Sensitization, Duration, and Pharmacological Blockade of Anxiety-Like Behavior Following Repeated Ethanol Withdrawal in Adolescent and Adult Rats

Background: Repeated ethanol withdrawal sensitizes anxiety‐like behavior in adult rats and causes anxiety‐like behavior and decreased seizure thresholds in adolescent rats. Current experiments determined if adolescent rats exhibit sensitized anxiety‐like behavior, the duration of this effect, if drug pretreatments blocked these effects, and if these effects differed from those seen in adults. Methods: Male adolescent rats received three 5‐day cycles of 2.5% ethanol diet (ED) separated by two 2‐day withdrawal periods, continuous 15 days of 2.5%ED, or a single 5‐day cycle of 2.5%ED. Male adult rats received three 5‐day cycles of either 2.5% or 3.5%ED. These groups were tested 5 hours into the final withdrawal for social interaction (SI) deficits (an index of anxiety‐like behavior). Ethanol intake was monitored throughout and blood concentrations were obtained from separate groups of rats. Additionally, adolescent rats were tested for SI 1, 2, 7, 14, and 18 days and adults 1 and 2 days after the final withdrawal. Some adolescent rats were also pretreated with the CRF1 antagonist CP‐154,526, the 5‐HT1A agonist buspirone, or the benzodiazepine receptor antagonist flumazenil during the first 2 withdrawals. Results: SI was reduced in adolescent rats following repeated withdrawals of 2.5%ED while neither a continuous or single cycle ED exposure caused this effect. Adult rats also had reduced SI following repeated withdrawals from both 2.5% and 3.5%ED. This effect was present up to 1 week following the final withdrawal in adolescents but returned to baseline by 1 day in adults. CP‐154,526, buspirone, or flumazenil prevented this reduction in SI in adolescent rats. Conclusions: Adolescent rats exhibit sensitized anxiety‐like behavior following repeated withdrawals at ED concentrations similar to those used in adults. However, this effect is longer lasting in adolescent rats. Drugs modulating CRF, 5‐HT, or GABA systems during initial withdrawals prevent the development of anxiety‐like behavior otherwise manifest during a final withdrawal in adolescent rats.