BEHAVIORAL AND NEURAL CONCOMITANTS OF ETHANOL WITHDRAWAL

从慢性乙醇暴露中退出可伴有强烈的

Withdrawal from chronic ethanol exposure can be accompanied by an intense anxiety---a component of the withdrawal syndrome for which the neurochemical mechanisms and relevant neuroanatomical sites are unknown. Recent data suggests that measurement of air puff-induced ultrasonic vocalizations USVs in rats during withdrawal may be a particularly relevant model for evaluating the increased anxiety observed during withdrawal. Based upon this model, Specific Aim I of the present proposal will evaluate the pharmacology of this behavioral response as well as behavior in the elevated plus maze. Drugs to be evaluated during acute withdrawal from chronic ethanol exposure are chosen based on their effects on serotonergic receptor subtypes that have been demonstrated to modulate anxiety. A benzodiazepine and an NMDA antagonist will serve as positive controls for this experimental series. Specific Aim II will identify brain sites where Fos-Like Immunoreactivity (Fos-LI) and c-Fos mRNA are affected by drug treatments that block air puff induced ultrasonic vocalizations and produce anxiolytic effects in the elevated plus maze during ethanol withdrawal. This effort will identify specific regions of brain activated during ethanol withdrawal and will allow for systematic testing of specific sites for anti-anxiety effects of drugs. Specific Aim III will determine the effects of drugs injected in specific brain regions on ultrasonic vocalizations, plus maze behavior, and Fos-LI and c-fos mRNA in ethanol withdrawal. This last aim will confirm which regions expressing Fos-LI and c-fos mRNA may be relevant to the anti- anxiety action of these drugs. This work will provide data that will quantify the capacity of the serotonergic system to modulate the symptom of withdrawal anxiety and will suggest brain regions and cellular mechanisms responsible for ethanol withdrawal anxiety. Such efforts will provide a better basis for understanding the neuroanatomical basis of ethanol withdrawal anxiety as well as provide a framework for improved pharmacotherapeutic strategies to treat this symptom in the future.