce GABA release from these neurons, thereby disinhibiting downstream ventral pallidum neurons. Our findings identify D2-MSNs as the source and enkephalin as the opioid responsible for this striatal circuit plasticity. More broadly, this suggests a synaptic mechanism by which synthetic opioids may potentiate cocaine seeking and promote opioid-cocaine polysubstance use.