Repeated Alcohol Withdrawals During Adolescence Sensitize Anxiety-like Behavior

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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.