Pleil Kristen E, Rinker Jennifer A, Lowery-Gionta Emily G, Mazzone Christopher M, McCall Nora M, Kendra Alexis M, Olson David P, Lowell Bradford B, Grant Kathleen A, Thiele Todd E, Kash Thomas L
1] Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [2] Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
1] Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA. [2] Department of Psychology, University of North Carolina, Chapel Hill, North Carolina, USA.
Nat Neurosci. 2015 Apr;18(4):545-52. doi: 10.1038/nn.3972. Epub 2015 Mar 9.
Binge alcohol drinking is a tremendous public health problem because it leads to the development of numerous pathologies, including alcohol abuse and anxiety. It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). The central actions of NPY and CRF have opposing functions in the regulation of emotional and reward-seeking behaviors; thus, dysfunctional interactions between these peptidergic systems could be involved in the development of these pathologies. We used converging physiological, pharmacological and chemogenetic approaches to identify a precise neural mechanism in the bed nucleus of the stria terminalis (BNST), a limbic brain region involved in pathological reward and anxiety behaviors, underlying the interactions between NPY and CRF in the regulation of binge alcohol drinking in both mice and monkeys. We found that NPY Y1 receptor (Y1R) activation in the BNST suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission specifically in CRF neurons via a previously unknown Gi-mediated, PKA-dependent postsynaptic mechanism. Furthermore, chronic alcohol drinking led to persistent alterations in Y1R function in the BNST of both mice and monkeys, highlighting the enduring, conserved nature of this effect across mammalian species. Together, these data provide both a cellular locus and signaling framework for the development of new therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders.
暴饮酒精是一个严重的公共卫生问题，因为它会导致多种疾病的发生，包括酒精滥用和焦虑症。人们认为，它是通过劫持调节压力和奖赏的大脑系统来做到这一点的，这些系统包括神经肽Y（NPY）和促肾上腺皮质激素释放因子（CRF）。NPY和CRF的中枢作用在调节情绪和寻求奖赏行为方面具有相反的功能；因此，这些肽能系统之间的功能失调相互作用可能与这些疾病的发生有关。我们使用了生理学、药理学和化学遗传学相结合的方法，在终纹床核（BNST）中确定了一种精确的神经机制，BNST是一个参与病理性奖赏和焦虑行为的边缘脑区，它是NPY和CRF在调节小鼠和猴子暴饮酒精过程中相互作用的基础。我们发现，BNST中NPY Y1受体（Y1R）的激活通过一种以前未知的Gi介导、PKA依赖的突触后机制，特异性地增强CRF神经元中的抑制性突触传递，从而抑制暴饮酒精。此外，长期饮酒导致小鼠和猴子的BNST中YlR功能持续改变，突出了这种效应在哺乳动物物种中的持久性和保守性。总之，这些数据为开发治疗神经精神疾病（包括酒精使用障碍）的新疗法提供了细胞位点和信号框架。
