Repeated daily cocaine injections have been shown to alter mu-opioid receptor densities in the caudate putamen and nucleus accumbens of rat brain (Unterwald et al., 1991, 1992). Adenylyl cyclase activity was measured in rat rostral caudate putamen and nucleus accumbens following repeated cocaine administration to determine the functional consequences of cocaine-induced opioid receptor changes. Male Fischer rats were injected daily for 14 days with saline or cocaine HCl (30 or 45 mg/kg/day, i.p.) in three equal doses at 1-hr intervals. Basal adenylyl cyclase activity and the effects of the selective mu- and delta-opioid agonists [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO) and [D-penicillamine2,D-Penicillamine5]enkephalin (DPDPE), respectively, on adenylyl cyclase activity were examined 30 min after the last injection using a cAMP radioligand binding assay in crude membrane preparations. Basal adenylyl cyclase activity was 49% and 34% lower in the caudate putamen of animals treated with 30 and 45 mg/kg/day of cocaine, respectively, as compared to those receiving saline injections. Basal adenylyl cyclase activity was unchanged in the nucleus accumbens following cocaine treatment. DAMGO and DPDPE each maximally inhibited approximately 25% and 30%, respectively, of basal adenylyl cyclase in the caudate putamen and nucleus accumbens of saline-injected animals. Administration of cocaine attenuated the ability of DPDPE to inhibit adenylyl cyclase in both brain regions, but had no effect on the efficacy or potency of DAMGO for inhibiting adenylyl cyclase activity. These results suggest that chronic, repeated cocaine administration results in a selective impairment of delta-opioid receptor-mediated effector function in the caudate putamen and nucleus accumbens.