Chronic exposure of NG108-15 cells to inhibitory acting drugs reduces stimulatory prostaglandin E(1) receptor number

Prolonged exposure of neuroblastoma X glioma (NG108-15) hybrid cells to inhibitory acting drugs results in sensitization of adenylate cyclase. We now report that chronic activation (3 days) of either inhibitory delta-opioid receptors, alpha(2B)-adrenoceptor, or muscarinic M(4) receptors significantly decreases the number of stimulatory, adenylate cyclase-coupled prostaglandin E(1) receptors. Pharmacological characterization further revealed that the loss of [H-3]prostaglandin E(1)-binding sites most likely corresponds to a reduction of the number of high-affinity, G protein-coupled prostaglandin E(1) receptors. The decline in functionally active prostaglandin E(1) receptors developed in a time- and dose-dependent manner and could be prevented by pretreatment of the cells with pertussis toxin. Heterologous prostaglandin E(1) receptor regulation was blocked by concomitant exposure of the cells to antagonists for inhibitory receptors and was rapidly reversed (t(1/2) < 30 min) upon termination of chronic inhibitory drug treatment. The decrease in high-affinity prostaglandin E(1) receptors developed regardless of whether full or partial agonists were used for pretreatment. In addition, the concentrations of inhibitory drugs required to maximally affect prostaglandin E(1) receptor number closely resembled those mediating maximal adenylate cyclase inhibition. The data demonstrate that chronic inhibitory drug treatment of NG108-15 hybrid cells reduces the number of functionally active, excitatory prostaglandin E(1) receptors. Thus, it is proposed that adaptations at the level of stimulatory receptor systems contribute to the regulatory mechanisms associated with drug dependence.