Thermoregulatory, behavioural and neurochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related stimulant drugs.

Abstract

3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is an amphetamine derivative widely used in rave party and club scenes. In some users, MDMA causes fatalities, most often due to acute hyperthermia which leads eventually to multi-organ failure. Other structurally related drugs, including methamphetamine and para-methoxyamphetamine (PMA), as well as structurally unrelated cocaine, have also been associated with death due to hyperthermia, and are also often taken with or instead of MDMA. Harm minimisation advice to prevent this acute hyperthermia depends on appropriate thermoregulatory behaviour by drug users, an aspect of thermoregulation which had not been studied with respect to MDMA previously. The purpose of this thesis was to use a novel behavioural thermoregulation model in rats to investigate the effects of MDMA and other stimulant drugs on behavioural thermoregulation and related physiological parameters, as well as investigating residual neurochemical changes caused by these substances. The behavioural thermoregulation model used throughout most of this thesis involved rats being administered a drug, immediately prior to being confined to a set ambient temperature (30 ± 1º or 21.5 ± 1.5ºC) for 30 minutes. Rats were then immediately allowed access to a thermally graded runway (11-41ºC) where they were able to choose their preferred temperature for a further 4 hours. The final study consisted of giving rats a drug in their home cages at an elevated ambient temperature. Firstly, a dose-response study was conducted using MDMA, PMA, methamphetamine and cocaine. All drugs lead to a dose dependent increase in core temperature at high ambient temperature, and this led to animals seeking the cool end of the runway after MDMA, methamphetamine and cocaine administration, but not after PMA. Methamphetamine was the most potent drug at increasing core temperature, followed by MDMA and PMA, then cocaine as the least potent, however, MDMA and PMA showed steeper slopes on the doseresponse curves than methamphetamine and cocaine. The second study consisted of rats receiving MDMA at 30 or 21.5ºC for three consecutive days a week for one week or 6 weeks before being tested in the thermal gradient. The main findings of this study were that heart rate (HR) response to MDMA progressively decreased with repeated dosing over 6 weeks at both ambient temperatures, and that there was a difference in core temperature between rats treated for 6 weeks compared to 1 week when they were in the thermal gradient. The third study looked at the effects of MDMA in an animal model of depression, the Flinders Sensitive Line (FSL) rat. We showed that FSL rats were much more sensitive to the effects of MDMA at a high ambient temperature compared to Sprague-Dawley controls, however there were limited differences in behaviour in the thermal gradient between the strains. Pharmacokinetic analysis showed that there was no difference in blood or brain concentrations of MDMA, or its metabolite 3,4- methylenedioxyamphetamine (MDA) which could have explained the different responses. These concentrations also showed that the dosing regimens used throughout this thesis led to similar plasma concentration as those reported in human users. The final study was a pilot study done to see if proteomics could be a useful method to investigate the effects of MDMA and other stimulants on the brain after administration at a high ambient temperature. Rats were administered MDMA, methamphetamine or a combination, and several changes in protein expression were found. These were mostly evident in rats treated with MDMA which was in contrast to the effects on neurotransmitter concentration and acute hyperthermia, which was only seen in rats treated with MDMA and methamphetamine together. Three of the four results chapters in this thesis have been published or have been accepted for publication, while the fourth has been prepared as a manuscript ready for publication.