DIFFERENTIAL-EFFECTS OF CHRONIC AGONIST ADMINISTRATION ON MU-OPIOID RECEPTOR-REGULATED AND MUSCARINIC RECEPTOR-REGULATED ADENYLATE-CYCLASE IN RAT STRIATAL NEURONS

In cultured rat striatal neurons exposed to 10-mu-M morphine or oxotremorine for 24 hours, we observed an increased (about 30 %) dopamine D1 receptor-stimulated cyclic AMP production, whereas no desensitization of mu-opioid receptor or muscarinic cholinergic receptor was found. However, whereas upregulation of dopamine D1 receptor-stimulated adenylate cyclase activity upon 7 days morphine exposure was at least as pronounced as observed after 24 hours of exposure to the opioid, this adaptive phenomenon was virtually absent following one week of oxotremorine treatment. This reduced adenylate cyclase sensitization upon 7 days oxotremorine exposure appeared to coincide with desensitization of muscarinic cholinergic receptors. A possible role of the resistance of mu-receptors to desensitization and the (resulting) upregulation of the neuronal adenylate cyclase system upon chronic receptor activation in the development of opiate tolerance and dependence is suggested.