Abstract
Millions of individuals globally meet the current diagnostic criteria for cocaine use disorder (CUD), and cocaine misuse contributes to thousands of overdose deaths every year in the United States. Current hypotheses suggest that cocaine misuse imparts a diminished ability for synaptic plasticity (i.e., drug-induced metaplasticity). This metaplasticity impairs adaptive learning, which has been proposed to contribute to the likelihood of cocaine relapse. Delineating plasticity processes that mediate drug-seeking behavior can facilitate the development of therapeutic interventions for CUD. We used behavioral pharmacology and ex vivo patch-clamp electrophysiology to test the hypothesis that escalating cocaine doses elicit long-lasting, drug-seeking behavior that is correlated with a persisting decrease of GABAergic transmission in the mouse ventral hippocampus (vH) CA1 region. We found that noncontingent cocaine conditioning reduced the amplitude of evoked inhibitory postsynaptic currents measured from vH CA1 pyramidal cells 4-5 weeks after the last dose, suggesting sustained synaptic disinhibition. The magnitude of drug-seeking behavior observed 4 weeks, but not 1 day, after cocaine abstinence predicted the extent of synaptic disinhibition. Persisting inhibition of GABAergic transmission occurred in the absence of altered IPSC kinetics. We conclude that cocaine conditioning evokes a progressive metaplasticity that persistently shifts the GABAergic tone of the vH CA1 region, and these synaptic actions are correlated with long-lasting drug-seeking behavior in mice. Our results suggest that targeting metaplastic processes that modulate vH neuronal excitability represents a promising therapeutic strategy for relieving symptoms associated with CUD.