Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebovascular hyperfusion in adult male wistar rats

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van Donkelaar, Eva and Dawson, Neil and Kelly, Paul A.T and Blokland, Arjan and Prickaerts, Jos and Steinbusch, Harry WM and Ferrington, Linda (2010) Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebovascular hyperfusion in adult male wistar rats. Journal of Neuroscience Research, 88. pp. 1557-1568. ISSN 0360-4012 (https://doi.org/10.1002/jnr.22308)

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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 neurotoxicty (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 [14C]2-deoxyglucose and [14C]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.

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