Chronic exposure of NG 108-15 cells to inhibitory acting drugs reduces stimulatory prostaglandin E1 receptor number.
Prolonged exposure of neuroblastoma x glioma (NG 108-15) 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-adrenoceptors, or muscarinic M4 receptors significantly decreases the number of stimulatory, adenylate cyclase-coupled prostaglandin E1 receptors. Pharmacological characterization further revealed that the loss of [3H]prostaglandin E1-binding sites most likely corresponds to a reduction of the number of high-affinity, G protein-coupled prostaglandin E1 receptors. The decline in functionally active prostaglandin E1 receptors developed in a time- and dose-dependent manner and could be prevented by pretreatment of the cells with pertussis toxin. Heterologous prostaglandin E1 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 E1 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 E1 receptor number closely resembled those mediating maximal adenylate cyclase inhibition. The data demonstrate that chronic inhibitory drug treatment of NG 108-15 hybrid cells reduces the number of functionally active, excitatory prostaglandin E1 receptors. Thus, it is proposed that adaptations at the level of stimulatory receptor systems contribute to the regulatory mechanisms associated with drug dependence.
Ammer
H
H
Institute of Pharmacology, Toxicology and Pharmacy, University of Munich, Germany.
Schulz
R
R
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000316:Adrenergic alpha-Agonists / Q000378:metabolism; D000527:Alprostadil / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D003000:Clonidine / Q000378:metabolism; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects / Q000378:metabolism; D018721:Muscarinic Agonists / Q000378:metabolism; D009270:Naloxone / Q000378:metabolism; D009292:Narcotic Antagonists / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism*; D010095:Oxotremorine / Q000378:metabolism; D037342:Pertussis Toxin; D017465:Receptors, Opioid, delta / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000187:drug effects* / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000378:metabolism
D037361:Adenylate Cyclase Toxin; D000316:Adrenergic alpha-Agonists; D018721:Muscarinic Agonists; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D018078:Receptors, Prostaglandin E; D010566:Virulence Factors, Bordetella; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D010095:Oxotremorine; D016308:Enkephalin, Leucine-2-Alanine; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D000527:Alprostadil; D003000:Clonidine