title: Effects of topiramate on ethanol-cocaine interactions and DNA methyltransferase gene expression in the rat prefrontal cortex.
abstract: OBJECTIVE
  Recent and ongoing clinical studies have indicated that topiramate (Topamax®) could be effective in treating ethanol or cocaine abuse. However, the effects of topiramate on the co-administration of ethanol and cocaine remain largely unknown.
  
  
  METHODS
  We studied the effects of topiramate, in Wistar rats, on operant ethanol self-administration with the co-administration of cocaine (i.p.). The psychomotor effects of topiramate were examined before ethanol self-administration and cocaine exposure. Blood samples were collected to analyse ethanol and cocaine metabolism (blood ethanol levels and benzoylecgonine). Quantitative real-time PCR was used to characterize the gene expression in the prefrontal cortex.
  
  
  RESULTS
  Topiramate prevented the cocaine-induced increased response to ethanol in a dose-dependent manner without causing any motor impairment by itself. This effect was observed when topiramate was administered before ethanol access, but not when topiramate was administered before the cocaine injection. Topiramate did not block cocaine-induced psychomotor stimulation. Topiramate reduced blood ethanol levels but did not affect cocaine metabolism. Ethanol increased the gene expression of DNA methyltransferases (Dnmt1 and Dnmt3a), the corepressor Dnmt1-associated protein 1 (Dmap1), and the RNA methyltransferase Trdmt1. These effects were prevented by topiramate or cocaine. Gene expression of histone deacetylase-2 and glutamate receptor kainate-1 were only increased by cocaine treatment. Topiramate and cocaine co-administration caused an up-regulation of dopamine (Drd1, Th) and opioid (Oprm1) receptor genes. Topiramate showed a tendency to alter episodic-like memory.
  
  
  CONCLUSIONS
  Topiramate is an effective inhibitor of the cocaine-induced increase in operant ethanol self-administration.
authors: Department of Psychobiology, School of Psychology, Campus de Somosaguas, Complutense University of Madrid, Madrid, Spain.
authors: V
authors: V
authors: Echeverry-Alzate
authors: E
authors: E
authors: Giné
authors: K M
authors: KM
authors: Bühler
authors: J
authors: J
authors: Calleja-Conde
authors: P
authors: P
authors: Olmos
authors: M A
authors: MA
authors: Gorriti
authors: R
authors: R
authors: Nadal
authors: F
authors: F
authors: Rodríguez de Fonseca
authors: J A
authors: JA
authors: López-Moreno
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D003216:Conditioning, Operant; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D000090205:DNA Methyltransferase 3A; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D007274:Injections, Intraperitoneal; D008297:Male; D061212:Memory, Episodic; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000201:enzymology; D011597:Psychomotor Performance / Q000187:drug effects; D017208:Rats, Wistar; D012646:Self Administration; D013997:Time Factors; D000077236:Topiramate
chemical_list: D000077236:Topiramate; D005632:Fructose; D000431:Ethanol; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619382:Dnmt1 protein, rat; D003042:Cocaine
keywords: DNA methyltransferases; Dnmt1 corepressors; addiction; dual dependence; gene expression; histone deacetylase-2; operant ethanol self-administration