Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebrovascular hyperperfusion in adult male Wistar rats.
Eva L Van Donkelaar, Paul A. Kelly, Neil Dawson, Arjan Blokland, Jos Prickaerts, Harry W M Steinbusch, Linda Ferrington
Journal of Neuroscience Research May 15, 2010 DOI: 10.1002/jnr.22308 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled animal experiment Peer reviewed |
|---|---|
| Population | Male Wistar rats |
| Interventions | MDMA Acute tryptophan depletion (ATD) |
| Dose | 20 mg kg(-1), twice daily for 4 days |
| Duration | 4-day MDMA treatment, challenged 3 weeks later |
| Measures | Paroxetine binding to 5-HT transporter sites, plasma TRP/sum large neutral amino acids ratio, cerebral metabolic rate of glucose (CMRG), cerebral blood flow (CBF) |
| Topics | MDMA |
| Key findings | Prior MDMA treatment depleted serotonin terminals and reversed the cerebrovascular response to acute tryptophan depletion: ATD lowered the cerebral blood flow-to-metabolism ratio in control rats but raised it in MDMA-treated rats. The authors suggest this indicates an ATD-induced loss of cerebrovascular tone in MDMA-exposed animals that might contribute to the behavioral dysfunction of depression. |
Abstract
The serotonergic (5-hydroxytryptamine; 5-HT) dysfunction found in depression may affect not only brain function (mood) but also cerebrovascular control. Similar, but possibly occult, disturbances may also be induced by 3,4-methylenedioxymethamphetamine-induced neurotoxicity (MDMA, or "ecstasy"). Acute tryptophan depletion (ATD) is widely used to identify vulnerability to depression, and we hypothesized that repeated MDMA administration would increase the sensitivity of rats to this acute serotonergic challenge. In this study, male Wistar rats were injected with MDMA (20 mg kg(-1), twice daily for 4 days) and challenged 3 weeks later with ATD, induced by intragastric administration of a nutritional mixture with tryptophan (TRP) removed. Cerebral metabolism (CMRG) and blood flow (CBF) were measured in parallel groups of animals following ATD by using quantitative [(14)C]2-deoxyglucose and [(14)C]iodoantipyrine autoradiographic techniques, respectively. A significant reduction in paroxetine binding to 5-HT transporter sites in MDMA-treated rats indicated 5HT terminal depletion, whereas the plasma TRP/sum large neutral amino acids ratio was reduced by 40% following ATD. Under all experimental conditions, the normal close correlation between CBF and metabolic demand was maintained. However, a global analysis of all brain regions revealed a significant decrease in the overall ratio of CBF to CMRG after ATD in control animals, whereas a higher ratio was observed after ATD in the MDMA-treated group. This increase in blood flow relative to cerebral metabolism suggests an ATD-induced loss of cerebrovascular tone in MDMA-treated animals that could have pathophysiological consequences and might conceivably contribute to the behavioral dysfunction of depression.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
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- (±)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-Induced Serotonin Neurotoxicity: Studies in Animals Neuropsychobiology 2000
- 3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings Psychopharmacology March 15, 2006
- Is Recreational Ecstasy (MDMA) Use Associated with Higher Levels of Depressive Symptoms? Journal of Psychoactive Drugs March 1, 2007
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