| Biol Psychiatry IF 8.9 Activation of nuclear PPARgamma receptors by the antidiabetic agent pioglitazone suppresses alcohol drinking and relapse to alcohol seeking.
Stopponi S, Somaini L, Cippitelli A, Cannella N, Braconi S, Kallupi M, Ruggeri B, Heilig M, Demopulos G, Gaitanaris G, Massi M, Ciccocioppo R
BACKGROUND: Pioglitazone and rosiglitazone belong to the class of thiazolidinediones (TZDs). They were first developed as antioxidants and then approved for the clinical treatment of insulin resistance and Type 2 diabetes. TZDs bind with high affinity and activate peroxisome proliferator-activated receptor-gamma (PPARgamma) receptors, which in the brain are expressed both in neurons and in glia. METHODS: We evaluated the effect of PPARgamma activation by TZDs on alcohol drinking, relapse-like behavior, and withdrawal in the rat. We also tested the effect of TZDs on alcohol and saccharin self-administration. RESULTS: We showed that activation of PPARgamma receptors by pioglitazone (0, 10, and 30 mg/kg) and rosiglitazone (0, 10 and 30 mg/kg) given orally selectively reduced alcohol drinking. The effect was blocked by pretreatment with the selective PPARgamma antagonist GW9662 (5 mug/rat) given into the lateral cerebroventricle, suggesting that this TZD's effect is mediated by PPARgamma receptors in the central nervous system. Pioglitazone abolished reinstatement of alcohol seeking, a relapse-like behavior, induced by yohimbine, a pharmacologic stressor, but did not affect cue-induced relapse. In the self-administration experiments, pioglitazone reduced lever pressing for alcohol but not for saccharin. Finally, pioglitazone prevented the expression of somatic signs of alcohol withdrawal. CONCLUSIONS: These findings provide new information about the role of brain PPARgamma receptors and identify pioglitazone as candidate treatments for alcoholism and possibly other addictions.