To increase our understanding of factors that contribute to the transition from moderate use of ethanol to excessive, compulsive use (i.e., alcoholism), this proposal investigates the initial development and progression o ethanol dependence using rodent models of distinct components (affective, autonomic, somatic) of withdrawal. While humans will voluntarily initiate ethanol consumption without the induction of dependence, a proportion o users will become dependent upon alcohol, and consequently relief or avoidance of withdrawal symptoms may become an additional motivational factor. Moreover, ethanol withdrawal severity may be potentiated by repeated episodes of withdrawal (""""""""kindling""""""""), and therefore the motivational impact of withdrawal may increase as function of frequency of abstinence. Finally, data with ethanol and other drugs of abuse indicates that affective (emotional) signs of withdrawal playa more prominent role in maintaining compulsive use than other (e.g., somatic) components of withdrawal. Thus, a guiding hypothesis for this proposal is that affective, autonomic, and somatic signs of withdrawal are dissociable in terms of the conditions (dose, duration of exposure) that lead to their initial expression and the conditions under which their severity increases with repeated cycles of exposure and withdrawal (Specific Aim 1). Also, it has been suggested that previous experience with ethanol dependence and withdrawal may lead to a more rapid reinstatement of dependence (""""""""readdiction""""""""), even after periods of prolonged abstinence. Studies have shown that when rats are subjected to multiple (12+) cycles of intermittent intragastric ethanol exposure and withdrawal, severity of seizures remains potentiated after 3-4 weeks of complete abstinence. Thus, a second hypothesis under test is that neuroadaptive responses that are initiated through a """"""""kindling"""""""" process may be quite persistent, and that withdrawal severity may continue to increase across repeated """"""""kindling"""""""" cycles separated by periods of prolonged abstinence (Specific Aim 2). Using rats as subjects, affective signs of withdrawal will be assessed by monitoring brain stimulation reward thresholds, autonomic signs (blood pressure, HR) will be monitored with radiotelemetry, and somatic signs such as tremors, tail rigidity, splayed gait, and ventromedial distal limb flexion reflex (VMD) will be rated. These experiments will establish the basic framework and necessary tools for subsequent elucidation of the cellular and molecular mechanisms which mediate initial and prolonged neuroadaptive responses to ethanol, thereby providing information critical for prevention and treatment of alcohol dependence and drug dependence in general.
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