CHRONIC REPEATED COCAINE ADMINISTRATION ALTERS BASAL AND OPIOID-REGULATED ADENYLYL-CYCLASE ACTIVITY

Repeated daily cocaine injections have been shown to alter mu-opioid r eceptor densities in the caudate putamen and nucleus accumbens of rat brain (Unterwald et al., 1991, 1992). Adenylyl cyclase activity was me asured in rat rostral caudate putamen and nucleus accumbens following repeated cocaine administration to determine the functional consequenc es of cocaine-induced opioid receptor changes. Male Fischer rats were injected daily for 14 days with saline or cocaine HCI (30 or 45 mg/kg/ day, i.p.) in three equal doses at 1-hr intervals. Basal adenylyl cycl ase activity and the effects of the selective mu- and delta-opioid ago nists [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (DAMGO) and [D-penicillamin e2,D-Penicillamine5]enkephalin (DPDPE), respectively, on adenylyl cycl ase activity were examined 30 min after the last injection using a cAM P radioligand binding assay in crude membrane preparations. Basal aden ylyl 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 trea tment. DAMGO and DPDPE each maximally inhibited approximately 25% and 30%, respectively, of basal adenylyl cyclase in the caudate putamen an d nucleus accumbens of saline-injected animals. Administration of coca ine attenuated the ability of DPDPE to inhibit adenylyl cyclase in bot h 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 impair ment of delta-opioid receptor-mediated effector function in the caudat e putamen and nucleus accumbens. (C) 1993 Wiley-Liss, Inc.