Metabolic shift of the kynurenine pathway impairs alcohol and cocaine seeking and relapse

• Verfasst von: Vengeliene, Valentina [VerfasserIn]
• Verfasst von: Spanagel, Rainer [VerfasserIn]
• Titel: Metabolic shift of the kynurenine pathway impairs alcohol and cocaine seeking and relapse
• Verf.angabe: Valentina Vengeliene, Nazzareno Cannella, Tatiane Takahashi, Rainer Spanagel
• E-Jahr: 2016
• Jahr: 30 July 2016
• Umfang: 11 S.
• Fussnoten: Gesehen am 21.01.2019
• Titel Quelle: Enthalten in: Psychopharmacology
• Ort Quelle: Berlin : Springer, 1959
• Jahr Quelle: 2016
• Band/Heft Quelle: 233(2016), 18, Seite 3449-3459
• ISSN Quelle: 1432-2072
• DOI: doi:10.1007/s00213-016-4384-9
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Cocaine
• Sach-SW: Craving
• Sach-SW: Ethanol
• Sach-SW: Kynurenic acid
• Sach-SW: Kynurenine-3-monooxygenase
• Sach-SW: Relapse
• K10plus-PPN: 1586421700

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.