A 5-hydroxytryptamine-like mode of anorectic action for 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212)

Abstract

The mechanism of the reduction in food consumption elicited by 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) administered systemically was investigated in the rat. (+/-)-Fenfluramine and (+)-amphetamine were included in some studies for comparative purposes. 2 Pretreatment with methergoline, a 5-hydroxytryptamine (5-HT) antagonist, reduced the magnitude of the anorectic effect of 1.5 and 3 mg/kg of MK-212, while the anti-5-HT agents, cyproheptadine and cinanserin, were likewise effective against the 3 mg/kg dose. 3 Xylamidine, an antagonist of 5-HT that penetrates poorly into the central nervous system, completely blocked the decrease in food intake caused by 5-HT administered peripherally, while not antagonizing an equianorectic dose of MK-212. 4 Reduction of brain 5-HT by intraventricular injection of 5,6-dihydroxytryptamine, intraperitoneal administration of p-chloroamphetamine or placement of a lesion in the region of the median raphé nucleus diminished the anorectic response to 3 mg/kg of MK-212. The anorectic effect of amphetamine was reduced by p-chloroamphetamine or lesion in the raphé, but not by 5,6-dihydroxytryptamine. The decrease in food consumption produced by 1.5 mg/kg of MK-212 was antagonized by prior treatment with p-chloroamphetamine, but not by 5,6-dihydroxytryptamine. 5 Haloperidol, which blocks receptors for dopamine, antagonized the anorexigenic effect of amphetamine, but was ineffective in offsetting the action of MK-212, 3 mg/kg. 6 Pretreatment with chlorimipramine to inhibit the 5-hydroxytryptaminergic uptake mechanism did not affect the anorectic response to 3 mg/kg of MK-212, whereas the response to fenfluramine was diminished. 7 The results indicate that the anorectic action of MK-212 involves a 5-HT-like component which is more evident at the higher dose level of the compound. The anorexigenic property of MK-212 may depend, at least partly, upon the integrity of 5-HT-containing neurones in the central nervous system.