Comparative neuropharmacology of the substituted amphetamines: p-methoxyamphetamine (PMA) & 3,4-methylenedioxymethamphetamine (MDMA)

Abstract

Dramatic growth in substituted amphetamines (‘Ecstasy’) use since the 1980’s has correlated with increased incidence of acute toxicity and residual neuropsychological deficits. This thesis aimed to characterise the acute neurochemical mechanisms and residual neurochemical alterations produced by p-methoxyamphetamine (PMA), which is usually sold as ‘ecstasy’ and is associated with greater acute toxicity than 3,4-methylenedioxymethamphetamine (MDMA). While both PMA and MDMA primarily modulate dopaminergic and serotonergic neurotransmission, little is known of the differences in the neurochemical effects of PMA within the central nervous system, in vivo. This thesis used in vivo chronoamperometry to elucidate the acute neurochemical alterations in monoaminergic pharmacology in vivo after local application of PMA or MDMA within discrete brain nuclei in anaesthetised rats. Measurement of evoked release of monoamines including serotonin (5-HT), and inhibition of neurotransmitter uptake via membrane transporters were assessed. Initial studies compared pharmacodynamic responses of PMA and MDMA, showing PMA to have greater efficacy and potency for alteration of core body temperature in rats, a primary cause of acute toxicity, within minimal alteration in locomotion. Dose-response studies indicated local PMA application within striatum resulted in significantly greater 5-HT evoked release than MDMA, yet lesser dopaminergic release, as predicted by the pharmacodynamic data. Only PMA-evoked release could be partially blocked by pre-treatment with a 5-HT reuptake inhibitor (SERT). Differences in both the qualitative and quantitative nature of striatal evoked-release of 5HT and dopamine were noted for both drugs, which had not been previously seen. Both PMA and MDMA inhibited 5-HT clearance, but only MDMA inhibited dopamine clearance in striatum. Doseresponse studies in the CA3 region of hippocampus indicated PMA was also more efficacious than MDMA in the inhibition of 5-HT clearance in vivo. While the question of whether long term MDMA use induces selective neurodegeneration (reductions in serotonergic in vitro biomarkers) is still unclear, it was not known for PMA prior to this work. Repeated PMA administration was shown to result in reductions in cortical SERT (indicative of potential loss of 5-HT terminal axons), cortical 5-HT content was unaltered. A subsequent comprehensive study followed, comparing the residual effects of PMA or MDMA administration on in vitro serotonergic biomarkers (markers of selective neurodegeneration) and SERT function in vivo. PMA administration resulted in reductions in hippocampal SERT binding and [3H]-5HT synaptosomal uptake, correlating with in vitro biomarkers previously used. SERT function in vivo using chronoamperometric techniques was reduced, as would be predicted. However, hippocampal 5-HT content was again not reduced, indicating that selective neurodegeneration of 5-HT fibres may not in fact be occurring. MDMA administration reduced all measured in vitro serotonergic biomarkers, however SERT function in vivo was completely unaltered. These data indicate that reductions of in vitro biomarkers of 5-HT axonal degeneration do not necessarily predict the potential compensatory mechanisms that maintain SERT function in vivo. Compensatory mechanisms appear to exist in vivo to maintain clearance of extracellular 5- HT that may be disrupted or eliminated during tissue preparation for in vitro assays. In summary, while PMA produced significantly greater alterations, compared to MDMA, in processes intrinsic to 5-HT neurotransmission in both striatum and hippocampus, the magnitude of these responses did not explain the significantly higher risk of acute toxicity seen clinically with PMA use. The second component of the thesis extended beyond prior work, investigating the potential neurodegenerative effects of PMA and MDMA through the assessment of changes in key functional processes in 5-HT neurotransmisson. It is hoped this will contribute to the subsequent characterisation of the mechanism(s) of functional compensation in 5-HT neurotransmission which may lead to more targeted treatments to modulate potential psychological/psychiatric deficits that occur in regular ‘ecstasy’ users.