Effects of repeated ethanol withdrawal and stress/withdrawal paradigms in adolescent rats

Adolescence is a period of development that is marked with increased vulnerability to the use and abuse of alcohol. Many studies have illustrated that adolescents respond to ethanol in ways that are distinct from adults. The adult literature has established the importance of understating the negative affect (i.e anxiety) produced from alcohol withdrawal and how the cyclic nature of ethanol exposure can modulate its development. Initial studies showed that adolescent and adult rats seem to display similar withdrawal-related behaviors (anxiety and seizure thresholds) following repeated withdrawals once corrections were made for differences in ethanol intake. This anxiety-like behavior was shown to be sensitized by repeated ethanol withdrawals in adolescent rats, as was previously demonstrated in adult rats. However, this anxiety-like behavior in adolescent rats was much longer lasting than in adult rats. Additional work was conducted to determine the role of stress in the development of this anxiety-like behavior. Stress was shown to substitute for these early withdrawals and sensitize anxiety-like behavior in adolescent rats. In contrast to the effects of repeated withdrawals, the anxiety-like behavior of this stress/withdrawal paradigm was not long lasting. The reduced effect of stress in adolescents was also produced when assessing acute stress. A common mechanism between for both stress and ethanol actions may be related to corticotrophin releasing factor (CRF). Dose-response studies illustrated that CRF could substitute for early stress/withdrawal episodes and produce anxiety-like behavior. The dose required to produce this effect was higher in adolescents than adults, which suggested a reduced sensitivity to CRF. The reduced sensitivity to stress and CRF in adolescents may be due to higher basal CRF levels found in adolescent rats. Finally, it was illustrated that repeated withdrawals decreased CRF immunoreactivity within the central nucleus of the amygdala only in adolescent rats. This work illustrates that adolescents are equally and sometimes more vulnerable to effects of repeated ethanol withdrawal. Further, there is a clear interaction of stress and CRF in this process. Therefore, this work would encourage the development and use of treatments that focus on the modulation of this system in adolescents.