PPAR? Activation Attenuates Opioid Consumption and Modulates Mesolimbic Dopamine Transmission.

Neuropsychopharmacology

PubMedID: 25311134

de Guglielmo G, Melis M, De Luca MA, Kallupi M, Wu Li H, Niswender K, Giordano A, Senzacqua M, Somaini L, Cippitelli A, Gaitanaris G, Demopulos G, Damadzic R, Tapocik J, Heilig M, Ciccocioppo R. PPAR? Activation Attenuates Opioid Consumption and Modulates Mesolimbic Dopamine Transmission. Neuropsychopharmacology. 2014;.
PPAR? 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. PPAR? 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 PPAR? by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. These effects are associated with a marked reduction of heroin-induced increase 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 PPAR? 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 PPAR? may represent a new pharmacotherapeutic option for the treatment of opioid addiction.Neuropsychopharmacology accepted article preview online, 14 October 2014. doi:10.1038/npp.2014.268.