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

• Published in: Psychopharmacology Vol. 233; no. 18; pp. 3449 - 3459
• Main Authors: Vengeliene, Valentina, Cannella, Nazzareno, Takahashi, Tatiane, Spanagel, Rainer
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2016; Springer; Springer Nature B.V
• Subjects: Alcohol use; Alcoholic beverages; Animals; Behavior, Animal - drug effects; Biomedical and Life Sciences; Biomedicine; Central Nervous System Depressants - administration & dosage; Cocaine; Cocaine - administration & dosage; Dopamine Uptake Inhibitors - administration & dosage; Drug-Seeking Behavior - drug effects; Ethanol - administration & dosage; Health aspects; Kynurenine - metabolism; Kynurenine 3-Monooxygenase - antagonists & inhibitors; Male; Metabolic disorders; Metabolic Networks and Pathways; Metabolites; N-methyl-D-aspartate; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry; Psychological aspects; Psychopharmacology; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - metabolism; Recurrence; Self Administration; Substance abuse; Sulfonamides - pharmacology; Thiazoles - pharmacology; Kynurenine-3-monooxygenase; Relapse; Cocaine; Kynurenic acid; Ethanol; Craving
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-016-4384-9

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.