3,4-N-Methlenedioxymethamphetamine-Induced Hypophagia is Maintained in 5-HT(1B) Receptor Knockout Mice, but Suppressed by the 5-HT(2C) Receptor Antagonist RS102221
Conductier G, Crosson C, Hen R, Bockaert J, Compan V.
1UPR CNRS 5203, Genomique Fonctionnelle, Montpellier Cedex, France.
Neuropsychopharmacology. 2005 Jan 19


3,4-Methylenedioxy-N-methamphetamine (MDMA or 'ecstasy') is a psychoactive substance, first described as an appetite suppressant in humans, inducing side effects and even death. MDMA increases serotonin (5-HT) levels, and 5-HT inhibits food intake, but the 5-HT receptors involved in MDMA-induced changes in feeding behavior are unknown. We examined whether a systemic MDMA injection would reduce the physiological drive to eat in starved mice and tested if the inactivation of 5-HT(1B) or 5-HT(2C) receptors could restore this response. Our results indicate that in starved mice, MDMA (10 mg/kg) provoked an initial hypophagia for 1 h (-77%) followed by a period of hyperphagia (studied between 1 and 3 h). This biphasic feeding behavior due to MDMA treatment was maintained in 5-HT(1B) receptor-null mice or in animals treated with the 5-HT(1B/1D) receptor antagonist GR127935 (3 or 10 mg/kg). In contrast, MDMA-induced hypophagia (for the first 1 h period) was suppressed when combined with the 5-HT(2C) receptor antagonist RS102221 (2 mg/kg). However, RS102221 did not alter MDMA-induced hyperphagia (for the 1-3 h period) but did exert a stimulant effect, when administered alone, during that period. We have previously shown that MDMA or 5-HT(1A/1B) receptor agonist RU24969 fails to stimulate locomotor activity in 5-HT(1B) receptor-null mice. Our present data indicate that the 5-HT(2C) receptor antagonist RS102221 suppresses MDMA-induced hyperlocomotion. These findings provide the first evidence that the inactivation of 5-HT(2C) receptors may reduce hypophagia and motor response to MDMA, while a genetic deficit or pharmacological inactivation of 5-HT(1B) receptors was insufficient to alter the feeding response to MDMA.

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