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Repeated administration of MDMA causes transient down-regulation of serotonin 5-HT2 receptors
U Scheffel1, J R Lever, M Stathis
1Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205.
Abstract:
The present study examined short- and long-term effects of MDMA (3,4-methylene-dioxymethamphetamine) on serotonin (5-HT2 and 5-HT1c) receptors in the brain of the rat. N1-Methyl-2-[125I]lysergic acid diethylamide ([125I]MIL) was used to label these receptors in vitro and in vivo. The usefulness of [125I]MIL for in vivo detection of changes in 5-HT2 receptors was confirmed in preliminary experiments in which rats were treated chronically with mianserin (5 mg/kg, once daily for 10 days). Decreases in specific in vivo binding of [125I]MIL, after treatment with mianserin were found to be of the same magnitude as those determined by others, using in vitro methods. The MDMA (8 doses; 5-20 mg/kg each) was administered to rats over a period of 4 days. At various times after administration of the last dose of MDMA, the binding of [125I]MIL was measured. Acutely, treatment with MDMA (20 mg/kg) reduced specific in vivo binding of [125I]MIL in all regions of brain studied. For example, in the frontal cortex, specific binding of [125I]MIL was decreased by 80% at 6 hr and by 62% at 24 hr, after cessation of treatment with MDMA. Twenty-one days after administration of MDMA however, the number of binding sites for [125I]MIL was back to control levels. Reductions in in vivo binding of [125I]MIL in frontal cortex were dependent on the dose of MDMA injected and were associated with decreases in the number of binding sites for [125I]MIL (Bmax values) in tissue homogenates of the same area. Autoradiographic studies of MDMA-treated rats confirmed the decreased density of 5-HT2 receptors and also suggested that the 5-HT1c receptor of the choroid plexus was not affected. These results indicate that repeated administration of MDMA caused transient down-regulation of 5-HT2 receptors in the brain of the rat. Further, they demonstrated that [125I]MIL is a suitable radioligand for labeling 5-HT2 receptors, both in vitro and in vivo. Once labeled with an appropriate radionuclide for SPECT (single photon emission computed tomography) or PET (positron emission tomography), MIL should prove useful for monitoring changes in the density of serotonin receptors in the living mammalian brain.
Insights
MDMA (3,4-methylene-dioxymethamphetamine) temporarily reduced serotonin 5-HT2 receptors in rat brains, with levels returning to normal within 21 days. This study confirms [125I]MIL
Area of Science:
- Neuroscience
- Pharmacology
- Radioligand Development
Background:
- Serotonin receptors, particularly 5-HT2, are crucial in brain function.
- MDMA (3,4-methylene-dioxymethamphetamine) is known to affect serotonin systems.
- Understanding MDMA's impact on serotonin receptors is vital for neuroscience and addiction research.
Purpose of the Study:
- To investigate the short- and long-term effects of MDMA on rat brain serotonin 5-HT2 and 5-HT1c receptors.
- To validate the use of N1-Methyl-2-[125I]lysergic acid diethylamide ([125I]MIL) as a radioligand for in vivo and in vitro receptor binding studies.
- To assess the reversibility of MDMA-induced changes in serotonin receptor density.
Main Methods:
- Utilized [125I]MIL to label serotonin 5-HT2 receptors in rat brain tissue and in vivo.
- Administered MDMA to rats over four days at doses ranging from 5-20 mg/kg.
- Measured [125I]MIL binding at various time points post-MDMA administration and performed autoradiographic studies.
Main Results:
- Acute MDMA administration (20 mg/kg) significantly reduced [125I]MIL binding in all brain regions studied, with frontal cortex showing an 80% decrease at 6 hours.
- Receptor binding returned to control levels 21 days after MDMA treatment, indicating transient effects.
- MDMA-induced reductions in binding were dose-dependent and correlated with decreased Bmax values, suggesting receptor down-regulation, while 5-HT1c receptors remained unaffected.
Conclusions:
- Repeated MDMA administration leads to a transient down-regulation of serotonin 5-HT2 receptors in the rat brain.
- [125I]MIL is a suitable radioligand for both in vitro and in vivo labeling of 5-HT2 receptors.
- MIL, when labeled for SPECT or PET imaging, holds potential for monitoring serotonin receptor density changes in living mammalian brains.