title: PPARγ activation attenuates opioid consumption and modulates mesolimbic dopamine transmission.
abstract: PPARγ is one of the three isoforms identified for the peroxisome proliferator-activated receptors (PPARs) and is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. PPARγ has been long studied for its role in adipogenesis and glucose metabolism, but the discovery of the localization in ventral tegmental area (VTA) neurons opens new vistas for a potential role in the regulation of reward processing and motivated behavior in drug addiction. Here, we demonstrate that activation of PPARγ by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. These effects are associated with a marked reduction of heroin-induced increase in phosphorylation of DARPP-32 protein in the nucleus accumbens (NAc) and with a marked and selective reduction of acute heroin-induced elevation of extracellular dopamine (DA) levels in the NAc shell, as measured by in vivo microdialysis. Through ex vivo electrophysiology in acute midbrain slices, we also show that stimulation of PPARγ attenuates opioid-induced excitation of VTA DA neurons via reduction of presynaptic GABA release from the rostromedial tegmental nucleus (RMTg). Consistent with this finding, site-specific microinjection of pioglitazone into the RMTg but not into the VTA reduced heroin taking. Our data illustrate that activation of PPARγ may represent a new pharmacotherapeutic option for the treatment of opioid addiction.
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
authors.forename: Giordano
authors.initials: G
authors.lastname: de Guglielmo
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Melis
authors.affiliation: 1] Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy [2] INN, National Institute of Neuroscience, Cagliari, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: De Luca
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
authors.forename: Marsida
authors.initials: M
authors.lastname: Kallupi
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
authors.forename: Hong Wu
authors.initials: HW
authors.lastname: Li
authors.affiliation: 1] Tennessee Valley Healthcare System, Nashville, TN, USA [2] Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Niswender
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Senzacqua
authors.affiliation: Addiction Treatment Centre, Health Local Unit, ASL 12 Biella, Biella, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Somaini
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cippitelli
authors.affiliation: Omeros Corporation, Seattle, WA, USA.
authors.forename: George
authors.initials: G
authors.lastname: Gaitanaris
authors.affiliation: Omeros Corporation, Seattle, WA, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Demopulos
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Damadzic
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Jenica
authors.initials: J
authors.lastname: Tapocik
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects; D003932:Heroin / Q000008:administration & dosage*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage*; D009714:Nucleus Accumbens / Q000187:drug effects*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D007004:Hypoglycemic Agents; D009294:Narcotics; D047495:PPAR gamma; D045162:Thiazolidinediones; D005680:gamma-Aminobutyric Acid; D003932:Heroin; D009020:Morphine; D004298:Dopamine; D000077205:Pioglitazone