Fiorella D, Helsley S, Rabin R A, Winter J C
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, USA.
Psychopharmacology (Berl). 1995 Dec;122(3):237-43. doi: 10.1007/BF02246545.
The present study was designed to investigate the hypothesis that agonist interactions at 5-HT2C receptors mediate the discriminative stimulus properties of m-chlorophenylpiperazine (mCPP). Three structural classes of compounds have been described to stimulate increases in phosphoinositide (PI) hydrolysis at the 5-HT2C receptor site: phenylpiperazines, phenylalkylamines, and indolamines. Four representative phenylpiperazines, 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 choroid plexus, and (2) in vivo with respect to their abilities to substitute for the mCPP discriminative stimulus. In vitro intrinsic activity at the 5-HT2C site was expressed as a fraction of the maximal PI hydrolysis response elicited by serotonin (5-HT). MK-212 (fractional efficacy = 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 respect to the stimulation of PI hydrolysis at the 5-HT2C receptor. In vivo, each of the phenylpiperazines fully substituted for the mCPP stimulus, while (-)DOM (75%), and LSD (67%) elicited only partial substitution. 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 with respect to the stimulation of PI turnover and maximal substitution for the mCPP stimulus in vivo. The present data suggest that mCPP elicits a compound stimulus which is mediated by agonist interactions at the 5-HT2C receptor and possibly additional interactions with 5-HT2A, 5-HT3, and/or 5-HT1B receptors.
本研究旨在探讨5-羟色胺2C（5-HT2C）受体上的激动剂相互作用介导间氯苯基哌嗪（mCPP）辨别刺激特性的假说。已描述了三类化合物可刺激5-HT2C受体位点的磷酸肌醇（PI）水解增加：苯基哌嗪、苯烷基胺和吲哚胺。本研究采用了四种代表性的苯基哌嗪，即mCPP、三氟甲基苯哌嗪（TFMPP）、MK-212和喹哌嗪，一种苯烷基胺（-）DOM，以及一种吲哚胺，即麦角酸二乙酰胺（LSD）。这些化合物的效力通过以下方式定义：（1）在体外，根据它们刺激脉络丛中PI水解增加的能力；（2）在体内，根据它们替代mCPP辨别刺激的能力。5-HT2C位点的体外内在活性表示为血清素（5-HT）引发的最大PI水解反应的分数。MK-212（效价分数 = 1.1）和（-）DOM（0.77）是完全激动剂，而mCPP（0.72）、LSD（0.27）、喹哌嗪（0.24）和TFMPP（0.22）在刺激5-HT2C受体处的PI水解方面是部分激动剂。在体内，每种苯基哌嗪都能完全替代mCPP刺激，而（-）DOM（75%）和LSD（67%）仅引起部分替代。虽然在体外对5-HT2C受体具有激动剂活性的化合物在体内可替代mCPP刺激，但在5-HT2C受体处关于刺激PI周转的体外内在活性与在体内对mCPP刺激的最大替代之间不存在明确关系。目前的数据表明，mCPP引发一种复合刺激，该刺激由5-HT2C受体上的激动剂相互作用介导，并可能与5-HT2A、5-HT3和/或5-HT1B受体存在额外相互作用。
