Drug challenges reveal differences in mediation of stress facilitation of voluntary alcohol drinking and withdrawal-induced anxiety in alcohol-preferring P rats

Background: There is controversy over whether exposure to stress precipitates relapse and/or increases alcohol (ethanol) intake. Our laboratory has demonstrated that repeated stress prior to withdrawal from a brief forced exposure to alcohol results in withdrawal-induced anxiety-like behavior. Because anxiety is often regarded as a precipitating factor in relapsing alcoholics, we decided to examine the consequences of stressing alcohol-preferring P rats on both voluntary alcohol drinking and withdrawal-induced anxiety. Methods: P rats were subjected to 3 cycles of 5 days of voluntary alcohol drinking and 2 days of deprivation. Restraint stress (60 min) was applied to some animals during the first and second deprivations/withdrawals (at 4 h). Drugs (flumazenil, buspirone, SB242,084, CP154,526, CRA1000, naloxone, haloperidol, olanzapine, naloxone, and haloperidol) were given to some rats 30 min prior to restraint stress. Results: Stressed, deprived P rats exhibited both a longer duration of elevated alcohol drinking and anxiety-like behavior in the social interaction test upon withdrawal after the third cycle of voluntary alcohol drinking. When given prior to each of the restraint stresses, the benzodiazepine receptor antagonist flumazenil (5 mg/kg), the corticotrophin releasing factor receptor antagonists CRA1000 (3 mg/kg) and CP154,526 (10 mg/kg), the serotonin 5-HT1A receptor partial agonist buspirone (0.6 mg/kg), and the mixed 5-HT2C/D2 receptor antagonist olanzapine were effective in reducing the increased duration of elevated alcohol drinking and the withdrawal-induced anxiety-like behavior. In contrast, while the opiate receptor antagonist naloxone (20 mg/kg), the 5-HT2C receptor antagonist SB242084 (3 mg/kg), and the dopamine receptor antagonist haloperidol (0.1 mg/kg) also reduced drinking, they did not significantly alter anxiety like behavior. Conclusion: These results suggest that stress-induced facilitation of alcohol drinking and withdrawal-induced anxiety-like behavior in P rats may be closely but imperfectly linked.