Repeated Alcohol Withdrawals During Adolescence Sensitize Anxiety-like Behavior

描述（由申请人提供）：引燃/压力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的促成因素。这一假设是基于研究表明，慢性4.5%酒精饮食暴露的三个5天周期，每个周期持续两天，会使焦虑（低酒精剂量）和癫痫发作（高酒精剂量）等行为变得敏感。重要的是，这种敏化在一个周期或非周期酒精后都没有出现，这些行为的敏化也持续存在，因为在戒酒期间再次接触酒精会产生类似焦虑的行为。此外，用压力代替前两个慢性酒精循环会引起对随后的单一酒精暴露周期的类似焦虑的反应。这种适应至少部分是由CRF调节的，CRF1拮抗剂可以阻断致敏，而ICV给药CRF可以替代应激/戒断。因此，该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。这一模式还有待在一个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，与成年人相比，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更敏感。此外，青少年时期的长期酒精治疗可以持续诱导青少年对未来成年期酒精暴露的敏感性。青少年的初步数据也表明，多次从相对较低浓度的酒精中戒酒会使焦虑样行为变得敏感。此外，青少年表现出戒断引起的焦虑从一个周期的酒精暴露，而成年人没有。这些数据表明，青少年的脆弱性有所增加。本研究需要验证的关键假设是：1)青少年更容易对慢性酒精循环和压力致敏；2)致敏的适应是持续的；3)CRF参与了这一适应过程。

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.