Further evidence for the involvement of the PPAR[gamma] 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 i...

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Published in:Psychopharmacology 2020-10, Vol.237 (10), p.2983
Main Authors: Domi, Esi, Domi, Ana, Ubaldi, Massimo, Somaini, Lorenzo, Demopulos, Gregory, Gaitanaris, George, Ciccocioppo, Roberto
Format: Article
Language:English
Subjects:
Alcoholism
Care and treatment
Diabetes therapy
Drinking of alcoholic beverages
Substance abuse
Type 2 diabetes
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Summary: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 PPAR[gamma] 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 PPAR[gamma] 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 PPAR[gamma] antagonist GW9662 (5 mg/kg) completely prevented the effect of pioglitazone, demonstrating that its action is specifically mediated by activation of PPAR[gamma]. In line with this result, repeated administration of pioglitazone (30 mg/kg) attenuated binge alcohol consumption in PPAR[gamma].sup.(+/+) mice. Whereas in PPAR[gamma].sup.(-/-) mice, which exhibit reduced alcohol consumption, pioglitazone had no effect. Of note, PPAR[gamma].sup.(-/-) mice exhibited lower patterns of alcohol drinking without showing difference in sucrose (control) intake. Interestingly, PPAR[gamma].sup.(-/-) 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 PPAR[gamma] agonists, and specifically pioglitazone, could be potential therapeutics for the treatment of binge alcohol drinking.
ISSN:0033-3158
DOI:10.1007/s00213-020-05586-w