Hysek, Cédric Marc.
The role of norephinephrine in the pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy").
PhD Thesis, University of Basel,
Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10358
The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a widely used recreational drug, which produces strong psychological effects such as increased empathy and sociability. MDMA inhibits the uptake of and releases serotonin, dopamine, and norepinephrine via an interaction with the respective monoamine transporter. While the role of serotonin in the human pharmacology of MDMA has been well described, the role of norepinephrine in the mediation of the effect of MDMA is mostly unexplored. Preclinical data indicate that norepinephrine may play a crucial role in the effects of MDMA. This project focused on the role of norepinephrine in the pharmacology of MDMA in humans. We performed five experimental clinical studies and analyzed data from a previously performed study investigating the role of norepinephrine in the mechanism of action of MDMA. All studies were pharmacological interaction studies with selective medications used as research tools to inhibit the effects of MDMA in healthy subjects. All clinical studies used placebo-controlled, double-bind cross-over designs and were each performed in 16 healthy subjects in the University Hospital of Basel. In the first study, we showed that the selective norepinephrine transporter inhibitor reboxetine reduced the MDMA-induced increases in circulating plasma norepinephrine, psychostimulant, and cardiovascular effects in healthy volunteers. Moreover, we also showed that the observed pharmacodynamic interaction in this study was not attributed to a pharmacokinetic interaction between reboxetine and MDMA, because reboxetine decreased the pharmacodynamics effects of MDMA although it increased MDMA plasma levels. The results demonstrate a critical role for transporter-mediated norephinephrine release in the cardiovascular and the subjective stimulant-like effects of MDMA in humans. Norephinephrine transporter inhibitors could therefore be useful in the clinical treatment of stimulant addiction. In the second study, we then demonstrated that the a2 agonist clonidine, an inhibitor of the vesicular norepinephrine release, did not inhibit the response to MDMA in healthy subjects confirming that vesicular release of norepinephrine is not responsible for the effects of MDMA in humans. This study also confirmed indirectly that the monoamine transporter is the primary target of psychostimulants such as MDMA and that physiological impulse-dependent release of monoamines does not appear to be critical for the effects of MDMA in humans. In the ensuing studies we addressed the roles of the postsynaptic adrenergic receptors where the norepinephrine released by MDMA would be expected to act. We analyzed data from a previously performed study and showed that the non-selective ß adrenergic receptor antagonist pindolol reduced MDMA-induced increases in heart rate but had no effect on blood pressure or body temperature elevations produced by MDMA. In the third study, we assessed the effects of the postsynaptic a1 and ß adrenergic receptor antagonist carvedilol on the cardiostimulant, thermogenic, and subjective response to MDMA in healthy subjects. Carvedilol reduced elevations in blood pressure, heart rate, and body temperature but did not affect the subjective effects produced by MDMA. Thus, a1 and ß adrenergic receptors contribute to the cardiostimulant and thermogenic effects of MDMA in humans. The findings suggest that carvedilol would be useful in the treatment of cardiovascular and hyperthermic complications associated with ecstasy use. In the fourth study, we determined the effect of a pretreatment with the selective a1 adrenergic receptor blocker doxazosin on the response to MDMA. Doxazosin reduced MDMA-induced increases in blood pressure but did not affect heart rate responses to MDMA. Doxazosin also attenuated some of the subjective effects of MDMA indicating that a1 adrenergic also contribute to the psychotropic effects of MDMA. Taken together, the studies suggest a role for norepinephrine in particular in the cardio- and the psychostimulant aspects of the MDMA effect in humans. However, MDMA is not only a potent releaser of norepinephrine but also serotonin. Previous clinical studies have shown that inhibition of the serotonin transporter reduced positive psychotropic effects produced by MDMA. However, selective serotonin or norepinephrine transporter inhibitors, when used alone, only moderately affected the response to MDMA in humans. In fifth study we therefore tested the effects of the dual serotonin and norepinephrine transporter inhibitor duloxetine on the acute effects of MDMA in humans. We demonstrated that duloxetine almost completely prevented the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevation in MDMA plasma levels. The serotonin and norepinephrine transporters may therefore both be potential targets for the treatment of psychostimulant dependence.
|Committee Members:||Liechti, Matthias Emanuel and Borgwardt, Stefan|
|Faculties and Departments:||05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmakologie (Krähenbühl)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||164 S.|
|Last Modified:||30 Jun 2016 10:52|
|Deposited On:||30 Apr 2013 10:29|
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