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Metabolic Shift of the Kynurenine Pathway Impairs Alcohol and Cocaine Seeking and Relapse

Metabolic Shift of the Kynurenine Pathway Impairs Alcohol and Cocaine Seeking and Relapse

Valentina Vengeliene, Nazzareno Cannella, Tatiane Takahashi, Rainer Spanagel

Psychopharmacology (Berl). 2016 Sep;233(18):3449-59.

PMID: 27475106

Abstract:

Rationale:
The glutamatergic system plays a key role in the maintenance of drug use and development of drug-related conditioned behaviours. In particular, hyper-glutamatergic activity and N-methyl-D-aspartate receptor (NMDAR) activation may drive drug craving and relapse. Inhibition of kynurenine-3-monooxygenase (KMO) shifts the metabolic kynurenine pathway towards production of kynurenic acid, which leads to a reduction of glutamatergic/NMDAR activity via different mechanisms.
Objectives:
In this study, we investigated whether drug-seeking and relapse behaviour could be modified by the metabolic shift of endogenous kynurenine pathway.
Methods:
An inhibitor of kynurenine-3-monooxygenase (KMO) Ro61-8048 (4 and 40 mg/kg) and its prodrug JM6 (100 and 200 mg/kg) were tested in two behavioural rat models for drug seeking and relapse-the alcohol deprivation effect (ADE) model in long-term alcohol-drinking rats and the model of cue-induced reinstatement of alcohol- and cocaine-seeking behaviour.
Results:
Our results show that relapse-like alcohol drinking during the ADE was abolished by repeated intraperitoneal administration of Ro61-8048 and significantly reduced by its oral prodrug JM6. Cue-induced reinstatement of both alcohol- and cocaine-seeking behaviour was also abolished by administration of Ro61-8048.
Conclusions:
Pharmacological enhancement of endogenous kynurenic acid levels provides a novel treatment strategy to interfere with glutamatergic/NMDAR activity as well as with craving and relapse in alcohol-dependent patients and drug addicts.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1008119832	JM6		1008119-83-2	Price

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