Matsumura, K.; Lyuboslavsky, P.; Nicot, A.; Dobbs, L. K.

Abstinence from repeated cocaine exposure is associated with reduced GABA release from striatal medium spiny neurons that express D2 dopamine receptors (D2-MSN) and project to the ventral pallidum (VP). As a consequence, VP principle neuronal activity is increased and drives cocaine seeking. Abstinence from cocaine is also associated with increased expression of enkephalin in D2-MSNs. This study tested the hypothesis that release of enkephalin from D2-MSNs during cocaine abstinence inhibits GABA release from these same neurons and thereby drives VP excitation. To test this hypothesis, we used mice with conditional knockout of Penk, which encodes enkephalin, in D2-MSNs (D2-PenkKO mice). Cocaine abstinence was associated with reduced GABA release from D2-MSNs to the VP in ex vivo 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.