The purpose of this study was twofold: to investigate whether the medial prefrontal cortex (mPFC) is involved in the expression of extinction in previously drug-conditioned rats, and whether the mPFC is involved in the reacquisition of heroin-seeking induced by drug re-exposure. Using the conditioned place preference technique, animals underwent conditioning (0.3mg/kg), extinction, and reconditioning (1.0mg/kg). Either 15min before an extinction recall test, or 15min post-heroin reconditioning, intra-mPFC infusions of the GABA A/B agonists muscimol and baclofen (M+B, 0.03 and 0.3 nmol, respectively in 0.5 [mu]l/side over 2min) were administered to temporarily inactivate the area. M+B precipitated heroin seeking in extinguished rats, but did not block reacquisition, suggesting that the mPFC is necessary for the expression of extinction, and therefore critical for the inhibition of heroin seeking resulting from extinction learning. Furthermore, inactivation of prefrontal inhibitory mechanisms precipitates a return to drug seeking similar to that resulting from the reconditioning of drug-associated cues.