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.
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:Doxazosindecreases 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.
Authors: Lorenzo Leggio; Silvia Cardone; Anna Ferrulli; George A Kenna; Marco Diana; Robert M Swift; Giovanni Addolorato Journal: Curr Pharm Des Date: 2010 Impact factor: 3.116
Authors: Dennis D Rasmussen; Laura L Alexander; Murray A Raskind; Janice C Froehlich Journal: Alcohol Clin Exp Res Date: 2008-11-19 Impact factor: 3.455
Authors: Tracy L Simpson; Andrew J Saxon; Charles W Meredith; Carol A Malte; Brittney McBride; Laura C Ferguson; Christopher A Gross; Kim L Hart; Murray Raskind Journal: Alcohol Clin Exp Res Date: 2008-10-21 Impact factor: 3.455
Authors: Marcelo F Lopez; Sarah E Reasons; Benjamin A Carper; Tracy L Nolen; Rick L Williams; Howard C Becker Journal: Alcohol Date: 2020-07-24 Impact factor: 2.405
Authors: George A Kenna; Carolina L Haass-Koffler; William H Zywiak; Steven M Edwards; Michael B Brickley; Robert M Swift; Lorenzo Leggio Journal: Addict Biol Date: 2015-06-02 Impact factor: 4.280
Authors: Terril L Verplaetse; Andrea H Weinberger; Lindsay M Oberleitner; Kathryn Mz Smith; Brian P Pittman; Julia M Shi; Jeanette M Tetrault; Meaghan E Lavery; Marina R Picciotto; Sherry A McKee Journal: J Psychopharmacol Date: 2017-04-25 Impact factor: 4.153
Authors: Verica Milivojevic; Gustavo A Angarita; Gretchen Hermes; Rajita Sinha; Helen C Fox Journal: Alcohol Clin Exp Res Date: 2020-06-12 Impact factor: 3.455
Authors: Sudie E Back; Julianne C Flanagan; Jennifer L Jones; Isabel Augur; Alan L Peterson; Stacey Young-McCaughan; David W Shirley; Aisling Henschel; Jane E Joseph; Brett T Litz; Allison K Hancock; John D Roache; Jim Mintz; Jennifer S Wachen; Terence M Keane; Kathleen T Brady Journal: Contemp Clin Trials Date: 2018-08-24 Impact factor: 2.226