Increased kynurenine concentration attenuates serotonergic neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats through activation of aryl hydrocarbon receptor.
C. Abuin-Martínez, Rebeca Vidal, Maria D Gutierrez-Lopez, Mercedes Pérez-Hernández, P. Giménez-Gómez, N. Morales-Puerto, Esther O'Shea, Maria I Colado
Neuropharmacology February 16, 2021 DOI: 10.1016/j.neuropharm.2021.108490 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | MDMA 680C91 CH-223191 L-kynurenine 3 3'-diindolylmethane (DIM) |
| Measures | CYP1B1 mRNA expression, autoradiographic quantification of serotonin transporters |
| Topics | MDMA Serotonin |
| Key findings | MDMA activated the kynurenine pathway via hepatic TDO and increased AhR activity in rats. Inhibiting TDO or AhR potentiated MDMA-induced serotonergic neurotoxicity, whereas L-kynurenine or DIM partially prevented it, leading the authors to propose that these changes act to limit the drug's neurotoxicity. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 2
- Differential alterations in peripheral tryptophan pathways in methamphetamine versus MDMA users are linked to their contrasting psychiatric symptoms. Translational Psychiatry May 21, 2026
- Therapeutic effects of methimazole on 3,4-methylenedioxymethamphetamine-induced hyperthermia and serotonergic neurotoxicity. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie August 1, 2023
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