Role of BLA kappa opioid receptors in adolescent anxiety and ethanol consumption

乙醇使用在世界范围内是一种常见的现象，乙醇暴露的发生是一个主要的 导致乙醇滥用的因素。青春期是一个发育期， 通常是发起的，这使得它成为一个非常脆弱的时间，易于未来的虐待， 神经行为功能的改变。此外，青少年每年消耗更多的乙醇。 饮酒会议比成年人，也许是由于更敏感的抗焦虑性质， 在这个高度紧张和焦虑的发展阶段。但 青少年急性酒精中毒的神经生物学机制尚不清楚。阿片类药物 系统是乙醇和κ阿片受体（KORs）的主要靶点，特别是， 显示出在乙醇的神经生理学效应中起主要作用， 电路.基底外侧杏仁核（BLA）是奖励和焦虑回路的关键结构， 参与了寻找乙醇的行为。具体地说，在GABA传输的改变内， BLA与乙醇和乙醇寻求的抗焦虑特性相关。重要的是， KOR激活调节年龄依赖性BLA兴奋性和焦虑样行为 的方式，这表明KOR可能显着有助于增加敏感性， 乙醇在青少年中的抗焦虑特性，这可能会导致乙醇消费量增加 在青春期。因此，本提案的首要目标是测试 青少年的BLA KOR和乙醇消费量。重要的是，初步调查结果表明， KOR激动剂增强青少年BLA内的GABA能传递， 成年人，这种效果类似于急性乙醇。这表明乙醇可能劫持 KOR系统，从而导致抗焦虑，这有助于促进乙醇消耗， 青少年。两个具体目标将（1）确定BLA KOR之间的功能相互作用 （2）检查BLA KOR和急性乙醇的相互作用 乙醇对焦虑样行为和乙醇消耗的影响。这些创新的研究将测试 新的和独特的假设，围绕乙醇的发展差异， 描述青少年酒精暴露的神经机制。

Ethanol use is a common occurrence worldwide, and the onset of ethanol exposure is a major contributing factor to ethanol abuse. Adolescence is a developmental period when ethanol use is typically initiated, making it a highly vulnerable time to predispose future abuse and alterations in neurobehavioral function. Moreover, adolescents consume more ethanol per drinking session than adults, perhaps due to the greater sensitivity to the anxiolytic properties of ethanol during this highly stressful and anxiety-provoking developmental stage. However, the neurobiological mechanisms of acute ethanol in adolescents are poorly understood. The opioid system is a major target of ethanol and kappa opioid receptors (KORs), particularly, have been shown to play a major role in the neurophysiological effects of ethanol in the reward and anxiety circuits. The basolateral amygdala (BLA), a key structure of the reward and anxiety circuits, is involved in ethanol-seeking behaviors. Specifically, alterations in GABA transmission within the BLA are associated with the anxiolytic properties of ethanol and ethanol-seeking. Importantly, KOR activation modulates BLA excitability and anxiety-like behaviors in an age-dependent manner, suggesting that KORs may significantly contribute to the increased sensitivity to the anxiolytic properties of ethanol in adolescents, which may drive increased ethanol consumption in adolescence. Thus, the overarching goal of this proposal is to test the interactions between BLA KORs and ethanol consumption in adolescents. Importantly, preliminary findings indicate that a KOR agonist potentiates GABAergic transmission within the BLA of adolescents, but not adults, and this effect is similar to that of acute ethanol. This suggests that ethanol may hijack the KOR system, thereby resulting in anxiolysis, which helps promote ethanol consumption in adolescents. Two Specific Aims will (1) determine the functional interactions between BLA KOR activation and acute ethanol in vitro and (2) examine the interaction of BLA KORs and acute ethanol on anxiety-like behavior and ethanol consumption. These innovative studies will test novel and unique hypotheses surrounding the developmental differences of ethanol and describe neural mechanisms specific to adolescent ethanol exposure.