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MDMA induced dopamine release in vivo: role of endogenous serotonin
1Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
Abstract:
Acting as a substrate at the serotonin (5-HT) transporter, (+)-MDMA (3,4-methylenedioxymethamphetamine), is a potent releaser of 5-HT and causes toxicity to 5-HT neurons after repeated exposure. (+)-MDMA also releases dopamine (DA), although with less potency. Since we have shown previously that the intrastriatal application of 5-HT facilities DA release, it was hypothesized that increased release of striatal 5-HT after MDMA may influence extracellular levels of DA. Using microdialysis in vivo, we found that (+)-MDMA (4.7 mumol/kg, i.v.) administration increased extracellular striatal DA levels to 501% of control (p < 0.01, n = 12). However, in the presence of fluoxetine (14.4 mumol/kg, s.c.), which prevents (+)-MDMA effects on 5-HT release, the (+)-MDMA-induced increase in DA was significantly less (to 375% of control, p < 0.05, vs. no fluoxetine, n = 8). In vitro studies with striatal slices, to test drug selectivity, showed that (+)-MDMA (0.3-3 microM) increased extracellular levels of both DA and 5-HT in a dose-dependent manner. Fluoxetine (3 microM) completely blocked the effects of (+)-MDMA on 5-HT release, but did not alter (+)-MDMA-induced DA release in vitro. The selective DA transport inhibitor GBR-12909 (1 microM), blocked (+)-MDMA's effect on DA release. It is concluded that 5-HT release after (+)-MDMA treatment partially contributes to (+)-MDMA's effect on DA release in vivo.
Insights
(+)-MDMA releases serotonin (5-HT) and dopamine (DA). This study shows that 5-HT release partially drives the increase in dopamine levels observed after MDMA administration in vivo.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- (+)-MDMA (3,4-methylenedioxymethamphetamine) is known to affect serotonin (5-HT) and dopamine (DA) systems.
- Previous research indicated that 5-HT can facilitate DA release in the striatum.
Purpose of the Study:
- To investigate the hypothesis that increased striatal 5-HT release following MDMA administration contributes to elevated extracellular DA levels.
- To elucidate the specific roles of 5-HT and DA transporters in MDMA's neurochemical effects.
Main Methods:
- In vivo microdialysis in rats to measure extracellular DA and 5-HT levels in the striatum after MDMA administration.
- In vitro studies using striatal slices to assess the direct effects of MDMA on DA and 5-HT release.
- Pharmacological interventions using fluoxetine (a 5-HT reuptake inhibitor) and GBR-12909 (a selective DA transporter inhibitor).
Main Results:
- (+)-MDMA administration significantly increased extracellular striatal DA levels in vivo.
- Blocking 5-HT release with fluoxetine partially attenuated the MDMA-induced increase in DA, suggesting a role for 5-HT.
- In vitro, MDMA increased both DA and 5-HT release dose-dependently, but fluoxetine only blocked 5-HT release, while GBR-12909 blocked DA release.
- MDMA's effect on DA release in vitro was independent of 5-HT release.
Conclusions:
- 5-HT release induced by (+)-MDMA plays a partial role in elevating extracellular DA levels in the striatum in vivo.
- (+)-MDMA's effects on DA release in vitro are mediated directly via the DA transporter and are not dependent on 5-HT release.
- The findings highlight the complex interplay between serotonergic and dopaminergic systems modulated by MDMA.