Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebrovascular hyperperfusion in adult male Wistar rats

E.L. van Donkelaar, P.A. Kelly, N. Dawson, A. Blokland, J. Prickaerts, H.W.M. Steinbusch, L. Ferrington

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Abstract

The serotonergic (5-hydroxytryptannine; 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 neurotoxicty (MDMA, or "ecstasy"). Acute tryptophan depletion (AID) 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 AID by using quantitative [C-14]2-deoxyglucose and [C-14]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 AID. 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 AID in control animals, whereas a higher ratio was observed after AID 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. (C) 2009 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)1557-1568
Number of pages12
JournalJournal of Neuroscience Research
Volume88
Issue number7
DOIs
Publication statusPublished - 15 May 2010

Keywords

  • 5-HT RELEASE
  • CEREBRAL-BLOOD-FLOW
  • COGNITIVE PERFORMANCE
  • GELATIN-BASED MIXTURE
  • GLUCOSE-UTILIZATION
  • IMPAIRS OBJECT MEMORY
  • NEUTRAL AMINO-ACIDS
  • NITRIC-OXIDE SYNTHASE
  • RHESUS-MONKEYS
  • SEROTONIN UPTAKE SITES
  • cerebrovascular dysfunction
  • ecstacy
  • flow-metabolism coupling
  • plasma tryptophan
  • serotonin

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