Trace amine associated receptor 1 modulates behavioral effects of ethanol.
Trace amine associated receptor 1 modulates behavioral effects of ethanol.
复制标题
DOI：
10.4137/sart.s12110
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Miller GM
中科院分区：
文献类型：
--
作者：
Lynch LJ;Sullivan KA;Vallender EJ;Rowlett JK;Platt DM;Miller GM
酒精使用障碍（AUD）的治疗选择很少，迫切需要更多。在这里，我们评估了微量胺相关受体1（TAAR 1），一种脑单胺系统的调节剂，是否参与乙醇的行为和代谢相关效应，以及它是否可能作为治疗靶点。在乙醇消耗（两瓶选择[TBC]）、运动损伤（翻正反射丧失，[LORR]，自发活动）和乙醇清除（血液乙醇水平[BEL]）试验中比较野生型（WT）和TAAR 1敲除（KO）小鼠（75% C57 J/BL 6和25% 129 S1/Sv背景）。与WT小鼠相比，KO小鼠表现出（1）在TBC范例中对乙醇的显著更大偏好和消耗（在10周内递增3%-11%vol/vol），在具有蔗糖的TBC中未观察到显著差异（1%-3%）;（2）急性乙醇（2.0或2.5g/kg，腹膜内[i. p.]）表现为在较低剂量和较长时间下观察到的LORR，具有相似的BEL和乙醇清除率;和（3）响应于急性乙醇攻击（1.0-2.5 g/kg，i. p.）的60分钟内较低的累积运动活性。目前的研究结果首次将TAAR 1与乙醇的行为和酒精相关效应联系起来，并提出了一个问题，即靶向TAAR 1的特定药物是否可能减少AUD患者的酒精消费。
Few treatment options for alcohol use disorders (AUDs) exist and more are critically needed. Here, we assessed whether trace amine associated receptor 1 (TAAR1), a modulator of brain monoamine systems, is involved in the behavioral and reinforcement-related effects of ethanol and whether it could potentially serve as a therapeutic target. Wild-type (WT) and TAAR1 knockout (KO) mice (75% C57J/BL6 and 25% 129S1/Sv background) were compared in tests of ethanol consumption (two-bottle choice [TBC]), motor impairment (loss of righting reflex, [LORR], locomotor activity) and ethanol clearance (blood ethanol level [BEL]). As compared with WT mice, KO mice displayed (1) significantly greater preference for and consumption of ethanol in a TBC paradigm (3%–11% vol/vol escalating over 10 weeks), with no significant difference observed in TBC with sucrose (1%–3%); (2) significantly greater sedative-like effects of acute ethanol (2.0 or 2.5 g/kg, intraperitoneal [i.p.]) manifested as LORR observed at a lower dose and for longer time, with similar BELs and rates of ethanol clearance; and (3) lower cumulative locomotor activity over 60 minutes in response to an acute ethanol challenge (1.0–2.5 g/kg, i.p.). The present findings are the first to implicate TAAR1 in the behavioral and reinforcement-related effects of ethanol and raise the question of whether specific drugs that target TAAR1 could potentially reduce alcohol consumption in humans with AUDs.