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Comparison of hippocampal G protein activation by 5-HT1A receptor agonists and the atypical antipsychotics clozapine and S16924.

Newman-Tancredi A, Rivet JM, Cussac D, Touzard M, Chaput C, Marini L, Millan MJ.
Naunyn Schmiedebergs Arch Pharmacol. 2003 Sep;368(3):188-99. Epub 2003 Aug 16.

This study employed [35S]guanosine 5'- O-(3-thiotriphosphate) ([35S]GTPgammaS) binding to compare the actions of antipsychotic agents known to stimulate cloned, human 5-HT1A receptors with those of reference agonists at postsynaptic 5-HT1A receptors. In rat hippocampal membranes, the following order of efficacy was observed (maximum efficacy, Emax, values relative to 5-HT=100): (+)8-OH-DPAT (85), flesinoxan (62), eltoprazine (60), S14506 (59), S16924 (48), buspirone (41), S15535 (22), clozapine (22), ziprasidone (21), pindolol (7), p-MPPI (0), WAY100,635 (0), spiperone (0). Despite differences in species and tissue source, the efficacy and potency (pEC50) of agonists (with the exception of clozapine) correlated well with those determined previously at human 5-HT1A receptors expressed in Chinese hamster ovary (CHO) cells. In contrast, clozapine was more potent at hippocampal membranes. The selective antagonists p-MPPI and WAY100635 abolished stimulation of binding by (+)8-OH-DPAT, clozapine and S16924 (p-MPPI), indicating that these actions were mediated specifically by 5-HT1A receptors. Clozapine and S16924 also attenuated 5-HT- and (+)8-OH-DPAT-stimulated [35S]GTPgammaS binding, consistent with partial agonist properties. In [35S]GTPgammaS autoradiographic studies, 5-HT-induced stimulation, mediated through 5-HT1A receptors, was more potent in the septum (pEC50 approximately 6.5) than in the dentate gyrus of the hippocampus (pEC50 approximately 5) suggesting potential differences in coupling efficiency or G protein expression. Though clozapine (30 and 100 microM) did not enhance [35S]GTPgammaS labelling in any structure, S16924 (10 micro M) modestly increased [35S]GTPgammaS labelling in the dentate gyrus. On the other hand, both these antipsychotic agents attenuated 5-HT (10 microM)-stimulated [35S]GTPgammaS binding in the dentate gyrus and septum. In conclusion, clozapine, S16924 and ziprasidone act as partial agonists for G protein activation at postsynaptic 5-HT1A receptors in the hippocampus. These data support a role of postsynaptic 5-HT1A receptors in the functional profiles of certain antipsychotic agents.