Cocaine‐elicited imbalances in ventromedial prefrontal cortex H omer1 versus H omer2 expression: implications for relapse

Withdrawal from a history of extended access to self‐administered cocaine produces a time‐dependent intensification of drug seeking, which might relate to a cocaine‐induced imbalance in the relative expression of constitutively expressed H omer1 versus H omer2 isoforms within the ventromedial aspect of the prefrontal cortex ( vmPFC ). Thus, we employed immunoblotting to examine the relation between cue‐reinforced lever pressing at 3‐ versus 30‐day withdrawal from a 10‐day history of extended access (6 hours/day) to intravenous cocaine (0.25 mg/infusion) or saline ( Sal6h ), and the expression of H omer1b/c and H omer2a/b within the vmPFC versus the more dorsomedial aspect of this structure ( dmPFC ). Behavioral studies employed adeno‐associated virus ( AAV ) vectors to reverse cocaine‐elicited changes in the relative expression of H omer1 versus H omer2 isoforms and tested animals for cocaine prime‐, and cue‐induced responding following extinction training. Cocaine self‐administration elevated both H omer1b/c and H omer2a/b levels within the vmPFC at 3‐day withdrawal, and the rise in H omer2a/b persisted for at least 30 days. dmPFC H omer levels did not change as a function of self‐administration history. Reversing the relative increase in H omer2 versus H omer1 expression via H omer1c overexpression or H omer2b knockdown failed to influence cue‐reinforced lever pressing when animals were tested in a drug‐free state, but both AAV treatments prevented cocaine‐primed reinstatement of lever‐pressing behavior. These data suggest that a cocaine‐elicited imbalance in the relative expression of constitutively expressed H omer2 versus H omer1 within the vmPFC is necessary for the capacity of cocaine to reinstate drug‐seeking behavior, posing drug‐induced changes in vmPFC H omer expression as a molecular trigger contributing to drug‐elicited relapse.