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Neuropsychopharmacology. 2015 Mar;40(4):927-37. doi: 10.1038/npp.2014.268. Epub 2014 Sep 14.

PPARγ activation attenuates opioid consumption and modulates mesolimbic dopamine transmission.

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School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
1] Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy [2] INN, National Institute of Neuroscience, Cagliari, Italy.
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.
Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Università Politecnica delle Marche, Ancona, Italy.
Addiction Treatment Centre, Health Local Unit, ASL 12 Biella, Biella, Italy.
Omeros Corporation, Seattle, WA, USA.
Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.


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.

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