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

Abstract

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 [35S]-GTPγS 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 [35S]-GTPγS binding was significantly attenuated in both the dorsal and median raphe nuclei. 3. 5-HT1A receptor-stimulated [35S]-GTPγS binding was significantly attenuated in the CA1 region of the hippocampus after 7, but not 14 days of 8-OH-DPAT administration. 5-HT1A receptor-stimulated [35S]-GTPγS binding was not altered in other forebrain areas examined. 4. The binding of [3H]-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 [35S]-GTPγS 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-G 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.