Schild analyses reveal that the cerebral cortical serotonin 5HT/sub 2/ site is linked to phosphoinositide (PI) hydrolysis: relative efficacies of piperazines

Cerebral cortical slices were prelabelled with /sup 3/H-inositol and serotonin (5HT) stimulated release of /sup 3/H-inositol-1-phosphate was measured as an index of PI hydrolysis. Antagonist Kd values at the PI linked receptor were determined by Schild analyses. A highly significant positive correlation (r = 0.99) was found between these Kd values and Ki values at the 5HT/sub 2/ binding site labelled with /sup 3/H-ketanserin, suggesting that the PI linked receptor and the 5HT/sub 2/ site are identical. The 5HT/sub 2/ mediated PI response was used to determine relative efficacies of piperazine derivatives. Both quipazine and 6-chloro-2(1-piperzinyl)-pyrazine (MK-212) stimulated PI hydrolysis in a ketanserin sensitive manner but with maximal responses which were lower than that of 5HT. m-Trifluoro-methylphenylpiperazine (TFMPP), m-chlorophenylpiperazine (MCPP) and 1-(1-naphthyl) piperazine (1-NP) did not stimulate PI hydrolysis, but blocked the effect of 5HT. These data suggest that the 5HT/sub 2/ site is a functional receptor which is linked to PI hydrolysis and that quipazine and MK-212 are partial 5HT/sub 2/ agonists while 1-NP, MCPP and TFMPP are pure 5HT/sub 2/ antagonists.