Effects of prazosin and doxazosin on yohimbine-induced reinstatement of alcohol seeking in rats.

Abstract

Alpha-1 adrenoceptor antagonists, such as prazosin, show promise in treating alcoholism. In rats, prazosin reduces alcohol self-administration and relapse induced by footshock stress and the alpha-2 antagonist yohimbine, but the processes involved in these effects of prazosin are not known. Here, we present studies on the central mechanisms underlying the effects of prazosin on yohimbine-induced reinstatement of alcohol seeking. In experiment 1, we trained rats to self-administer alcohol (12% w/v, 1h/day), extinguished their responding, and tested the effects of prazosin, administered ICV (2 and 6nmol) or systemically (1mg/kg) on yohimbine (1.25mg/kg)-induced reinstatement. In experiment 2, we determined potential central sites of action by analyzing effects of prazosin (1mg/kg) on yohimbine (1.25mg/kg)-induced Fos expression. In experiment 3, we determined the effects of doxazosin (1.25, 2.5, and 5mg/kg), an alpha-1 antagonist with a longer half-life on yohimbine-induced reinstatement. Yohimbine-induced reinstatement of alcohol seeking was reduced significantly by ICV and systemic prazosin (50 and 69% decreases, respectively). Systemic prazosin reduced yohimbine-induced Fos expression in the prefrontal cortex, accumbens shell, ventral bed nucleus of the stria terminalis, and basolateral amygdala (46-67% decreases). Doxazosin reduced yohimbine-induced reinstatement of alcohol seeking (78% decrease). Prazosin acts centrally to reduce yohimbine-induced alcohol seeking. The Fos mapping study suggests candidate sites where it may act. Doxazosin is also effective in reducing yohimbine-induced reinstatement. These data provide information on the mechanisms of alpha-1 antagonists on yohimbine-induced alcohol seeking and indicate their further investigation for the treatment of alcoholism.