Corticotropin-releasing factor (CRF) signaling in the mesocorticolimbic system is known to modulate anxiety-like behavior and alcohol consumption, behaviors that also have been associated with the hyper-glutamatergic state of the lateral habenula (LHb) neurons in rats. However, the role of CRF signaling in the LHb on the glutamate transmission, anxiety-like behaviors and alcohol consumption is unknown. Here, we used male rats that had been consuming alcohol for three months to address this gap in the literature. First, using electrophysiological techniques, we evaluated CRF's effects on the glutamate transmission in LHb neurons in brain slices. CRF facilitated glutamate transmission. The facilitation was greater in neurons of alcohol-withdrawing rats than in those of naïve rats. The facilitation was mimicked by the activation of CRF receptor 1 (CRF1R) but attenuated by the activation of CRF receptor 2 (CRF2R). This facilitation was mediated by upregulating CRF1R-protein kinase A signaling. Conversely, protein kinase C blockade attenuated CRF's facilitation in neurons of naïve rats but promoted it in neurons of alcohol-withdrawing rats. Next, using site-direct pharmacology, we evaluated the role of CRF signaling in the LHb on anxiety-like behaviors and alcohol consumption. Intra-LHb inhibition of CRF1R or activation of CRF2R ameliorated the anxiety-like behaviors in alcohol-withdrawing rats and reduced their alcohol intake when drinking was resumed. These observations provide the first direct behavioral pharmacological and cellular evidence that CRF signaling in the LHb modulates glutamate transmission, anxiety-like behaviors and alcohol consumption, and that adaptation occurs in CRF signaling in the LHb after chronic alcohol consumption.

已知中皮质边缘系统中的促肾上腺皮质激素释放因子 (CRF) 信号可以调节焦虑样行为和饮酒，这些行为也与大鼠外侧缰核 (LHb) 神经元的高谷氨酸能状态有关。然而，CRF 信号在 LHb 中对谷氨酸传递、焦虑样行为和饮酒的作用尚不清楚。在这里，我们使用已经饮酒三个月的雄性大鼠来解决文献中的这一空白。首先，我们使用电生理技术评估了 CRF 对脑切片中 LHb 神经元谷氨酸传递的影响。CRF促进谷氨酸传递。酒精戒断大鼠的神经元的促进作用比幼稚大鼠的神经元更大。这种促进作用被 CRF 受体 1 (CRF1R) 的激活模拟，但被 CRF 受体 2 (CRF2R) 的激活减弱。这种促进作用是通过上调 CRF1R 蛋白激酶 A 信号传导来介导的。相反，蛋白激酶 C 阻断减弱了幼稚大鼠神经元中 CRF 的促进作用，但促进了戒酒大鼠神经元中的 CRF 促进作用。接下来，使用定点直接药理学，我们评估了 LHb 中 CRF 信号传导对焦虑样行为和饮酒的作用。LHb 内抑制 CRF1R 或激活 CRF2R 可改善戒酒大鼠的焦虑样行为，并在恢复饮酒时减少酒精摄入量。这些观察提供了第一个直接的行为药理学和细胞证据，证明 LHb 中的 CRF 信号调节谷氨酸传递，