New Insights on Different Response of MDMA-Elicited Serotonin Syndrome to Systemic and Intracranial Administrations in the Rat Brain.
Ibrahim M. Shokry, John J. Callanan, John Sousa, Rui Tao
PLoS One 2016 DOI: 10.1371/journal.pone.0155551 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Adult male Sprague Dawley rats |
| Intervention | MDMA |
| Topics | MDMA Serotonin |
| Key findings | Intraperitoneal MDMA produced excess serotonin at all five brain sites examined and hypothermia, whereas intracerebroventricular and reverse-microdialysis MDMA produced excess serotonin only at the delivery site without changing body-core temperature. The authors argue that serotonin syndrome requires simultaneous serotonin excess in many brain areas, and that poor diffusion from localized administration explains why intracranial MDMA does not reproduce it. |
Abstract
In spite of the fact that systemic administration of MDMA elicits serotonin syndrome, direct intracranial administration fails to reproduce the effect. To reconcile these findings, it has been suggested that the cause of serotonin syndrome is attributed mainly to MDMA hepatic metabolites, and less likely to MDMA itself. Recently, however, this explanation has been challenged, and alternative hypotheses need to be explored. Here, we tested the hypothesis that serotonin syndrome is the result of excessive 5HT simultaneously in many brain areas, while MDMA administered intracranially fails to cause serotonin syndrome because it produces only a localized effect at the delivery site and not to other parts of the brain. This hypothesis was examined using adult male Sprague Dawley rats by comparing 5HT responses in the right and left hemispheric frontal cortices, right and left hemispheric diencephalons, and medullar raphe nucleus. Occurrence of serotonin syndrome was confirmed by measuring change in body temperature. Administration routes included intraperitoneal (IP), intracerebroventricular (ICV) and reverse microdialysis. First, we found that IP administration caused excessive 5HT in all five sites investigated and induced hypothermia, suggesting the development of the serotonin syndrome. In contrast, ICV and reverse microdialysis caused excessive 5HT only in regions of delivery sites without changes in body-core temperature, suggesting the absence of the syndrome. Next, chemical dyes were used to trace differences in distribution and diffusion patterns between administration routes. After systemic administration, the dyes were found to be evenly distributed in the brain. However, the dyes administered through ICV or reverse microdialysis injection still remained in the delivery sites, poorly diffusing to the brain. In conclusion, intracranial MDMA administration in one area has no or little effect on other areas, which must be considered a plausible reason for the difference in MDMA-elicited serotonin syndrome between systemic and intracranial administrations.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 2
- Examining the Role of Oxytocinergic Signaling and Neuroinflammatory Markers in the Therapeutic Effects of MDMA in a Rat Model for PTSD. Pharmaceuticals June 27, 2024
- Differential role of dose and environment in initiating and intensifying neurotoxicity caused by MDMA in rats BMC Pharmacology and Toxicology August 5, 2019
Cites 12
- Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat Journal of Neuroscience July 1, 1998
- 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings Psychopharmacology March 15, 2006
- The Role of Metabolism in 3,4-(±)-Methylenedioxyamphetamine and 3,4-(±)-Methylenedioxymethamphetamine (Ecstasy) toxicity Therapeutic Drug Monitoring March 19, 2004
- MDMA (ecstasy) effects on cultured serotonergic neurons: evidence for Ca2+-dependent toxicity linked to release Brain Research February 1, 1990
- Stimulant effects of 3,4-methylenedioxymethamphetamine in the nucleus accumbens of rat. European Journal of Pharmacology April 7, 1992
and 7 more in the library