title: Pioglitazone attenuates the opioid withdrawal and vulnerability to relapse to heroin seeking in rodents.
abstract: Relapse to opioids is often driven by the avoidance of the aversive states of opioid withdrawal. We recently demonstrated that activation of peroxisome proliferator-activated receptor gamma (PPARγ) by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. However, the role of PPARγ in withdrawal and other forms of relapse to heroin is unknown.
  
  
  
  To further address this issue, we investigated the role of PPARγ on the development and expression of morphine withdrawal in mice and the effect of pioglitazone on several forms of heroin relapse in rats.
  
  
  
  We induced physical dependence to morphine in mice by injecting morphine twice daily for 6 days. Withdrawal syndrome was precipitated on day 6 with an injection of naloxone. In addition, different groups of rats were trained to self-administer heroin and, after the extinction, the relapse was elicited by cues, priming, or stress. The effect of different doses of pioglitazone was tested on these different paradigms.
  
  
  
  Data show that chronic and acute administration of pioglitazone attenuates morphine withdrawal symptoms, and these effects are mediated by activation of PPARγ receptors. Activation of PPARγ by pioglitazone also abolishes yohimbine-induced reinstatement of heroin seeking and reduces heroin-induced reinstatement, while it does not affect cue-induced relapse.
  
  
  
  These findings provide new insights on the role of PPARγ on opioid dependence and suggest that pioglitazone may be useful for the treatment of opioid withdrawal in opioid-addicted individuals.
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, via Madonna delle Carceri, 62032, Camerino, MC, Italy. giordano@scripps.edu.|Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA. giordano@scripps.edu.
authors.forename: Giordano
authors.initials: G
authors.lastname: de Guglielmo
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, via Madonna delle Carceri, 62032, Camerino, MC, Italy.|Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Marsida
authors.initials: M
authors.lastname: Kallupi
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, via Madonna delle Carceri, 62032, Camerino, MC, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Scuppa
authors.affiliation: Omeros Corporation, 201 Elliot Avenue West, Seattle, WA, 98119, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Demopulos
authors.affiliation: Omeros Corporation, 201 Elliot Avenue West, Seattle, WA, 98119, USA.
authors.forename: George
authors.initials: G
authors.lastname: Gaitanaris
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, via Madonna delle Carceri, 62032, Camerino, MC, Italy. roberto.ciccocioppo@unicam.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage; D000818:Animals; D016739:Behavior, Addictive / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003932:Heroin / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage; D009294:Narcotics / Q000008:administration & dosage; D009293:Opioid-Related Disorders / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D012008:Recurrence; D012377:Rodentia; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D000701:Analgesics, Opioid; D009294:Narcotics; D045162:Thiazolidinediones; D003932:Heroin; D009020:Morphine; D000077205:Pioglitazone
keywords: Addiction; Cues; Heroin; Pioglitazone; Priming; Relapse; Withdrawal; Yohimbine