In vivo partial inactivation of dopamine D1 receptors induces hypersensitivity of cortical dopamine-sensitive adenylate cyclase: permissive role of alpha 1-adrenergic receptors.
As shown by autoradiography, peripheral injections of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) induced a dose-dependent decrease of [3H]SCH 23390 and [3H]prazosin high-affinity binding sites in the rat prefrontal cortex. EEDQ showed similar efficacy in inactivating cortical and striatal dopamine (DA) D1 receptors, whereas prazosin-sensitive alpha 1-adrenergic receptors were more sensitive to the action of the alkylating agent, as for all doses of EEDQ tested (from 0.8 to 3 mg/kg, i.p.), the decrease in cortical [3H]SCH 23390 binding was less pronounced than that of [3H]prazosin. The effects of EEDQ on [3H]SCH 23390 binding and DA-sensitive adenylate cyclase activity were then simultaneously compared in individual rats. In the striatum, whatever the dose of EEDQ used, the decrease of DA-sensitive adenylate cyclase activity was always lower than that of D1 binding sites, suggesting the occurrence of a large proportion of spare D1 receptors. In the prefrontal cortex, a significant increase in DA-sensitive adenylate cyclase activity was observed in rats treated with a low dose of EEDQ (0.8 mg/kg), this effect being associated with a slight reduction in [3H]SCH 23390 binding sites (-20%). Parallel decreases in the enzyme activity and D1 binding sites were observed with higher doses. The EEDQ-induced supersensitivity of DA-sensitive adenylate cyclase did not occur in rats in which the decrease in [3H]prazosin binding sites was higher than 35%.(ABSTRACT TRUNCATED AT 250 WORDS)
Trovero
F
F
Laboratoire de Neuropharmacologie, Collège de France, Paris, France.
Hervé
D
D
Blanc
G
G
Glowinski
J
J
Tassin
J P
JP
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001552:Benzazepines / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D003342:Corpus Striatum / Q000201:enzymology*; D004298:Dopamine / Q000494:pharmacology*; D004351:Drug Resistance; D005625:Frontal Lobe / Q000201:enzymology*; D008297:Male; D011224:Prazosin / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D017447:Receptors, Dopamine D1
D000317:Adrenergic alpha-Antagonists; D001552:Benzazepines; D011804:Quinolines; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; C000470:EEDQ; D000262:Adenylyl Cyclases; D004298:Dopamine; D011224:Prazosin