The α1-adrenergic receptor antagonist, doxazosin, reduces alcohol drinking in alcohol-preferring (P) Rats

Abstract

Background: Evidence supports a role for the noradrenergic system in alcohol drinking in animals and humans. Our previous studies demonstrated the efficacy of prazosin, an α1-adrenergic antagonist, in decreasing alcohol drinking in rat models of alcohol dependence. Prazosin has also been shown to decrease alcohol drinking in treatment-seeking alcohol-dependent men. Clinically, the use of prazosin is limited by the requirement for multiple daily administrations, whereas doxazosin, a structurally similar α1-adrenergic antagonist, requires only once-daily dosing. In this study, we tested the hypothesis that doxazosin, like prazosin, would decrease alcohol drinking in rats selectively bred for alcohol preference (P line).

Methods: Adult male P rats were given 2 h/d scheduled access to a 2-bottle choice (15% v/v alcohol vs. water) session 5 d/wk (M-F), with food and water available ad libitum 24 h/d. Rats were injected with doxazosin (0 to 10 mg/kg, IP) 40 minutes prior to initiation of the alcohol access session in 3 trials (of 3, 5, and 5 consecutive days) each separated by 5 to 8 weeks. The third trial included 1 day without alcohol access (for locomotor testing), and 1 day of a single hour of alcohol access (for plasma alcohol determination).

Results: Doxazosin significantly reduced alcohol intake in all 3 trials. The 5 mg/kg dose consistently reduced alcohol intake, increased water drinking, did not affect locomotor activity, and resulted in lower plasma alcohol concentrations, suggesting that the doxazosin-induced reduction in alcohol drinking was not dependent on a motor impairment or an alteration in alcohol clearance.

Conclusions: Doxazosin decreases voluntary alcohol consumption by male alcohol-preferring (P) rats, supporting a role for the noradrenergic system in alcohol drinking in P rats and suggesting that doxazosin could potentially be an effective once-daily pharmacotherapeutic agent for the treatment of alcohol use disorders.

Fig. 1

Trial 1, 3-day treatment: Effects of doxazosin (1.25 – 5 mg/kg, IP) on alcohol intake (mean ±S.E.M). Doxazosin dose-dependently decreased alcohol intake, independent of day. Each bar represents data from 11-12 rats. ***p < .001 versus vehicle control treatment for 1.25, 2.5 and 5 mg/kg; ^a p < .01, 5 mg/kg versus 1.25 and 2.5 mg/kg. For significant differences between days, see text. Pre-treatment values reflect the averages from 5 daily sessions.

Fig. 2

Trial 1, 3-day treatment: Effects of doxazosin (1.25 – 5 mg/kg, IP) on water intake (mean ±S.E.M). Doxazosin dose-dependently increased water intake, independent of day. Each bar represents data from 11-12 rats. ***p < .001, 2.5 and 5 mg/kg versus vehicle control treatment; ^a p < .05, 2.5 and 5 mg/kg versus 1.25 mg/kg. Pre-treatment values reflect the averages from 5 daily sessions.

Fig. 3

Trial 2, 5-day treatment: Effects of doxazosin (2.5 – 10 mg/kg, IP) on alcohol intake (mean ±S.E.M). Each bar represents data from 11 - 12 rats. “A” and “B” indicate behavioral tests discussed in the Results section. *p < .05, **p < .001, ***p < .001 versus vehicle control treatment within individual days. For significant differences between doxazosin doses and between days, see text. Pre-treatment values reflect the averages from 5 daily sessions.

Fig. 4

Trial 2, 5-day treatment: Effects of doxazosin (2.5 – 10 mg/kg, IP) on water intake (mean ±S.E.M). Each bar represents data from 11 - 12 rats. *p < .05 versus vehicle control treatment, ^a p < .01 versus 10 mg/kg, within individual days. For significant differences between days, see text. Pre-treatment values reflect the averages from 5 daily sessions.

Fig. 5

Trial 3, 5-day treatment: Effects of doxazosin (2.5 – 10 mg/kg, IP) on alcohol intake (mean ±S.E.M). On Treatment Day 4 no alcohol was provided. On Treatment Day 5, the alcohol session was limited to 1 hour. Doxazosin dose-dependently decreased alcohol intake, independent of day. Each bar represents data from 11-12 rats. “A”: Time of test of doxazosin + alcohol effects on drinking ability (see discussion in Results section); “B”: Time of tests of doxazosin effects on drinking ability (see discussion in Results section) and locomotor function (see Fig. 7); “C”: Time of determination of plasma alcohol levels (see Fig. 8). ***p ≤ .001, 5 and 10 mg/kg versus vehicle control treatment; ^a p ≤ .001, 5 and 10 mg/kg versus 2.5 mg/kg; ^b p < .05, 10 mg/kg versus 5 mg/kg. For significant differences between days, see text. Pre-treatment values reflect the averages from 2 daily sessions.

Fig. 6

Trial 3, 5-day treatment: Effects of doxazosin (2.5 – 10 mg/kg, IP) on water intake (mean ±S.E.M). On Treatment Day 4 no alcohol was provided. On Treatment Day 5, the alcohol access session was limited to 1 hour. Doxazosin dose-dependently increased water intake, independent of day. Each bar represents data from 11 – 12 rats. ***p < .001, 5 mg/kg versus vehicle control treatment; ^a p < .05, 5 mg/kg versus both 2.5 and 10 mg/kg. For significant differences between days, see text. Pre-treatment values reflect the averages from 2 daily sessions.

Fig. 7

Effects of doxazosin on locomotor activity in a novel environment (“B” in Fig. 5). **p < .01 versus vehicle control treatment; ^a p < .05 versus 2.5 and 5 mg/kg.

Fig. 8

Effects of doxazosin on plasma alcohol concentration (C in Fig. 5). ***p < .001 versus vehicle control treatment, **p < .01 versus vehicle control treatment, ^a p ≤ .01 versus 2.5 mg/kg.