Activation of PPARgamma receptors by pioglitazone leads to reduction of alcohol drinking and relapse to alcohol seeking: An effect that is potentiated by concomitant administration of naltrexone

The PPARgamma receptor is a ligand-activated transcription factor of the nuclear hormone receptor superfamily activated by selective agonists belong to the class of thiazolidinediones (TZDs).In the brain PPARgamma receptors are widely expressed in glia cells as well as in neurones. Recently, we investigated the role of this receptors in alcohol addictive related behaviors in genetically selected alcohol preferring Marchigian Sardinian (msP) rats. For this purpose we tested the effect of pioglitazone (Actos®), a prototypical TZD approved for the treatment of insulin resistance in Type II diabetes, on alcohol drinking and relapse behavior in msP rats We also investigated to whether pioglitazone potentiates the effect of naltrexone (drug approved for the treatment of alcoholim) on alcohol drinking and relapse. Results showed that activation of PPARgamma by pioglitazone (0-30 mg/kg) lowers alcohol intake and relapse to alcohol seeking elicited administration of yohimbine (a pharmacological stressor) but not by cues predictive of alcohol availability. On the other hand, naltrexone (0-1 mg/kg) lowered ethanol consumption and cue- but not yohimbine-induced relapse We have, then, investigated the effect of concomitant administration of the two drugs. Results showed that drug combination elicits a more pronounced inhibition of ethanol intake. Moreover, simultaneous administration results in a pronounced inhibition of both cue and yohimbine stress-induced alcohol seeking. These findings opens new vistas in the use pioglitazone in combination with naltrexone for the treatment of alcoholism.