Ernest Gallo Clinic and Research Center, University of California at San Francisco, San Francisco, California, USA.
Nat Neurosci. 2013 Aug;16(8):1094-100. doi: 10.1038/nn.3445. Epub 2013 Jun 30.
Compulsive drinking despite serious adverse medical, social and economic consequences is a characteristic of alcohol use disorders in humans. Although frontal cortical areas have been implicated in alcohol use disorders, little is known about the molecular mechanisms and pathways that sustain aversion-resistant intake. Here, we show that nucleus accumbens core (NAcore) NMDA-type glutamate receptors and medial prefrontal (mPFC) and insula glutamatergic inputs to the NAcore are necessary for aversion-resistant alcohol consumption in rats. Aversion-resistant intake was associated with a new type of NMDA receptor adaptation, in which hyperpolarization-active NMDA receptors were present at mPFC and insula but not amygdalar inputs in the NAcore. Accordingly, inhibition of Grin2c NMDA receptor subunits in the NAcore reduced aversion-resistant alcohol intake. None of these manipulations altered intake when alcohol was not paired with an aversive consequence. Our results identify a mechanism by which hyperpolarization-active NMDA receptors under mPFC- and insula-to-NAcore inputs sustain aversion-resistant alcohol intake.
尽管存在严重的医学、社会和经济后果，但仍强迫性饮酒是人类酒精使用障碍的特征。尽管额皮质区域与酒精使用障碍有关，但维持厌恶抵抗摄入的分子机制和途径知之甚少。在这里，我们表明，伏隔核核心（NAcore）NMDA 型谷氨酸受体以及内侧前额叶（mPFC）和岛叶谷氨酸能传入到 NAcore 对于大鼠的厌恶抵抗性饮酒是必要的。厌恶抵抗性摄入与 NMDA 受体的一种新型适应有关，其中超极化活性 NMDA 受体存在于 mPFC 和岛叶，但不存在于杏仁核输入到 NAcore 中。相应地，在 NAcore 中抑制 Grin2c NMDA 受体亚基可减少厌恶抵抗性酒精摄入。当酒精没有与厌恶后果配对时，这些操作都不会改变摄入。我们的结果确定了一种机制，即 mPFC 和岛叶传入到 NAcore 的超极化活性 NMDA 受体维持厌恶抵抗性酒精摄入。
