5-HT2C RECEPTOR-MEDIATED PHOSPHOINOSITIDE TURNOVER AND THE STIMULUS EFFECTS OF M-CHLOROPHENYL PIPERAZINE

The present study was designed to investigate the hypothesis that agon ist interactions at 5-HT2C receptors mediate the discriminative stimul us properties of m-chlorophenylpiperazine (mCPP). Three structural cla sses of compounds have been described to stimulate increases in phosph oinositide (PI) hydrolysis at the 5-HT2C receptor site: phenylpiperazi nes, phenylalkylamines, and indolamines. Four representative phenylpip erazines, mCPP, TFMPP, MK-212 and quipazine, one phenylalkylamine, (-) DOM, and one indolamine, LSD, were employed in the present study. The efficacies of these compounds were defined (1) in vitro, with respect to their abilities to stimulate increases in PI hydrolysis in the chor oid plexus, and (2) in vivo with respect to their abilities to substit ute for the mCPP discriminative stimulus. In vitro intrinsic activity at the 5-HT2C site was expressed as a fraction of the maximal PI hydro lysis response elicited by serotonin (5-HT). MK-212 (fractional effica cy=1.1) and (-)DOM (0.77) were full agonists, while mCPP (0.72), LSD ( 0.27), quipazine (0.24), and TFMPP (0.22) were partial agonists with r espect to the stimulation of PI hydrolysis at the 5-HT2C receptor. In vivo, each of the phenylpiperazines fully substituted for the mCPP sti mulus, while (-)DOM (75%), and LSD (67%) elicited only partial substit ution. While compounds with agonist activity at the 5-HT2C receptor in vitro substitute for the mCPP stimulus in vivo, no clear relationship exists between in vitro intrinsic activity at the 5-HT2C receptor wit h respect to the stimulation of PI turnover and maximal substitution f or the mCPP stimulus in vivo. The present data suggest that mCPP elici ts a compound stimulus which is mediated by agonist interactions at th e 5-HT2C receptor and possibly additional interactions with 5-HT2A, 5- HT3, and/or 5-HT1B receptors.