The α1-Adrenergic Receptor Antagonist, Doxazosin, Reduces Alcohol Drinking in Alcohol-Preferring (P) Rats
Version of Record online: 3 JUL 2012
Copyright © 2012 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 37, Issue 2, pages 202–212, February 2013
How to Cite
O'Neil, M. L., Beckwith, L. E., Kincaid, C. L. and Rasmussen, D. D. (2013), The α1-Adrenergic Receptor Antagonist, Doxazosin, Reduces Alcohol Drinking in Alcohol-Preferring (P) Rats. Alcoholism: Clinical and Experimental Research, 37: 202–212. doi: 10.1111/j.1530-0277.2012.01884.x
- Issue online: 1 FEB 2013
- Version of Record online: 3 JUL 2012
- Manuscript Accepted: 2 MAY 2012
- Manuscript Received: 9 DEC 2011
- VA Puget Sound Health Care System
- NIH. Grant Numbers: P20 AA017839, R24 AA015512
- P Rats
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).
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).
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.
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.