Further evidence for the involvement of the PPARγ system on alcohol intake and sensitivity in rodents

Rationale: Peroxisome Proliferator Activator receptors (PPARs) are intracellular receptors that function as transcription factors, which regulate specific metabolic and inflammatory processes. PPARs are broadly distributed in the body and are also expressed in the central nervous system, especially in areas involved in addiction-related behavioral responses. Recent studies support a role of PPARs in alcoholism and pioglitazone: a PPARγ agonist used for treatment of type 2 diabetes showed efficacy in reducing alcohol drinking, stress-induced relapse, and alcohol withdrawal syndrome in rats. Objectives and Methods: In the current work, we tested the pharmacological effects of pioglitazone on binge-like alcohol consumption using an intermittent two-bottle choice paradigm in Wistar rats and on the “drinking in the dark” (DID) model in mice with selective deletion of PPARγ in neurons. Results: Our data show that repeated administration of pioglitazone (10, 30 mg/kg) reduces high voluntary alcohol consumption in Wistar rats. Pre-treatment with the selective PPARγ antagonist GW9662 (5 mg/kg) completely prevented the effect of pioglitazone, demonstrating that its action is specifically mediated by activation of PPARγ. In line with this result, repeated administration of pioglitazone (30 mg/kg) attenuated binge alcohol consumption in PPARγ(+/+) mice. Whereas in PPARγ(−/−) mice, which exhibit reduced alcohol consumption, pioglitazone had no effect. Of note, PPARγ(−/−) mice exhibited lower patterns of alcohol drinking without showing difference in sucrose (control) intake. Interestingly, PPARγ(−/−) mice displayed a higher sensitivity to the sedative and ataxic effect of alcohol compared with their wild-type counterpart. Conclusions: Collectively, these data suggest that PPARγ agonists, and specifically pioglitazone, could be potential therapeutics for the treatment of binge alcohol drinking.