Cocaine-induced reinstatement requires endogenous stimulation of mu-opioid receptors in the ventral pallidum.

The projection from the nucleus accumbens to the ventral pallidum regulates the reinstatement of cocaine seeking in rats extinguished from cocaine self-administration. This projection coexpresses GABA and enkephalin, posing a role for mu-opioid receptors in the ventral pallidum in mediating the reinstatement of cocaine seeking. Rats were extinguished from cocaine self-administration, and the reinstatement of active lever pressing by cocaine was blocked by intra-ventral pallidum administration of the mu receptor antagonist Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) (0.03-3.0 microg). Conversely, stimulating mu receptors with morphine (1-30 microg) in the ventral pallidum reinstated cocaine seeking. The ability of intra-ventral pallidum morphine to reinstate lever pressing was blocked by co-microinjection of the mu antagonist CTAP and was augmented by systemic cocaine administration. The reinstatement of cocaine seeking was associated with reduced extracellular GABA in the ventral pallidum, and the reduction in GABA was also prevented by blocking mu receptors with CTAP (10 microm). Although immunoblotting revealed that neither the total tissue concentration nor the membrane insertion of mu receptors in the ventral pallidum was altered by withdrawal from cocaine, the capacity of morphine (0.01-10 microm) to reduce ventral pallidum levels of extracellular GABA was augmented in rats extinguished from cocaine self-administration. These data are consistent with the reinstatement of cocaine seeking being modulated in part by coreleased enkephalin and GABA from the accumbens-ventral pallidal projection, a modulation that may involve the inhibition of GABA release by presynaptic mu receptors.