Factors Underlying +/- 3, 4-Methylenedioxymethamphetamine Self Administration

Abstract

Rationale: +/- 3, 4-Methylenedioxymethamphetamine (MDMA; Ecstasy) consumption has increased globally over the past two decades. Human studies have demonstrated that in a small proportion of users MDMA consumption may become problematic. Limited preclinical studies have evaluated the abuse potential of MDMA. Objectives: The present study sought to determine if MDMA selfadministration has similar addictive properties as other abused substances. Initial experiments sought to determine if MDMA could function as a reinforcer. Subsequent experiments assessed whether dopamine played a role in MDMA self-administration, whether MDMA self-administration was maintained by the presentation of a conditioned stimulus, and if extinguished MDMA self-administration could be reinstated. Methods: Animals were surgically implanted with indwelling intravenous catheters that allowed delivery of MDMA solution upon depression of an active lever. MDMA self-administration was examined in drug naïve and cocaine-trained animals. Further assessment of the reliability of self-administration was assessed using a yoked procedure, dose effect curves were obtained, vehicle substitution occurred, and progressive ratio procedures were used. The underlying role of dopamine in mediating MDMA self-administration was determined using the D1- like antagonist, SCH23390, and D2-like antagonist, eticlopride. Manipulation of the light and/or drug stimulus was used to provide initial assessment of the conditioning properties of MDMA. The ability of 10 mg/kg MDMA to reinstate responding previously maintained by MDMA was also determined. Results: MDMA was reliably self-administered in drug naïve and cocaine trained animals. Responding was selective to contingent MDMA administration, reduced with vehicle substitution, sensitive to dose manipulation, and increasing demand. A rightward shift in the dose effect curve was demonstrated after administration of SCH23390. Removal of both the light and drug stimuli produced a rapid reduction in responding. Removal of either the light or drug stimulus produced a gradual reduction over 15 days. Administration of MDMA reinstated responding previously maintained by MDMA. Conclusion: The demonstration of reliable MDMA self-administration provided a baseline for assessing MDMA abuse potential. MDMA selfadministration was mediated by dopaminergic mechanisms which may be similar to those demonstrated for other abused substances. MDMA selfadministration also produced conditioning - a feature of compulsive drug use. Responding previously maintained by MDMA was later reinstated by MDMA, demonstrating that MDMA use may result in relapse. MDMA has similar behavioural properties as other commonly abused substances.