Repeated Alcohol Withdrawals During Adolescence Sensitize Anxiety-like Behavior

描述(由申请人提供)：点燃/应激假说最近被提出作为一个概念框架，在这个框架中可以理解酒精中毒病因中的促成因素。这一假设是基于研究表明，三个5天的慢性4.5%酒精饮食暴露周期，然后两天的戒酒将使行为敏感，如焦虑(低酒精剂量)和癫痫(高酒精剂量)。重要的是，在一个周期或非循环酒精之后没有看到这种敏化，这些行为的敏化也是持久的，因为在戒酒期间再次暴露于酒精可以产生类似焦虑的行为的重新出现。此外，用压力代替前两个慢性酒精循环，会在随后的一个酒精循环中引发类似焦虑的反应。这种适应至少部分地受到CRF的调节，表现为CRF1拮抗剂将阻断敏化，脑室注射CRF将替代应激/戒断。因此，这个模型提供了关于禁欲期间持续的适应以及戒断和压力之间发生的相互作用的重要信息。这一模式尚未在潜在的高度脆弱人群--青少年中进行评估。临床和基础研究都表明，青少年和成年人对酒精的反应存在明显差异。在动物研究中，青少年对镇静作用不那么敏感，而对急性酒精暴露的记忆损害效应比成年人更敏感。此外，青春期的慢性酒精治疗可能会持续地诱导青少年对成年后未来的酒精暴露敏感。青少年的初步数据还表明，从相对较低的酒精浓度中多次戒酒会使类似焦虑的行为变得敏感。此外，青少年在一次酒精暴露中表现出戒断诱导的焦虑，而成年人则没有。这些数据表明，青少年的脆弱性增加了。本研究要检验的关键假设是：1)青少年更容易对慢性酒精循环和压力敏感，2)敏化的适应是持久的，3)CRF参与了这一适应过程。 这项研究将使我们能够获得更多关于青少年与成年人在酒精中毒发展方面的差异的信息。具体地说，这些实验将研究反复戒酒后大脑内发生的适应及其与压力的相互作用。

DESCRIPTION (provided by applicant): The kindling/stress hypothesis has recently been proposed as a conceptual framework in which contributory factors in the etiology of alcoholism can be understood. This hypothesis is based on studies illustrating that three 5-day cycles of chronic 4.5% alcohol diet exposure each followed by two days of withdrawal will sensitize behaviors like anxiety (with low alcohol doses) and seizures (with higher alcohol doses). Importantly, this sensitization was not seen after one cycle or after non-cycled alcohol, Sensitization of these behaviors is also persistent in that re-emergence of anxiety-like behavior can be produced from re-exposure to alcohol during abstinence. Further, substituting stress for the first two chronic alcohol cycles elicits a similar anxiety-like response to a subsequent single cycle of alcohol exposure. This adaptation is at least in part modulated by CRF as shown by the fact that a CRF1 antagonist will block sensitization and ICV administration of CRF will substitute for stress/withdrawal. Therefore, this model provided important information about adaptations that persist during abstinence and interactions that occur between withdrawals and stress. This model has yet to be evaluated in a potentially highly vulnerable population, adolescents. Both clinical and basic research demonstrated clear differences between responses to alcohol in adolescents and adults. In animal studies, adolescents are less sensitive to the sedative effects and more sensitive to the memory impairing effects of acute alcohol exposure than adults. Additionally, chronic alcohol treatment during adolescence can persistently induce adolescent-like sensitivities to future alcohol exposure in adulthood. Preliminary data in adolescents also suggest that multiple withdrawals from relatively low alcohol concentrations can sensitize anxiety-like behavior. In addition, adolescent exhibit withdrawal induced anxiety from a single cycle of alcohol exposure while adults do not. These data suggest increased vulnerability in adolescents. Key hypotheses to be tested in this research are that 1) adolescents are more vulnerable to sensitization to chronic alcohol cycles and stress 2) the adaptation underlying sensitization is persistent 3) CRF is involved in this adaptation process. This research will allow us to gain further information about the differences in the development of alcoholism in adolescent compared to adults. Specifically, these experiments will address adaptations that occur within the brain following repeated alcohol withdrawal and its interaction with stress.