Regulation of 5-HT1A receptor-stimulated [35S]-GTPγS binding as measured by quantitative autoradiography following chronic agonist administration

1 Because changes 5-HT1A receptor number do not occur following repeated agonist treatment, we hypothesized that the basis for 5-HT1A receptor desensitization involves changes in receptor-G protein coupling. We measured the effect of repeated agonist administration on 5-HT1A receptor-stimulated [S-35]-GTP gammaS binding in forebrain areas, (i.e. anterior cingulate cortex, lateral septum, hippocampus, entorhinal cortex), and serotonergic cell body areas, the dorsal and median raphe nuclei. 2 Following treatment of rats with (+/-)8-OH-DPAT (1 mg kg (1), s.c.) for 7 or 14 days, 5-HT1A receptor-stimulated [S-35]-GTP gammaS binding was significantly attenuated in both the dorsal and median raphe nuclei. 3 5-HT1A receptor-stimulated [S-35]-GTP gammaS binding was significantly attenuated in the CA(1) region of the hippocampus after 7, but not 14 days of 8-OH-DPAT administration. 5-HT1A receptorstimulated [S-35]-GTP gammaS binding was not altered in other forebrain areas examined. 4 The binding of [H-3]-MPPF to 5-HT1A receptor sites was not altered in any brain region examined following repeated agonist administration, suggesting that the observed changes in (+/-)8-OH-DPAT-stimulated [S-35]-GTP gammaS binding were not due to changes in 5-HT1A, receptor number. 5 Our data indicate that in serotonergic cell body areas the regulation of presynaptic 5-HT1A receptor function following repeated agonist administration occurs at the level of receptor-Ci protein interaction. In forebrain areas, however, the regulation of postsynaptic 5-HT1A receptor sensitivity appears not to be at the level of receptor-G protein coupling.