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The role of the dopamine/norepinephrine transporters (SLC6A3/2) and of genetic polymorphisms in the effects of MDMA (ecstasy)
Third-party funded project
Project title The role of the dopamine/norepinephrine transporters (SLC6A3/2) and of genetic polymorphisms in the effects of MDMA (ecstasy)
Principal Investigator(s) Liechti, Matthias Emanuel
Organisation / Research unit Departement Biomedizin / Psychopharmacology Research (Liechti),
Bereich Medizinische Fächer (Klinik) / Klinische Pharmakologie
Project start 01.10.2013
Probable end 30.09.2016
Status Completed
Abstract

Background: Abuse of amphetamine-type substances including MDMA (ecstasy) is prevalent in our society. MDMA releases serotonin (5-HT), norepinephrine (NE) and dopamine (DA) by interacting with the respective monoamine transporters. DA is implicated in the addictive properties of drugs of abuse and DA and NE possible also in drug-induced euphoria. 5-HT mediates many of the acute effects of MDMA. However, it is not clear whether DA/NE transporter (SLC6A3/2)-mediated DA/NE release contributes to the acute effects of MDMA in humans. In addition, marked interindividual differences exist in the euphoric response to psychostimulants and in the risk of developing drug addiction and polymorphisms in gens that code for monoamine transporters and receptors are likely to critically contribute to interindividual variations in the response to amphetamines including MDMA. Furthermore, MDMA is primarily metabolized by the polymorphic CYP 2D6 enzyme. Variance in the CYP2D6 geno- and phenotype may therefore be associated with interindividual differences in plasma concentrations and associated toxicity produced by MDMA. Aim: We aim to evaluate the role of the DA/NET transporter and genetic polymorphism in monoamine transporters/receptors and different CYPs including CYP2D6 in the human pharmacology and toxicology of MDMA. Method: In study 1, we will investigate the effects of a pretreatment with the DA/NE transporter inhibitor bupropion on the acute effects of MDMA in 16 healthy subjects using a randomized placebo-controlled four-period factorial study design. The primary hypothesis is that bupropion will reduce the positive mood effects of MDMA. Secondary outcomes include cardiovascular effects, emotion recognition, empathic effects, pupillometry, and neuroendocrine effects, pharmacokinetics of MDMA, and adverse effects. Failure to demonstrate inhibition of the response to MDMA by bupropion would support 5-HT as the primary mediator. After the completion of study 1 the data will be pooled with all our previous comprehensive clinical data to form a large and worldwide unique cohort of MDMA-treated subjects (N=142). In study 2 we will then analyze associations between the response to MDMA and genetic polymorphisms and haplotypes in transporter/receptors involved in monoaminergic neurotransmission in this pooled sample and in an international larger sample (N=222). All subjects will also be tested for CYP2D6 pheno- and CYP2D6/2C19/2B6/1A2 genotypes involved in the metabolism of MDMA. Significance: This is the first study to investigate the role of the DA transporter in the mechanism of action of MDMA in humans. It is also the first pharmacogenetic study to assess the contribution of genetic variations in the monaminergic system to the effects of MDMA. Worldwide, there are no similarly large cohorts that would allow for the testing of these associations including also CYP pheno- and genotype data. The study will contribute to our understanding of the role of DA/NE vs. SERT and in particular the genetic determinants underlying the interindividual differences in the effects of amphetamine-like substances.

Financed by Swiss National Science Foundation (SNSF)
   

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29/03/2024