PPARγ Activation Attenuates Opioid Consumption and Modulates Mesolimbic Dopamine Transmission
PPARγ Activation Attenuates Opioid Consumption and Modulates Mesolimbic Dopamine Transmission
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DOI：
10.1038/npp.2014.268
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发表时间：
2015-03-01
影响因子：
7.6
通讯作者：
Ciccocioppo, Roberto
中科院分区：
文献类型：
--
作者：
de Guglielmo, Giordano;Melis, Miriam;Ciccocioppo, Roberto
PPAR γ是过氧化物酶体增殖物激活受体（PPARs）的三种亚型之一，是噻唑烷二酮类抗糖尿病药物（包括吡格列酮）的受体。长期以来，人们一直在研究PPAR γ在脂肪形成和葡萄糖代谢中的作用，但腹侧被盖区（VTA）神经元定位的发现为药物成瘾中奖赏加工和动机行为的调节开辟了新的前景。在这里，我们证明，激活的过氧化物酶体增殖物激活受体γ吡格列酮减少海洛因的动机和衰减其奖励属性。这些作用与海洛因诱导的DARPP-32蛋白在核内磷酸化的显著减少有关，并且与急性海洛因诱导的细胞外多巴胺（DA）水平在NAc壳内升高的显著和选择性减少有关，如通过体内微透析测量的。通过离体电生理学在急性中脑切片，我们还表明，刺激的过氧化物酶体增殖物激活受体γ衰减阿片类药物诱导的兴奋腹侧被盖区DA神经元通过减少突触前GABA释放的头内侧被盖核（RMTg）。与这一发现相一致的是，将吡格列酮注射到RMTg而不是VTA中的位点特异性微量注射减少了海洛因摄入。我们的数据表明，激活的过氧化物酶体增殖物激活受体γ可能代表了一种新的药物治疗阿片类药物成瘾的选择。
PPAR gamma 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 gamma 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 gamma 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 PPAR gamma 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 gamma may represent a new pharmacotherapeutic option for the treatment of opioid addiction.