RT Journal Article
T1 Increased kynurenine concentration attenuates serotonergic neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats through activation of aryl hydrocarbon receptor
A1 Abuin Martínez, Cristina
A1 Vidal Casado, Rebeca
A1 Gutiérrez López, María Dolores
A1 Pérez Hernández, Mercedes
A1 O'Shea Gaya, María Esther
A1 Giménez Gómez, Pablo
A1 Morales Puerto, Nuria
A1 O'Shea Gaya, María Esther
A1 Colado Megías, María Isabel
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.
PB Elsevier
SN 0028-3908
YR 2021
FD 2021-04-01
LK https://hdl.handle.net/20.500.14352/112141
UL https://hdl.handle.net/20.500.14352/112141
LA eng
NO Abuin-Martínez C, Vidal R, Gutiérrez-López MD, Pérez-Hernández M, Giménez-Gómez P, Morales-Puerto N, O'Shea E, Colado MI. Increased kynurenine concentration attenuates serotonergic neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats through activation of aryl hydrocarbon receptor. Neuropharmacology. 2021 Apr 1;187:108490. doi: 10.1016/j.neuropharm.2021.108490
NO UCM Grant 910258
NO Ministerio de Economia y Competitividad (España)
NO Ministerio de Sanidad, Servicios Sociales e Igualdad (España)
NO Instituto de Salud Carlos III (España)
NO Universidad Complutense de Madrid
DS Docta Complutense
RD 4 ago 2025