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，其中可以理解酒精中毒病因学中的贡献因素。这一假设是基于研究表明，三个为期5天的慢性4.5%酒精饮食暴露周期，每个周期两天的戒断会使焦虑（低酒精剂量）和癫痫发作（高酒精剂量）等行为敏感。重要的是，在一个周期后或非周期性酒精后未观察到这种致敏作用。这些行为的致敏作用也是持久的，因为在戒酒期间再次暴露于酒精可导致焦虑样行为的再次出现。此外，用压力代替前两个慢性酒精循环，会对随后的一个酒精暴露循环产生类似的焦虑样反应。这种适应至少部分地由CRF调节，如CRF 1拮抗剂将阻断致敏和CRF的ICV给药将替代应激/戒断的事实所示。因此，这个模型提供了关于禁欲期间持续存在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太敏感，对急性酒精暴露的记忆损害作用比成年人更敏感。此外，青春期的慢性酒精治疗可以持续诱导成年后对未来酒精暴露的过敏性反应。在青少年中的初步数据也表明，多次从相对较低的酒精浓度中戒断会使焦虑样行为敏感化。此外，青少年表现出戒断诱导焦虑从一个单一的酒精暴露周期，而成年人没有。这些数据表明，青少年的脆弱性增加。在这项研究中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化; 2）敏感化背后的适应是持久的; 3）CRF参与了这一适应过程。 这项研究将使我们能够进一步了解青少年与成年人相比酒精中毒发展的差异。具体来说，这些实验将解决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.