Deficits in Ventromedial Prefrontal Cortex Group 1 Metabotropic Glutamate Receptor Function Mediate Resistance to Extinction during Protracted Withdrawal from an Extensive History of Cocaine Self-Administration

Anomalies in prefrontal cortex (PFC) function are posited to underpin difficulties in learning to suppress drug-seeking behavior during abstinence. As Group1 metabotropic glutamate receptors (mGluRs) regulate drug-related learning, we assayed the consequences of extended access to intravenous cocaine (6 hrs/day; 0.25 mg/infusion for 10 days) upon the PFC expression of Group1 mGluRs and the relevance of observed changes for cocaine-seeking. Following protracted withdrawal, cocaine-experienced animals exhibited a time-dependent intensification of cue-induced cocaine-seeking behavior and an impaired extinction of this behavior. These behavioral phenomena were associated with a time-dependent reduction in mGluR1/5 expression within ventromedial PFC (vmPFC) of cocaine-experienced animals exposed to extinction testing, but not in untested ones. Interestingly, pharmacological manipulations of vmPFC mGluR1/5 produced no immediate effects upon cue-induced cocaine-seeking behavior, but produced residual effects on a subsequent test for cocaine-seeking. At 3 days withdrawal, cocaine-experienced rats infused intra-vmPFC with mGluR1/5 antagonists, either before or after an initial test for cocaine-seeking, persisted in their cocaine-seeking akin to cocaine-experienced rats in protracted withdrawal. Conversely, cocaine-experienced rats infused with an mGluR1/5 agonist before the initial test for cocaine-seeking at 30 days withdrawal exhibited a facilitation of extinction learning. These data indicate that cue-elicited deficits in vmPFC Group1 mGluR function mediate resistance to extinction during protracted withdrawal from a history of extensive cocaine self-administration and pose pharmacological stimulation of these receptors as a potential approach to facilitate learned suppression of drug-seeking behavior which may aid drug abstinence.