title: Metabolic shift of the kynurenine pathway impairs alcohol and cocaine seeking and relapse.
abstract: 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.
  
  
  
  In this study, we investigated whether drug-seeking and relapse behaviour could be modified by the metabolic shift of endogenous kynurenine pathway.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. valentina.vengeliene@zi-mannheim.de.|Institute of Psychopharmacology, Central Institute of Mental Health, J5, 68159, Mannheim, Germany. valentina.vengeliene@zi-mannheim.de.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vengeliene
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Cannella
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Tatiane
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D003042:Cocaine / Q000008:administration & dosage*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D058999:Drug-Seeking Behavior / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage*; D007737:Kynurenine / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors; D008297:Male; D053858:Metabolic Networks and Pathways; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012008:Recurrence; D012646:Self Administration; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C560311:2-(3,4-dimethoxybenzenesulfonylamino)-4-(3-nitrophenyl)-5-(piperidin-1-yl)methylthiazole; D002492:Central Nervous System Depressants; D018765:Dopamine Uptake Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; D007737:Kynurenine; D000431:Ethanol; D050601:Kynurenine 3-Monooxygenase; D003042:Cocaine
keywords: Cocaine; Craving; Ethanol; Kynurenic acid; Kynurenine-3-monooxygenase; Relapse