Sensorimotor gating, which is severely disrupted in schizophrenic patients, can be measured by assessing prepulse inhibition of the acoustic startle response (PPI). Acute administration of D2-like receptor agonists such as quinpirole reduces PPI, but tolerance occurs upon repeated administration. In the present study, PPI in rats was reduced by acute quinpirole (0.1 mg/kg, s.c.), but not following repeated quinpirole treatment once daily for 28 days. Repeated quinpirole treatment did not alter the levels of basal-, forskolin- (5 microM), or SKF 82958- (10 microM) stimulated adenylate cyclase activity in the nucleus accumbens (NAc), but significantly increased cAMP-dependent protein kinase (PKA) activity. Phosphorylation of cAMP response element-binding protein (CREB) was significantly greater in the NAc after repeated quinpirole treatment than after repeated saline treatment with or without acute quinpirole challenge. Activation of PKA by intra-accumbens infusion of the cAMP analog, Sp-cAMPS, prevented acute quinpirole-induced PPI disruption, similar to the behavioral effect observed following repeated quinpirole treatment. Thus, repeated quinpirole treatment increases NAc PKA activity and CREB phosphorylation, and this neuroadaptive response might facilitate the recovery of sensorimotor gating in schizophrenia.