title: Cocaine reverses the naltrexone-induced reduction in operant ethanol self-administration: the effects on immediate-early gene expression in the rat prefrontal cortex.
abstract: Naltrexone is a clinically approved medication for alcoholism. We aimed to investigate the effectiveness of naltrexone co-administered with cocaine and the association of these substances with immediate-early gene expression in the rat prefrontal cortex. We used chronic operant ethanol self-administration and oral treatments prescribed for alcoholism and available in pharmacies to maximise the predictive validity in humans. We performed real-time PCR analysis to determine gene expression levels in the prefrontal cortex. Only the highest dose of naltrexone (1, 3, and 10 mg/kg, p.o.) reduced the response to ethanol. Cocaine increased ethanol self-administration in a dose-dependent manner (2.5, 10, 20 mg/kg, i.p.) and reversed the naltrexone-induced reduction. Naltrexone failed to prevent the cocaine-induced increase in locomotor activity observed in these animals. Chronic self-administration of ethanol reduced the expression of the C-fos gene 4- to 12-fold and increased expression of the COX-2 (up to 4-fold) and Homer1a genes in the rat prefrontal cortex. Chronic ethanol self-administration is prevented by naltrexone, but cocaine fully reverses this effect. This result suggests that cocaine may overcome naltrexone's effectiveness as a treatment for alcoholism. The ethanol-induced reduction in C-fos gene expression in the prefrontal cortex reveals an abnormal activity of these neurons, which may be relevant in the compulsive consumption of ethanol, the control of reward-related areas and the behavioural phenotype of ethanol addiction.
authors: Department of Psychobiology, Faculty of Psychology, Campus de Somosaguas, Complutense University, 28223 Madrid, Spain.
authors: Víctor
authors: V
authors: Echeverry-Alzate
authors: María
authors: M
authors: Tuda-Arízcun
authors: Kora-Mareen
authors: KM
authors: Bühler
authors: Ángel
authors: Á
authors: Santos
authors: Elena
authors: E
authors: Giné
authors: Pedro
authors: P
authors: Olmos
authors: Miguel Ángel
authors: MÁ
authors: Gorriti
authors: Evelio
authors: E
authors: Huertas
authors: Fernando
authors: F
authors: Rodríguez de Fonseca
authors: Jose Antonio
authors: JA
authors: López-Moreno
mesh_terms: D000077443:Acamprosate; D000427:Alcohol Deterrents / Q000494:pharmacology; D000428:Alcohol Drinking / Q000235:genetics* / Q000523:psychology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000235:genetics*; D016762:Genes, fos / Q000187:drug effects; D000072233:Homer Scaffolding Proteins; D008297:Male; D009043:Motor Activity; D009271:Naltrexone / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D012646:Self Administration; D013654:Taurine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000427:Alcohol Deterrents; D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D009292:Narcotic Antagonists; D013654:Taurine; D009271:Naltrexone; D051546:Cyclooxygenase 2; D003042:Cocaine; D000077443:Acamprosate