PMID- 33607146
OWN - NLM
STAT- MEDLINE
DCOM- 20211203
LR  - 20211214
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Linking)
VI  - 187
DP  - 2021 Apr 1
TI  - Increased kynurenine concentration attenuates serotonergic neurotoxicity induced 
      by 3,4-methylenedioxymethamphetamine (MDMA) in rats through activation of aryl 
      hydrocarbon receptor.
PG  - 108490
LID - S0028-3908(21)00044-7 [pii]
LID - 10.1016/j.neuropharm.2021.108490 [doi]
AB  - 3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that has 
      been shown to produce serotonergic damage in the brains of primates, including 
      humans, and of rats. Tryptophan, the precursor of serotonin, is primarily 
      degraded through the kynurenine (KYN) pathway, producing among others KYN, the 
      main metabolite of this route. KYN has been reported as an endogenous agonist of 
      the aryl hydrocarbon receptor (AhR), a transcription factor involved in several 
      neurological functions. This study aims to determine the effect of MDMA on the 
      KYN pathway and on AhR activity and to establish their role in the long-term 
      serotonergic neurotoxicity induced by the drug in rats. Our results show that 
      MDMA induces the activation of the KYN pathway, mediated by hepatic tryptophan 
      2,3-dioxygenase (TDO). MDMA also activated AhR as evidenced by increased AhR 
      nuclear translocation and CYP1B1 mRNA expression. Autoradiographic quantification 
      of serotonin transporters showed that both the TDO inhibitor 680C91 and the AhR 
      antagonist CH-223191 potentiated the neurotoxicity induced by MDMA, while 
      administration of exogenous l-kynurenine or of the AhR positive modulator 
      3,3'-diindolylmethane (DIM) partially prevented the serotonergic damage induced 
      by the drug. The results demonstrate for the first time that MDMA increases KYN 
      levels and AhR activity, and these changes appear to play a role in limiting the 
      neurotoxicity induced by the drug. This work provides a better understanding of 
      the physiological mechanisms that attenuate the brain damage induced by MDMA and 
      identify modulation of the KYN pathway and of AhR as potential therapeutic 
      strategies to limit the negative effects of MDMA.
CI  - Copyright (c) 2021 Elsevier Ltd. All rights reserved.
FAU - Abuin-Martinez, C
AU  - Abuin-Martinez C
AD  - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad 
      Complutense, Pza. Ramon y Cajal s/n, 28040, Madrid, Spain; Instituto de 
      Investigacion Sanitaria Hospital 12 de Octubre, Madrid, Spain; Red de Trastornos 
      Adictivos, Instituto de Salud Carlos III, Madrid, Spain; Instituto Universitario 
      de Investigacion Neuroquimica (IUIN), Universidad Complutense, Madrid, Spain.
FAU - Vidal, R
AU  - Vidal R
AD  - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad 
      Complutense, Pza. Ramon y Cajal s/n, 28040, Madrid, Spain; Instituto de 
      Investigacion Sanitaria Hospital 12 de Octubre, Madrid, Spain; Red de Trastornos 
      Adictivos, Instituto de Salud Carlos III, Madrid, Spain; Instituto Universitario 
      de Investigacion Neuroquimica (IUIN), Universidad Complutense, Madrid, Spain.
FAU - Gutierrez-Lopez, M D
AU  - Gutierrez-Lopez MD
AD  - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad 
      Complutense, Pza. Ramon y Cajal s/n, 28040, Madrid, Spain; Instituto de 
      Investigacion Sanitaria Hospital 12 de Octubre, Madrid, Spain; Red de Trastornos 
      Adictivos, Instituto de Salud Carlos III, Madrid, Spain; Instituto Universitario 
      de Investigacion Neuroquimica (IUIN), Universidad Complutense, Madrid, Spain.
FAU - Perez-Hernandez, M
AU  - Perez-Hernandez M
AD  - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad 
      Complutense, Pza. Ramon y Cajal s/n, 28040, Madrid, Spain; Instituto de 
      Investigacion Sanitaria Hospital 12 de Octubre, Madrid, Spain; Red de Trastornos 
      Adictivos, Instituto de Salud Carlos III, Madrid, Spain; Instituto Universitario 
      de Investigacion Neuroquimica (IUIN), Universidad Complutense, Madrid, Spain.
