α1-noradrenergic receptor antagonism blocks dependence-induced increases in responding for ethanol

Abstract

The purpose of this study was to test the hypothesis that blockade of α 1 -adrenergic receptors may suppress the excessive ethanol consumption associated with acute withdrawal in ethanol-dependent rats. Following the acquisition and stabilization of operant ethanol self-administration in male Wistar rats, dependence was induced in half the animals by subjecting them to a four-week intermittent vapor exposure period in which animals were exposed to ethanol vapor for 14 hours per day. Subsequent to dependence induction, the effect of prazosin (0.0, 0.25, 0.5, 1, 1.5 and 2.0 mg/kg IP) was tested on operant responding for ethanol in vapor-exposed and control rats during acute withdrawal. In ethanol-dependent animals, prazosin significantly suppressed responding at the 1.5 and 2.0 mg/kg doses, whereas only the 2.0 mg/kg dose was effective in nondependent animals, identifying an increase in the sensitivity to prazosin in dependent animals. Conversely, at the lowest dose tested (0.25 mg/kg), prazosin increased responding in nondependent animals, which is consistent with the effect of anxiolytics on ethanol self-administration in non-dependent animals. None of the doses tested reliably affected concurrent water self-administration. These results suggest the involvement of the noradrenergic system in the excessive alcohol drinking seen during acute withdrawal in ethanol-dependent rats.

Involvement of α1-adrenoceptors in conditioned place preference supported by nicotine in rats

“…Interestingly, prazosin was also found to attenuate cocaine-induced reinstatement of cocaine-seeking in rats (Zhang and Kosten 2005) and to inhibit the facilitation of cocaine SA behavior induced by repeated pre-exposure to this psychostimulant (Zhang and Kosten 2007). Likewise, prazosin decreased ethanol SA in ethanol-dependent rats (Walker et al 2008) and reduced cocaine and heroin SA in rats given extended access to these drugs (Greenwell et al 2009;Wee et al 2008). Accordingly, mice lacking the α1B-ARs (α1B-KO) neither developed CPP to morphine nor did they show preference for morphine or cocaine in oral SA paradigm (Drouin et al 2002a).…”

Modeling Relapse Situations in the Human Laboratory

“…For example, using animal models of drug self-administration and reinstatement, preclinical studies have shown CRF antagonists and α-2-adrenergic agonists to be efficacious in reducing stress-related drug seeking in addicted laboratory animals (see Shaham et al 2003;Weiss 2005 for review). Similarly, α1-adrenergic antagonists such as Prazosin have been found to decrease alcohol withdrawal symptoms, alcohol consumption and stress-induced relapse in animal models (Gilpin et al 2009;Rasmussen et al 2006;Walker et al 2008) and in a pilot clinical study of alcoholics (Simpson et al 2009). …”

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).…”