Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

Abstract

High or repeated doses of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy') produce long-lasting deficits in several markers of serotonin (5-HT) system integrity and also alter behavioral function. However, it is not yet clear whether MDMA-induced serotonergic neurotoxicity is responsible for these behavioral changes or whether other mechanisms are involved. The present experiment tested the hypothesis that blocking serotonergic neurotoxicity by pretreatment with the selective 5-HT reuptake inhibitor citalopram will also prevent the behavioral and physiological consequences of an MDMA binge administration. Male, SpragueDawley rats (N ¼ 67) received MDMA (4 Â 10 mg/kg) with or without citalopram (10 mg/kg) pretreatment. Core temperature, ejaculatory response, and body weight were monitored during and immediately following drug treatments. A battery of tests assessing motor, cognitive, exploratory, anxiety, and social behaviors was completed during a 10-week period following MDMA administration. Brain tissue was collected at 1 and 10 weeks after drug treatments for measurement of regional 5-HT transporter binding and (for the 1-week samples) 5-HT and 5-HIAA concentrations. Citalopram pretreatment blocked MDMA-related reductions in aggressive and exploratory behavior measured in the social interaction and hole-board tests respectively. Such pretreatment also had the expected protective effect against MDMA-induced 5-HT neurotoxicity at 1 week following the binge. In contrast, citalopram did not prevent most of the acute effects of MDMA (eg hyperthermia and weight loss), nor did it block the decreased motor activity seen in the binge-treated animals 1 day after dosing. These results suggest that some of the behavioral and physiological consequences of a high-dose MDMA regimen in rats are mediated by mechanisms other than the drug's effects on the serotonergic system. Elucidation of these mechanisms requires further study of the influence of MDMA on other neurotransmitter systems.

Residual social, memory and oxytocin-related changes in rats following repeated exposure to γ-hydroxybutyrate (GHB), 3,4-methylenedioxymethamphetamine (MDMA) or their combination

“…At 4 weeks following drug exposure, all drug pre-treated rats showed reduced social interaction relative to controls, with present results confirming that MDMA induces longterm residual deficits in social interaction and object recognition in rats (Fone et al 2002;McGregor et al 2003b;Morley et al 2001;Piper et al 2008). Importantly, the current study shows for the first time analogous residual adverse effects on social interaction with GHB, either given alone or in conjunction with MDMA.…”

“…Studies from several independent groups indicate that rats briefly exposed to MDMA display long-term adverse effects including increased anxiety, decreased social interaction and impaired object recognition memory (Able et al 2006;Fone et al 2002;McGregor et al 2003b;Morley et al 2001;Piper et al 2008). These effects of MDMA in laboratory animals agree with some reports of cognitive deficits and emotional problems in human MDMA users, although these human studies are frequently compromised by the methodological problems arising from the polydrug use that is typical of MDMA using populations (Rogers et al 2009).…”

“…The lasting effects of MDMA on memory and social behaviour can clearly occur in the absence of the characteristic 5-HT depletion that results from high-dose MDMA treatment (Clemens et al 2007;Fone et al 2002;McGregor et al 2003a). This suggests that non-serotonergic mechanisms may be implicated in MDMA-related harms (Baumann et al 2007;Piper et al 2008). Recent evidence indicates that the acute prosocial effects of MDMA in both rats and humans may involve the release of oxytocin (Dumont et al 2009;Thompson et al 2007), a neuropeptide that powerfully regulates mammalian affiliative behaviour (Neumann 2008).…”

Effects of MDMA on the Human Nervous System

“…Similar observations have been reported in animals (Piper et al, 2008). Of course, this leaves open the possibility that DA and NE, acting alone or in concert with 5-HT, may mediate MDMA's behavioral effects Vollenweider, 2000, 2001).…”

Rats preexposed to MDMA display attenuated responses to its aversive effects in the absence of persistent monoamine depletions

“…Following these CTA assessments, levels of several monoamines and metabolites in frontal cortex and caudateputamen were analyzed by HPLC-ED in a subset of subjects to determine if the observed behavioral responses to MDMA (and their change with drug preexposure) were associated with persistent changes in monoamine levels. This analysis stemmed from prior findings that persistent MDMA-induced behavioral plasticity may, in some cases, occur with long-term serotonin depletions (Piper et al 2008).…”