Pharmacological characterization of the 5-hydroxytryptamine-1A receptor-mediated activation of high-affinity GTP hydrolysis in rat hippocampal membranes.

The high-affinity GTP hydrolyzing activity stimulated by 5-hydroxytryptamine (5-HT) receptor agonists was pharmacologically characterized in rat hippocampal membranes. The addition of 100 microM 5-HT increased significantly the Vmax of high-affinity GTPase activity with an apparent Km of 0.37 microM in a Mg(++)-dependent fashion. 5-HT receptor agonists, except for the selective 5-HT2 receptor agonists, (+/-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, stimulated the activity in a concentration-dependent manner, with affinities indicative of the 5-HT1A receptor involvement. 2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane, buspirone, ipsapirone, metergoline and (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin showed activities characterizing these as partial agonists. The drug 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine was also characterized as a weak partial agonist. 5-HT (100 nM)-stimulated activity was potently antagonized by metitepine (also called methiothepin) and spiperone (with a Kb value of 37 nM in a competitive manner) but not by ketanserin. The affinities of the agonists obtained in this study correlated well with those for the 5-HT1A receptor-mediated inhibition of forskolin-stimulated adenylyl cyclase activity in guinea pig and rat hippocampal membranes reported in a previous article. The 5-HT-mediated activation of high-affinity GTPase in rat hippocampal membranes can be used to investigate a functional interaction between the 5-HT1A receptors and G proteins, in particular the Gi subfamily, associated with adenylyl cyclase inhibition.