Dopamine receptor system involving adenylate cyclase in canine caudate nucleus.
Two distinct dopamine binding sites, referred to as D1 and D2, exist in canine caudate nucleus, as characterized by [3H]dopamine binding to the synaptic membrane fraction. D1 has the low affinity for dopamine with the dissociation constant of a few micromolar, whereas the affinity for D2 is about two orders of magnitude greater. Classical neuroleptics such as haloperidol and chlorpromazine have no selectivity in the inhibition of D1 and D2 binding, whereas a number of 2-methoxy benzamide derivatives which have been synthesized in our laboratories exhibit rather different selectivity. Correlation between the selectivity of those benzamide derivatives for the two sites and the inhibition of apomorphine-induced stereotypy in rats suggests that D1 is more responsible for the stereotypy. Photoaffinity labeling of D1 and D2 with [3H]dopamine demonstrates that the two sites are distinct entities. In the D1 system, the adenylate cyclase which is responsive to Gpp(NH)p can be dissociable by the treatment with GTP-Sepharose into a guanine nucleotide binding unit and a catalytic unit which is insensitive to Gpp(NH)p. The catalytic unit restores the responsiveness to Gpp(NH)p after preincubation with the nucleotide binding unit. Furthermore, endogenous cAMP-dependent phosphorylation of two particular proteins (protein Ia and Ib) is shown, which may be at least partly responsible for stereotypy and dopamine turnover in the caudate nucleus.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001058:Apomorphine / Q000037:antagonists & inhibitors; D001549:Benzamides / Q000494:pharmacology; D002421:Caudate Nucleus / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D011954:Receptors, Dopamine / Q000378:metabolism*; D013239:Stereotyped Behavior / Q000187:drug effects
D001549:Benzamides; D011954:Receptors, Dopamine; D000262:Adenylyl Cyclases; D001058:Apomorphine