FAU - Gimenez-Gomez, P
AU  - Gimenez-Gomez P
AD  - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad 
      Complutense, Pza. Ramon y Cajal s/n, 28040, Madrid, Spain; Instituto de 
      Investigacion Sanitaria Hospital 12 de Octubre, Madrid, Spain; Red de Trastornos 
      Adictivos, Instituto de Salud Carlos III, Madrid, Spain; Instituto Universitario 
      de Investigacion Neuroquimica (IUIN), Universidad Complutense, Madrid, Spain.
FAU - Morales-Puerto, N
AU  - Morales-Puerto N
AD  - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad 
      Complutense, Pza. Ramon y Cajal s/n, 28040, Madrid, Spain; Instituto de 
      Investigacion Sanitaria Hospital 12 de Octubre, Madrid, Spain; Red de Trastornos 
      Adictivos, Instituto de Salud Carlos III, Madrid, Spain; Instituto Universitario 
      de Investigacion Neuroquimica (IUIN), Universidad Complutense, Madrid, Spain.
FAU - O'Shea, E
AU  - O'Shea E
AD  - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad 
      Complutense, Pza. Ramon y Cajal s/n, 28040, Madrid, Spain; Instituto de 
      Investigacion Sanitaria Hospital 12 de Octubre, Madrid, Spain; Red de Trastornos 
      Adictivos, Instituto de Salud Carlos III, Madrid, Spain; Instituto Universitario 
      de Investigacion Neuroquimica (IUIN), Universidad Complutense, Madrid, Spain. 
      Electronic address: estheros@ucm.es.
FAU - Colado, M I
AU  - Colado MI
AD  - Departamento de Farmacologia y Toxicologia, Facultad de Medicina, Universidad 
      Complutense, Pza. Ramon y Cajal s/n, 28040, Madrid, Spain; Instituto de 
      Investigacion Sanitaria Hospital 12 de Octubre, Madrid, Spain; Red de Trastornos 
      Adictivos, Instituto de Salud Carlos III, Madrid, Spain; Instituto Universitario 
      de Investigacion Neuroquimica (IUIN), Universidad Complutense, Madrid, Spain. 
      Electronic address: colado@ucm.es.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210216
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (Serotonin Agents)
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - 333DO1RDJY (Serotonin)
RN  - 343-65-7 (Kynurenine)
RN  - EC 1.13.11.11 (Tryptophan Oxygenase)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Animals
MH  - Autoradiography
MH  - Hippocampus/*drug effects/metabolism
MH  - Kynurenine/*metabolism/pharmacology
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*toxicity
MH  - Neurotoxicity Syndromes
MH  - Rats
MH  - Receptors, Aryl Hydrocarbon/antagonists & inhibitors/*drug effects/metabolism
MH  - Serotonin
MH  - Serotonin Agents/*toxicity
MH  - Serotonin Plasma Membrane Transport Proteins/metabolism
MH  - Tryptophan Oxygenase/antagonists & inhibitors/*drug effects/metabolism
OTO - NOTNLM
OT  - 3,3'-Diindolylmethane
OT  - 3,3'-Diindolylmethane (PubChem CID: 3071)
OT  - 680C91(PubChem CID: 10014426)
OT  - Aryl hydrocarbon receptors
OT  - CH-223191 (PubChem CID: 3091786)
OT  - INCB024360 (PubChem CID: 135424953)
OT  - Kynurenine
OT  - L-kynurenine sulfate (PubChem CID: 161165)
OT  - L-leucine (PubChem CID: 6106)
OT  - MDMA
OT  - MDMA, HCl (PubChem CID: 71285)
OT  - Neurotoxicity
OT  - Probenecid (PubChem CID: 4911)
OT  - Tryptophan 2,3-dioxygenase
EDAT- 2021/02/20 06:00
MHDA- 2021/12/15 06:00
CRDT- 2021/02/19 20:11
PHST- 2020/06/13 00:00 [received]
PHST- 2021/01/15 00:00 [revised]
PHST- 2021/02/02 00:00 [accepted]
PHST- 2021/02/20 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/02/19 20:11 [entrez]
AID - S0028-3908(21)00044-7 [pii]
AID - 10.1016/j.neuropharm.2021.108490 [doi]
PST - ppublish
SO  - Neuropharmacology. 2021 Apr 1;187:108490. doi: 10.1016/j.neuropharm.2021.108490. 
      Epub 2021 Feb 16.