MDMA self‐administration in rats: acquisition, progressive ratio responding and serotonin transporter binding

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) self-administration has been shown in animals with extensive drug histories, but only a small number of studies have examined high rates of responding maintained by MDMA in previously drug-naïve animals. In the present study, influence of dose (0.25 or 1.0 mg/kg/infusion) on the acquisition of MDMA self-administration was measured during daily 6-h sessions. Dose-effect data were obtained for MDMA (0.25-1.0 mg/kg/infusion) self-administration under a progressive ratio (PR) schedule of reinforcement. The effect of experimenter- or self-administered MDMA on [3H] paroxetine binding in several brain regions was measured. Acquisition of MDMA self-administration was highly variable and not different for 0.25 or 1.0 mg/kg/infusion progressed with approximately 60% of the rats acquiring reliable self-administration during the 15-day test period. The percentage of rats that acquired MDMA self-administration was lower than the percentage of rats that acquired cocaine (0.5 mg/kg/infusion) self-administration, and cocaine self-administration was acquired with a shorter latency. Responding maintained by MDMA was dose dependent, and breakpoints under a PR schedule increased with dose. Radioligand binding and autoradiography demonstrated lower densities of serotonin transporter sites (SERT) in MDMA self-administering rats as compared with controls across brain regions. The reduction in SERT densities was comparable in magnitude to rats treated with experimenter-administered doses of MDMA. These data support the idea that MDMA is a drug with high abuse liability, and long-term self-administration may lead to long-lasting deficits in serotonin neurotransmission.

Differential changes in mesolimbic dopamine following contingent and non-contingent MDMA self-administration in mice

“…However, most of these studies used high doses delivered by the experimenter, often producing neurotoxicity in the 5-HT system in rats (Clemens et al 2004;Colado et al 2004;Mayerhofer et al 2001;Thompson et al 2008) or in the DA system in mice (Colado et al 2004;Itzhak et al 2003). Recently, a decrease in striatal 5-HT binding was reported in rats 2 weeks after self-administration of high doses of MDMA (25 mg/kg/day) during 17 days (Schenk et al 2007). This effect was comparable to the one produced by the administration of similar doses by the experimenter.…”

“…In contrast to mice, changes in serotonergic markers of neurotoxicity have been observed in rats and monkeys without alterations in the dopaminergic system (Ricaurte et al 1988;Mayerhofer et al 2001;Green et al 2003;Colado et al 2004). More recently, a decrease in SERT binding was observed following 17 days of MDMA (1 mg/kg per infusion) self-administration in rats that had been initially trained to self-administer cocaine (Schenk et al 2007).…”

Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview

“…), indicating that these doses possess reinforcing efficacy [198,199]. Additionally, MDMA (1.0 mg/kg, i.v.)…”

Metabolism and Disposition of 3,4-Methylenedioxymethamphetamine (“Ecstasy”) in Baboons after Oral Administration: Comparison with Humans Reveals Marked Differences

“…In an effort to better understand effects of MDMA in humans, various laboratory animal models have been used to study the behavioral pharmacology and neurotoxicology of MDMA. Intravenous self-administration of MDMA (a measure of abuse liability) has been demonstrated in baboons (Lamb and Griffiths, 1987), rhesus macaques (Beardsley et al, 1986;Fantegrossi et al, 2002;Lile et al, 2005), and rats (Schenk et al, 2007). Likewise, the neurotoxic effects of MDMA have been reported in baboons (Scheffel et al, 1998), rhesus monkeys (Kleven et al, 1989), and rats (Commins et al, 1987;Schmidt, 1987).…”