title: Effects of naltrexone plus topiramate on ethanol self-administration and tyrosine hydroxylase gene expression changes.
abstract: The purpose of this study was to evaluate the effects of naltrexone (0.7 mg/kg) and/or topiramate (25 mg/kg) on ethanol consumption and the motivation to drink in an oral-operant conditioning paradigm in C57BL/6 mice. Subsequent real-time polymerase chain reaction (PCR) experiments were performed to analyze gene expression changes in tyrosine hydroxylase (TH) in the ventral tegmental area (VTA). The administration of naltrexone significantly reduced ethanol consumption and the motivation to drink during the different stages of the experiment, whereas the treatment with topiramate resulted in a much lower effect. Interestingly, the administration of naltrexone plus topiramate reduced ethanol consumption markedly compared with single-drug treatment. The water self-administration paradigm was also performed using the same drugs and no differences were found between treatment groups. Real-time PCR analyses revealed that naltrexone significantly normalized the increase of TH gene expression in the VTA induced by ethanol, whereas the administration of topiramate did not produce any significant effect. In the ethanol self-administration procedure, the combination of both drugs further reduced TH gene expression, reaching statistical significance compared with the vehicle, naltrexone or topiramate groups. Taken together, these findings indicate that the administration of naltrexone plus topiramate further reduced ethanol consumption and the motivation to drink in comparison with single-drug treatment. This action may be due, at least in part, to a greater decrease in TH gene expression in the VTA. These results suggest that the combination of both drugs deserves further exploration for the treatment of problems related to alcohol consumption.
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Spain; Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos (RTA), Instituto de Salud Carlos III, MICINN and FEDER, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Navarrete
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rubio
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
mesh_terms: D000284:Administration, Oral; D000428:Alcohol Drinking / Q000517:prevention & control*; D000704:Analysis of Variance; D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects; D004338:Drug Combinations; D000431:Ethanol / Q000008:administration & dosage; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D008810:Mice, Inbred C57BL; D009042:Motivation / Q000187:drug effects; D009271:Naltrexone / Q000494:pharmacology*; D012646:Self Administration; D000077236:Topiramate; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D002492:Central Nervous System Depressants; D004338:Drug Combinations; D000077236:Topiramate; D005632:Fructose; D000431:Ethanol; D009271:Naltrexone; D014446:Tyrosine 3-Monooxygenase
keywords: Ethanol self-administration; gene expression; naltrexone; topiramate; tyrosine hydroxylase; ventral tegmental area