Autoradiographic identification of D1 dopamine receptors labelled with [3H]dopamine: distribution, regulation and relationship to coupling.
On the basis of experiments made on striatal membranes, Leff and Creese [Molec. Pharmac. (1985) 27, 184-192] have proposed that tritiated dopamine binds to a high-affinity agonist state of D1 dopamine receptors (D1h) which adopt this conformation when they are associated with the GTP-binding protein involved in the transduction process. Quantitative autoradiography was thus used to look for the distribution of these D1h sites in the rat brain and to compare it with that of D1 receptors labelled with [3H]7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benz aze pine [( 3H]SCH23390), a D1 antagonist. The effects of unilateral 6-hydroxydopamine lesion of the ascending dopamine pathways on the density of [3H]dopamine D1h and [3H]SCH23390 binding sites in the striatum and the nucleus accumbens were also analysed. In the striatum, when D2 receptors were blocked by spiroperidol (20 nM), [3H]dopamine was found to bind specifically to dopamine receptors of the D1 type. Complementary experiments made with dopamine uptake blockers indicated that high-affinity dopamine uptake sites were not labelled by [3H]dopamine under our experimental conditions. The anatomical distribution of [3H]dopamine D1h binding sites was found to be markedly different from that of [3H]SCH23390 binding sites. This was particularly the case in the substantia nigra, some amygdaloid nuclei and the prefrontal cortex--structures in which the ratios between [3H]SCH23390 and [3H]dopamine binding sites were more than seven-fold higher than that observed in the striatum. [3H]SCH23390 binding was not significantly affected in either the striatum or the nucleus accumbens six weeks after a complete unilateral destruction of ascending dopamine pathways. In contrast, a marked decrease in [3H]dopamine D1h binding sites was found in both structures, but this effect was lower in the medioventral (-60%) than in the laterodorsal (-81%) part of the striatum, even though dopamine denervation was uniform throughout the structure. Preincubation of the sections with dopamine (0.5 microM) led to a partial recovery (+126%) in the lesioned striatum and an increase of [3H]dopamine labelling in the control striatum (+68%). This suggest that the presence of dopamine stabilizes the D1h state of D1 receptors. The absence or low amount of dopamine, either due to dopamine denervation or naturally occurring (prefrontal cortex), would then impair the [3H]dopamine D1h binding. In addition, a lower coupling of D1 receptors with adenylate cyclase was observed in the substantia nigra when compared to that in the striatum: this may explain the relatively weak [3H]dopamine binding in the substantia nigra.(ABSTRACT TRUNCATED AT 400 WORDS)
Hervé
D
D
Chaire de Neuropharmacologie, INSERM U.114, Collège de France, Paris.
Trovero
F
F
Blanc
G
G
Glowinski
J
J
Tassin
J P
JP
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001552:Benzazepines / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism* / Q000502:physiology; D017447:Receptors, Dopamine D1; D013134:Spiperone / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013563:Sympathectomy, Chemical
D001552:Benzazepines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D013134:Spiperone; D016627:Oxidopamine; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D004298:Dopamine