The role of Dopamine in the Sensitised Locomotor Activating Effects of Methylenedioxymethamphetamine (MDMA) in Rats

Under certain regimens of repeated pre-exposure, psychostimulant drugs show an increase in locomotor activity across days of testing and, after abstinence from the drug, a greater responsiveness to a subsequent challenge dose of the drug. This phenomenon, termed behavioural sensitisation, is thought to underlie certain aspects of drug addiction such as drug seeking and relapse. Repeated administration of +/-3, 4-Methylenedioxymethamphetamine (MDMA, ecstasy) produced sensitised hyperactivity in rats suggesting a lasting neurological change. The present studies sought to evaluate some of the parameters around both the induction and expression of behavioural sensitisation to MDMA and to evaluate if the sensitivity of the dopamine (DA) D1 and D2 receptors had altered under the current pre-exposure regimen of MDMA. Further, following MDMA pre-exposure that results n behavioural sensitisation, changes in potency to the reinforcing effects of MDMA were investigated through the self administration paradigm. Finally, high performance liquid chromatography (HPLC) was used to evaluate changes in brain amine levels following sensitisation to MDMA locomotor activating effects. Rats received a pre-treatment regimen consisting of 5 daily injections of MDMA (0.0, 5.0 or 10mg/kg i.p). MDMA-produced locomotor activity was measured after 2, 9 or 28 days of withdrawal. In other groups, hyperactivity following administration the DA D1 agonist SKF81297 (0.0, 0.5, 1.0, 2.0, 4.0 or 8.0 mg/kg), or the D2-like DA agonist apomorphine (0.0, 0.5, 1.0, 2.0 or 4.0 mg/kg) was measured in groups that received pre-exposure to MDMA (10.0 4mg/kg) or vehicle. The effects of the D1 antagonist SCH23390 (0.0, 0.01, 0.02, or 0.04 mg/kg), the D2 antagonist eticlopride (0.03, 0.01, 0.003, 0.05, 0.1, or 0.2 mg/kg) or the 5-HT2C antagonist RS102221 (0.0, 0.25, 0.5, or 1.0 mg/kg) on MDMA-produced hyperactivity in MDMA or vehicle pre-treated rats was also measured. In Experiment 3, effects of MDMA or vehicle pre-treatment on latency to acquisition of MDMA (0.5 or 1.0 mg/kg/infusion) selfadministration was measured. In Experiment 4 effects of pre-treatment on brain tissue levels of DA, its metabolite homovanillic acid (HVA), serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were determined. The regimen of 5 daily treatments of 10.0mg/kg produced persistent behavioural sensitisation and cross-sensitisation to hyperactivity produced by DA receptor agonists. These effects were not, however, reflected in sensitised responses to the ability of the antagonists to attenuate MDMA-produced hyperactivity. Pre-treatment with MDMA did not decrease latency to acquisition of self-administration. Rather, there was an increased latency to acquisition of self-administration in the MDMA pre-treated rats. MDMA pretreatment decreased levels of the serotonin metabolite 5-HIAA in the frontal cortex and hippocampus. Following the current pre-treatment regimen, MDMA produced behavioural sensitisation is mediated by neuroadaptations in central dopaminergic substrates. The persistent locomotor sensitisation is similar to that produced by other amphetamine-like stimulants and might underlie use and abuse of this compound.