Cocaine-elicited imbalances in ventromedial prefrontal cortex Homer1 versus Homer2 expression: implications for relapse (original) (raw)
Withdrawal from a history of extended access to self-administered cocaine produces a timedependent intensification of drug-seeking, which might relate to a cocaine-induced imbalance in the relative expression of constitutively expressed Homer1 versus Homer2 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 days withdrawal from a 10-day history of extended access (6 hrs/day) to intravenous cocaine (0.25 mg/infusion) or saline (Sal6h) and the expression of Homer1b/c and Homer2a/b within the vmPFC versus the more dorsomedial aspect of this structure (dmPFC). Behavioral studies employed adeno-associated viral vectors (AAVs) to reverse cocaine-elicited changes in the relative expression of Homer1 vs. Homer2 isoforms and tested animals for cocaine prime-, and cue-induced responding following extinction training. Cocaine self-administration elevated both Homer1b/c and Homer2a/b levels within the vmPFC at 3 days withdrawal and the rise in Homer2a/b persisted for at least 30 days. dmPFC Homer levels did not change as a function of self-administration history. Reversing the relative increase in Homer2 versus Homer1 expression via Homer1c over-expression or Homer2b knock-down failed to influence cue-reinforced lever-pressing when animals were tested in a drugfree 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 Homer2 versus Homer1 within the vmPFC is necessary for the capacity of cocaine to reinstate drug-seeking behavior, posing drug-induced changes in vmPFC Homer expression as a molecular trigger contributing to drug-elicited relapse.
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