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

酒精使用是世界范围内的常见现象，而酒精暴露的开始是一个主要的 酒精滥用的促成因素。青春期是使用酒精的发育期 通常是启动的，这使得现在是一个极易受到伤害的时刻，从而预先处理未来的滥用和 神经行为功能的改变。此外，青少年每年消费更多的酒精 饮酒时间比成年人多，这可能是因为他们对酒精的抗焦虑特性更敏感。 酒精在这个高度紧张和令人焦虑的发育阶段。然而， 青少年急性酒精中毒的神经生物学机制知之甚少。阿片类药物 系统是乙醇的主要靶标，尤其是kappa阿片受体(Kors) 研究表明，酒精在奖赏和焦虑的神经生理效应中起主要作用 电路。杏仁基底外侧核(BLA)是奖赏和焦虑回路的关键结构 参与了寻找酒精的行为。具体地说，体内GABA传递的变化 血乳酸与乙醇的抗焦虑特性和寻求酒精有关。重要的是 KOR激活对年龄依赖患者血乳酸兴奋性和焦虑样行为的调节 这表明KORS可能显著地促进了对 酒精在青少年中的抗焦虑特性，这可能会导致酒精摄入量增加 在青春期。因此，该提案的首要目标是测试 青少年中的血乳酸、KOR和酒精摄入量。重要的是，初步调查结果表明 KOR激动剂增强青少年血乳酸中的GABA能传递，但不是 成人，这种作用类似于急性乙醇。这表明乙醇可能会劫持 KOR系统，从而导致焦虑缓解，这有助于促进乙醇消费在 青少年。两个特定的目标将(1)决定BLA KOR之间的功能相互作用 体外激活和急性乙醇；(2)检测BLA、Kors和急性乙醇的相互作用 酒精对焦虑样行为和酒精消费的影响。这些创新的研究将检验 围绕乙醇和乙醇发育差异的新颖而独特的假说 描述青少年酒精暴露的特定神经机制。

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.