BACKGROUND The neuropeptide pituitary adenylyl cyclase-activating peptide (PACAP) and its receptors (PAC1 and VPAC2) are expressed in the ventral tegmental area and nucleus accumbens, raising the possibility that PACAP could be a potential modulator of the mesolimbic dopaminergic system. OBJECTIVE The present study was designed to determine if PACAP plays a role in acute motor stimulatory and rewarding actions of morphine. METHODS The effect of intracerebroventricular PACAP administration (0, 0.03, 0.3, 1.0, or 3.0 microg/3 microL) was studied on basal motor activity as well as on morphine (5 mg/kg)-stimulated motor activity. Motor stimulation and conditioned place preference (CPP) induced by morphine (5 or 10 mg/kg) were also determined in mice lacking PACAP and their wild-type controls. RESULTS Intracerebroventricular PACAP dose-dependently suppressed basal motor activity and PACAP-deficient mice exhibited higher basal motor activity than control mice, providing evidence that the action of endogenous PACAP on basal motor activity is inhibitory. Paradoxically, low doses of PACAP which did not alter basal motor activity were found to enhance the motor stimulatory action of morphine. Furthermore, morphine-induced motor stimulation was blunted in PACAP-deficient mice. Additionally, morphine-induced CPP following a single, but not repeated, alternate-day saline/morphine (10 mg/kg) conditioning was blunted in PACAP-deficient mice compared to their wild-type littermates/controls. CONCLUSIONS The present results suggest that endogenous PACAP, at low doses, positively modulates the acute motor stimulatory and rewarding actions of morphine.