title: Activation of nuclear PPARγ receptors by the antidiabetic agent pioglitazone suppresses alcohol drinking and relapse to alcohol seeking.
abstract: 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 (PPARγ) receptors, which in the brain are expressed both in neurons and in glia.
  
  
  METHODS
  We evaluated the effect of PPARγ 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 PPARγ 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 PPARγ antagonist GW9662 (5 μg/rat) given into the lateral cerebroventricle, suggesting that this TZD's effect is mediated by PPARγ 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 PPARγ receptors and identify pioglitazone as candidate treatments for alcoholism and possibly other addictions.
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Stopponi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Somaini
authors.forename: Andrea
authors.initials: A
authors.lastname: Cippitelli
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Cannella
authors.forename: Simone
authors.initials: S
authors.lastname: Braconi
authors.forename: Marsida
authors.initials: M
authors.lastname: Kallupi
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruggeri
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.forename: Gregory
authors.initials: G
authors.lastname: Demopulos
authors.forename: George
authors.initials: G
authors.lastname: Gaitanaris
authors.forename: Maurizio
authors.initials: M
authors.lastname: Massi
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000428:Alcohol Drinking / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology*; D000438:Alcohols / Q000008:administration & dosage* / Q000097:blood; D000704:Analysis of Variance; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005518:Food Preferences / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000523:psychology; D045162:Thiazolidinediones / Q000627:therapeutic use*; D015016:Yohimbine / Q000008:administration & dosage
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D058669:Adrenergic alpha-2 Receptor Antagonists; D000438:Alcohols; D000813:Anilides; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D015016:Yohimbine; D000077205:Pioglitazone