P rats develop physical dependence on alcohol via voluntary drinking: Changes in seizure thresholds, anxiety, and patterns of alcohol drinking

Background: It has been proposed that the alcohol-preferring P rat meets ma ny of the criteria for an animal model of alcoholism. However, the developm ent of alcohol dependence has not been explored in rats that self-administe r ethanol for less than 15-20 weeks. The present study investigated the dev elopment of physical dependence upon alcohol after 2-6 weeks of voluntary a lcohol intake. Changes in bicuculline-induced seizure thresholds, microstru cture of alcohol drinking, and anxiety-related behavior were used as indice s of alcohol dependence. In addition, we evaluated the microstructure of al cohol drinking associated with the development of physical dependence upon alcohol. Methods: Alcohol (10% ethanol solution) was measured in graduated drinking tubes with both alcohol and water available continuously. Microstructure of alcohol intake was monitored by a computerized drinkometer. Physical depen dence upon alcohol was determined by measuring bicuculline-induced seizure thresholds after alcohol withdrawal. Anxiety-related behavior of P rats aft er alcohol withdrawal was determined by the social interaction and elevated plus maze tests. Results: Initial alcohol intake in the alcohol-preferring P rat was relativ ely modest (3.9 +/- 0.4 g/kg/day). Four days of forced alcohol exposure (in itiation) followed by 6 weeks of voluntary drinking resulted in an increase of alcohol intake to 5.5 +/- 0.2 g/kg/day. Ethanol self-administration for 6 weeks, but not for 2 or 4 weeks, produced a significant reduction (30%; p < 0.05) in bicuculline-induced seizure thresholds during alcohol withdraw al. Alterations in the microstructure of alcohol intake (i.e., 90% increase in the size of alcohol drinking bouts compared to the baseline [p < 0.001] with no change in bout frequency) were associated with the development of alcohol dependence. Termination of alcohol intake after 6 weeks of voluntar y alcohol consumption resulted in increased anxiety according to both the s ocial interaction and elevated plus maze tests. Conclusions: The results of this study indicate that 6 weeks of voluntary a lcohol intake are sufficient for the development of physical dependence upo n alcohol in the alcohol-preferring P rats as measured by susceptibility to bicuculline-induced seizures. This lime is much shorter than the 15-20 wee ks reported earlier. Development of physical dependence to alcohol was asso ciated with an increase in daily alcohol intake (40% over the baseline), an increase in alcohol intake during each drinking bout (90% over the baselin e), and elevated anxiety during alcohol withdrawal.