Effects of Prazosin, an α1-Adrenergic Receptor Antagonist, on the Seeking and Intake of Alcohol and Sucrose in Alcohol-Preferring (P) Rats

Background: Previous studies show that prazosin, an alpha 1-adrenergic receptor antagonist, decreases alcohol drinking in animal models of alcohol use and dependence [Rasmussen et similar to al. (2009) Alcohol Clin Exp Res 3:264272; Walker et similar to al. (2008) Alcohol 42:9197] and in alcohol-dependent men [Simpson et similar to al. (2009) Alcohol Clin Exp Res 33:255263]. This study extended these findings by using a paradigm that allows for separate assessment of prazosin on motivation to seek versus consume alcohol or sucrose in selectively bred rats. Methods: Alcohol-preferring (P) rats were trained to complete an operant response that resulted in access to either 2% sucrose or 10% alcohol. A 4-week Seeking Test Phase examined responding in single, weekly extinction sessions when no reinforcer could be obtained. A 4-week Drinking Test Phase consisted of rats lever-pressing to pay a specified amount up front to gain access to unlimited alcohol (or sucrose) for a 20-minute period. On Seeking and Drinking test days, prazosin (0.0, 0.5, 1.0, and 1.5 mg/kg) was administered intraperitoneally 30 minutes prior to behavioral sessions. Results: Rats were self-administering an average of 0.9 (+/-0.09) g/kg alcohol on vehicle test day and had pharmacologically relevant blood ethanol concentrations. Prazosin significantly decreased alcohol seeking at all doses tested. The highest dose of prazosin also increased the latency to first response for alcohol and decreased alcohol intake. While sucrose-seeking and intake were similarly affected by prazosin, the high dose of prazosin did not increase response latency. Conclusions: These findings are consistent with and extend previous research and suggest that prazosin decreases motivation to initiate and engage in alcohol consumption. The specificity of prazosin in attenuating the initiation of alcohol- but not sucrose-seeking suggests that this effect is not because of prazosin-induced motor-impairment or malaise. Together with previous findings, these data suggest that prazosin may be an effective pharmacotherapy, with specific application in people that drink excessively or have a genetic predisposition to alcohol abuse.