Repeated Alcohol Withdrawals During Adolescence Sensitize Anxiety-like Behavior

青春期反复戒酒会使焦虑样行为变得敏感

• 批准号: 7219797
• 负责人: Tiffany A Wills
• 金额: $ 2.78万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2009-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7219797
• 关键词: adolescence (12-20); age difference; alcoholism /alcohol abuse; anxiety; behavior test; behavioral /social science research tag; behavioral habituation /sensitization; corticotropin releasing factor; disease /disorder etiology; drug withdrawal; immunocytochemistry; in situ hybridization; juvenile animal; laboratory rat; mature animal; messenger RNA; molecular psychobiology; neuropsychology; predoctoral investigator; psychological stressor; social behavior

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.

描述（由申请人提供）：最近提出了点燃/压力假说作为一个概念框架，其中可以理解酒精中毒病因的贡献因素。该假设基于研究表明，三个为期5天的慢性酒精饮食暴露的周期，每个周期随后戒断了两天，将使焦虑（低酒精剂量）和癫痫发作（含量较高的酒精剂量）敏感。重要的是，这种敏化在一个周期之后或非饮酒之后没有看到，这些行为的敏化也持续存在，因为在戒酒期间，可以从对酒精的重新暴露对焦虑行为的重新表现。此外，将应激代替前两个慢性酒精周期会引起与随后的酒精暴露周期相似的焦虑样反应。这种适应至少部分由CRF调节，如CRF1拮抗剂会阻止敏化，而CRF的ICV给药将代替压力/戒断。因此，该模型提供了有关在戒酒期间持续存在的适应和戒断与压力之间发生的相互作用的重要信息。该模型尚未在潜在的高度脆弱的人群（青少年）中进行评估。临床研究和基础研究都表明，青少年和成人对酒精的反应之间存在明显差异。在动物研究中，青少年对镇静作用不太敏感，并且对急性酒精暴露的记忆障碍的敏感性比成年人更敏感。此外，青春期的慢性酒精治疗可以持续诱导青春期样的敏感性，以使成年后未来的酒精暴露。青少年的初步数据还表明，从相对较低的酒精浓度中多次提取可以使焦虑样行为敏感。此外，青少年从单个酒精暴露周期中表现出戒断引起的焦虑，而成年人则没有。这些数据表明青少年的脆弱性增加。在这项研究中需要检验的主要假设是1）青少年更容易受到慢性酒精周期的敏感性和压力2）持续的适应性持续性3）CRF参与了这种适应过程。 这项研究将使我们能够获得有关与成年人相比，青少年酒精中毒发展差异的进一步信息。具体而言，这些实验将解决反复戒酒及其与压力的相互作用后大脑内发生的适应。