Serotonin antagonists fail to alter MDMA self-administration in rats
Aronsen, D., Bukholt, N., Foote, J., Highgate, Q., Schenk, S., Van de Wetering, R., Webster, J.
This vehicle-controlled rat study (n=23) investigated the role of serotonergic agonists in preventing relapse into drug-seeking behavior, in response to re-exposure to a single dose of MDMA or cocaine (10.0 mg/kg), or a conditioned light-cue associated with their drug-intake prior to extinction. Results indicate that 5-HT1A and 5-HT2A agonists prevent relapse into cocaine self-administration, but neither of the 5-HT1A, 5-HT1B, or 5-HT2A agonists could alter the maintenance of MDMA self-administration. However, the 5-HT1A agonists prevented relapse into drug-seeking behavior elicited by exposure to cues that had been associated with self-administered MDMA.
Abstract
Introduction: Acute exposure to ±3,4-methylenedioxymethamphetamine (MDMA) preferentially increases release of serotonin (5-HT), and a role of 5-HT in many of the behavioral effects of acute exposure to MDMA has been demonstrated. A role of 5-HT in MDMA self-administration in rats has not, however, been adequately determined. Therefore, the present study measured the effect of pharmacological manipulation of some 5-HT receptor subtypes on self-administration of MDMA.Methods: Rats received extensive experience with self-administered MDMA prior to tests with 5-HT ligands. Doses of the 5-HT1A antagonist, WAY 100635 (0.1-1.0 mg/kg), 5-HT1B antagonist, GR 127935 (1.0-3.0 mg/kg), and the 5-HT2A antagonist, ketanserin (1.0-3.0 mg/kg) that have previously been shown to decrease self-administration of other psychostimulants and that decreased MDMA-produced hyperactivity in the present study did not alter MDMA self-administration.Results: Experimenter-administered injections of MDMA (10.0 mg/kg, ip) reinstated extinguished drug-taking behavior, but this also was not decreased by any of the antagonists. In contrast, both WAY 100635 and ketanserin, but not GR 127935, decreased cocaine-produced drug seeking in rats that had been trained to self-administered cocaine. The 5-HT1A agonist, 8-OH-DPAT (0.1-1.0 mg/kg), but not the 5-HT1B/1A agonist, RU 24969 (0.3-3.0 mg/kg), decreased drug-seeking produced by the reintroduction of a light stimulus that had been paired with self-administered MDMA infusions.Discussion: These findings suggest a limited role of activation of 5-HT1A, 5-HT1B or 5-HT₂ receptor mechanisms in MDMA self-administration or in MDMA-produced drug-seeking following extinction. The data suggest, however, that 5-HT1A agonists inhibit cue-induced drug-seeking following extinction of MDMA self-administration and might, therefore, be useful adjuncts to therapies to limit relapse to MDMA use.