α1-肾上腺素能受体拮抗剂多沙唑嗪可减少酒精偏爱（P）大鼠的饮酒量。
The α1-adrenergic receptor antagonist, doxazosin, reduces alcohol drinking in alcohol-preferring (P) Rats.
机构信息
VA Puget Sound Health Care System , Seattle, Washington; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98108, USA.
出版信息
Alcohol Clin Exp Res. 2013 Feb;37(2):202-12. doi: 10.1111/j.1530-0277.2012.01884.x. Epub 2012 Jul 3.
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.
背景
有证据表明，去甲肾上腺素能系统在动物和人类的饮酒行为中起作用。我们之前的研究表明，α1-肾上腺素能拮抗剂普萘洛尔可有效减少酒精依赖大鼠模型的饮酒量。普萘洛尔也已被证明可减少寻求治疗的酒精依赖男性的饮酒量。临床上，普萘洛尔的使用受到需要每日多次给药的限制，而结构相似的α1-肾上腺素能拮抗剂多沙唑嗪只需每日一次给药。在这项研究中，我们测试了这样一个假设，即多沙唑嗪与普萘洛尔一样，可减少专门用于酒精偏好（P 线）的大鼠的饮酒量。
方法
成年雄性 P 大鼠每天接受 2 小时的 2 瓶选择（15%v/v 酒精与水），每周 5 天（M-F），24 小时内可自由获取食物和水。在 3 次试验（每次连续 3、5 和 5 天）中，在开始酒精摄入期之前 40 分钟，大鼠通过腹腔注射多沙唑嗪（0 至 10mg/kg），每次试验之间间隔 5 至 8 周。第三次试验包括一天无酒精摄入（用于运动测试）和一天单次 1 小时的酒精摄入（用于测定血浆酒精浓度）。
结果
多沙唑嗪在所有 3 次试验中均显著减少了酒精摄入量。5mg/kg 剂量持续减少酒精摄入量，增加了水的摄入量，对运动活动没有影响，并且导致较低的血浆酒精浓度，表明多沙唑嗪引起的饮酒减少与运动障碍或酒精清除率改变无关。
结论
多沙唑嗪可减少雄性酒精偏好（P）大鼠的自愿饮酒量，支持去甲肾上腺素能系统在 P 大鼠饮酒中的作用，并表明多沙唑嗪可能是治疗酒精使用障碍的有效每日一次的药物治疗剂。
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