Abstract: 5-HT1A receptors couple to different Go/Gi proteins in order to mediate a wide range of physiological actions. While activation of post-synaptic 5-HT1A receptors is mainly related to inhibition of adenylyl cyclase activity, functionality of autoreceptors located in raphe nuclei has been classically ascribed to modifications of the activity of potassium and calcium channels. In order to evaluate the possible existence of agonist-directed trafficking for 5-HT1A autoreceptors in the rat dorsal raphe nucleus, we studied their activation by two agonists with a different profile of efficacy [(+)8-OH-DPAT and buspirone], addressing simultaneously the identification of the specific G? subtypes ([35S]GTP?S labelling and immunoprecipitation) involved and the subsequent changes in cAMP formation. A significant increase (32%, p<0.05) in (+)8-OH-DPAT-induced [35S]GTP?S labelling of immunoprecipitates was obtained with anti-G?i3 antibodies but not with anti-G?o, anti-G?i1, anti-G?i2, anti-G?z or anti-G?s antibodies. In contrast, in the presence of buspirone, significant [35S]GTP?S labelling of immunoprecipitates was obtained with anti-G?i3 (50%, p<0.01), anti-G?o (32%, p<0.01) and anti-G?i2 (29%, p<0.05) antibodies, without any labelling with anti-G?i1, anti-G?z or anti-G?s. The selective 5-HT1A antagonist WAY 100635 blocked the labelling induced by both agonists. Furthermore, (+)8-OH-DPAT failed to modify forskolin-stimulated cAMP accumulation, while buspirone induced a dose-dependent, WAY 100635-sensitive, inhibition of this response (Imax 30.8±4.9, pIC50 5.95±0.46). These results demonstrate the existence of an agonist-dependency pattern of G-protein coupling and transduction for 5-HT1A autoreceptors in native brain tissue. These data also open new perspectives for the understanding of the differential profiles of agonist efficacy in pre- vs. post-synaptic 5-HT1A receptor-associated responses.

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