Prazosin Reduces Alcohol Drinking Throughout Prolonged Treatment and Blocks the Initiation of Drinking in Rats Selectively Bred for High Alcohol Intake

Abstract

BACKGROUND This study examined whether prazosin reduces alcohol drinking over the course of prolonged treatment and whether it blocks initiation of alcohol drinking in rats with a genetic predisposition toward high alcohol drinking, i.e, alcohol-preferring (P) rats. METHODS In study one, alcohol-experienced P rats that had been drinking alcohol 2 hrs/day for several months were treated daily with prazosin (0, 0.5, 1.0 or 2.0 mg/kg BW) for 7 weeks. In study two, alcohol-naïve P rats were treated daily with prazosin (0, 1.0 or 2.0 mg/kg BW) for two weeks prior to, or concomitantly with, initiation of alcohol access and throughout 3 weeks of alcohol availability. Prazosin treatment and alcohol access were then discontinued for 2 weeks followed by reinstatement of alcohol access without prazosin treatment for 4 weeks, followed by resumption of daily prazosin treatment (2.0 mg/kg BW) for 3 weeks. RESULTS Prazosin reduced alcohol drinking throughout 7 weeks of treatment in P rats accustomed to drinking alcohol. Following termination of prazosin treatment, alcohol drinking slowly returned to pretreatment baseline. Reduced alcohol intake was accompanied by increased water intake. In alcohol-naïve P rats, prazosin administration prior to the first opportunity to drink alcohol and throughout 3 weeks of alcohol access retarded acquisition of alcohol drinking and reduced the amount of alcohol consumed. When prazosin was administered concomitantly with the first opportunity to drink alcohol, it abolished acquisition of alcohol drinking. Discontinuation of prazosin treatment allowed expression of a genetic predisposition toward high alcohol drinking to gradually emerge. Prazosin retained the ability to reduce alcohol intake with repeated treatments. CONCLUSIONS Prazosin decreased alcohol drinking during prolonged treatment and may be useful for treating alcoholism and alcohol use disorders. Prazosin may also be useful for deterring initiation of drinking in individuals with a family history of alcoholism.

The α2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats

“…These results are consistent with our reports that prazosin, which decreases noradrenergic signaling by blocking post-synaptic α 1 -adrenergic receptors, decreases alcohol drinking in P rats when administered acutely (Rasmussen et al, 2009) or chronically (Froehlich, Hausauer, Federoff, et al, 2013;). The fact that two different pharmacologic interventions that decrease noradrenergic signaling, but via different mechanisms, are both capable of suppressing alcohol drinking is consistent with evidence that activation of the noradrenergic system plays a key role in mediating voluntary alcohol drinking.…”

“…Prazosin dose-dependently reduced withdrawal-induced operant self-administration of alcohol in alcohol-dependent Wistar rats (Walker, Rasmussen, Raskind, & Koob, 2008). Prazosin also suppressed voluntary alcohol drinking by rats selectively bred for alcohol preference (P line) when administered either acutely (Rasmussen, Alexander, Raskind, & Froehlich, 2009) or chronically (Froehlich, Hausauer, Federoff, Fischer, & Rasmussen, 2013; Froehlich, Hausauer, & Rasmussen, 2013). The ability of prazosin to reduce alcohol drinking has been confirmed in humans; Simpson and colleagues (2009) reported that prazosin decreased relapse alcohol drinking in treatment-seeking alcohol-dependent men.…”

Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations

“…We previously demonstrated that prazosin treatment acutely and chronically decreases voluntary alcohol drinking in P rats (Rasmussen et al, 2009;Froehlich et al, 2013), alcohol drinking in a rat model of relapse to alcohol drinking (Froehlich et al, 2015), alcohol seeking and drinking in operant paradigms (Verplaetse et al, 2011), and drinking during acute withdrawal in alcoholdependent outbred rats (Walker et al, 2008). Prazosin treatment also facilitates abstinence in treatment-seeking alcohol-dependent men, as demonstrated in a study in which the subjects were unaware of their treatment condition (prazosin vs placebo) and there were no differences in side effects reported (Simpson et al, 2009).…”

Low-dose prazosin alone and in combination with propranolol or naltrexone: effects on ethanol and sucrose seeking and self-administration in the P rat

“…Recent evidence suggests that the noradrenergic system plays a key role in mediating ethanol-motivated behaviors in both alcohol-dependent and non-dependent humans and rats (Froehlich et al 2013a,b; Fox et al 2012; Gilpin and Koob 2010; Rasmussen et al 2009; Simpson et al 2009; Verplaetse et al 2011; Walker et al 2008). Prazosin, an α 1 -adrenergic antagonist, has been found to reduce ethanol drinking in home cage, limited access paradigms in P rats (Rasmussen et al 2009) and block operant responding for ethanol in dependent Wistar rats, with higher doses necessary to be effective in non-dependent animals in a fixed ratio (FR) paradigm (Walker et al 2008).…”

“…Prazosin, an α 1 -adrenergic antagonist, has been found to reduce ethanol drinking in home cage, limited access paradigms in P rats (Rasmussen et al 2009) and block operant responding for ethanol in dependent Wistar rats, with higher doses necessary to be effective in non-dependent animals in a fixed ratio (FR) paradigm (Walker et al 2008). Prazosin blocks stress-induced reinstatement of ethanol-seeking in Wistar rats (Le et al 2011), and reduces ethanol drinking throughout prolonged treatment in alcohol-experienced P rats and impedes acquisition of ethanol drinking in naïve P rats (Froehlich et al 2013b). In the same paradigm used in the present investigation, prazosin attenuated ethanol- and sucrose-seeking and consumption in P rats (Verplaetse et al 2012).…”