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Pharmacological interaction between reboxetine and 3,4-Methylenedioxymeth-amphetamine (MDMA, Ecstasy): pharmacological effects and pharmacokinetics
| Third-party funded project |
| Project title |
Pharmacological interaction between reboxetine and 3,4-Methylenedioxymeth-amphetamine (MDMA, Ecstasy): pharmacological effects and pharmacokinetics |
| Principal Investigator(s) |
Liechti, Matthias Emanuel
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| Organisation / Research unit |
Departement Biomedizin / Clinical Pharmacology (Krähenbühl) |
| Project start |
01.06.2009 |
| Probable end |
31.05.2010 |
| Status |
Completed |
| Abstract |
3,4-methylenedioxymethamphetamine (MDMA, ecstasy ) is widely used by young people for its euphoric effects. MDMA releases norepinephrine, serotonin, and dopamine through an interaction with the corresponding presynaptic monoamine uptake transporter. Serotonin uptake inhibitors including citalopram, paroxetine, and fluoxetine have been shown to attenuate subjective and cardiovascular effects of MDMA in humans indicating that release of serotonin partly mediates the pharmacological action of MDMA. Dopamine plays an important role in the reinforcing effects of all drugs of abuse and has been shown to modulate some of the positive mood effects produced by MDMA. It is unknown, however, to what extent norepinephrine contributes to the effects of MDMA in humans. MDMA binds to the norepinephrine uptake site with high affinity and releases norepinephrine more potently than it releases serotonin or dopamine. In animals, the norepinephrine uptake inhibitor desipramine attenuated acute cognitive effects of MDMA. MDMA also increases plasma norepinephrine levels and postsynaptic blockade of noradrenergic receptors blocked the locomotor and hyperthermic response to MDMA in rats. These results suggest that norepinephrine partly mediates pharmacological effects of MDMA. We therefore suggest evaluating the effects of pretreatment with the selective norepinephrine transport blocker reboxetine on the pharmacodynamics and pharmacokinetics of MDMA. The study will use a randomized double-blind cross-over design with four experimental sessions. Reboxetine (8 mg) or placebo will be administered the night before the experimental session and 1 h before the administration of MDMA (125 mg) or placebo to 16 healthy volunteers. Subjective and cardiovascular responses and plasma samples for pharmacokinetics will be repeatedly assessed throughout the experiments. We hypothesize that the highly selective norepinephrine uptake inhibitor reboxetine will attenuate subjective and especially heart rate and blood pressure responses to MDMA. Such a result would indicate that norepinephrine is critically involved in the pharmacology of MDMA and may provide helpful in the use and development of treatments for Ecstasy intoxications. |
| Financed by |
Foundations and Associations
Private Sector / Industry
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10/05/2024
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