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

Eva van Donkelaar, Neil Dawson, Paul A.T Kelly, Arjan Blokland, Jos Prickaerts, Harry WM Steinbusch, Linda Ferrington

Research output: Contribution to journalArticle

6 Citations (Scopus)

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

Fingerprint

N-Methyl-3,4-methylenedioxyamphetamine
Tryptophan
Wistar Rats
Serotonin
Depression
Neutral Amino Acids
Paroxetine
Deoxyglucose
Brain

Keywords

  • neuroscience
  • cerebrovascular control
  • depression
  • numerical modelling
  • ecstacy
  • serotonin
  • plasma tryptophan

Cite this

van Donkelaar, E., Dawson, N., Kelly, P. A. T., Blokland, A., Prickaerts, J., Steinbusch, H. WM., & Ferrington, L. (2010). Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebovascular hyperfusion in adult male wistar rats. Journal of Neuroscience Research, 88, 1557-1568. https://doi.org/10.1002/jnr.22308
van Donkelaar, Eva ; Dawson, Neil ; Kelly, Paul A.T ; Blokland, Arjan ; Prickaerts, Jos ; Steinbusch, Harry WM ; Ferrington, Linda. / Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebovascular hyperfusion in adult male wistar rats. In: Journal of Neuroscience Research. 2010 ; Vol. 88. pp. 1557-1568.
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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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van Donkelaar, E, Dawson, N, Kelly, PAT, Blokland, A, Prickaerts, J, Steinbusch, HWM & Ferrington, L 2010, 'Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebovascular hyperfusion in adult male wistar rats', Journal of Neuroscience Research, vol. 88, pp. 1557-1568. https://doi.org/10.1002/jnr.22308

Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebovascular hyperfusion in adult male wistar rats. / van Donkelaar, Eva; Dawson, Neil; Kelly, Paul A.T; Blokland, Arjan; Prickaerts, Jos; Steinbusch, Harry WM; Ferrington, Linda.

In: Journal of Neuroscience Research, Vol. 88, 2010, p. 1557-1568.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebovascular hyperfusion in adult male wistar rats

AU - van Donkelaar, Eva

AU - Dawson, Neil

AU - Kelly, Paul A.T

AU - Blokland, Arjan

AU - Prickaerts, Jos

AU - Steinbusch, Harry WM

AU - Ferrington, Linda

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

KW - neuroscience

KW - cerebrovascular control

KW - depression

KW - numerical modelling

KW - ecstacy

KW - serotonin

KW - plasma tryptophan

U2 - 10.1002/jnr.22308

DO - 10.1002/jnr.22308

M3 - Article

VL - 88

SP - 1557

EP - 1568

JO - Journal of Neuroscience Research

JF - Journal of Neuroscience Research

SN - 0360-4012

ER -