The effect of doxycycline on alcohol consumption and sensitivity: consideration for inducible transgenic mouse models
The effect of doxycycline on alcohol consumption and sensitivity: consideration for inducible transgenic mouse models
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DOI：
10.1258/ebm.2012.012029
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发表时间：
2012-10-01
影响因子：
3.2
通讯作者：
Haydon, Philip G.
中科院分区：
文献类型：
--
作者：
McIver, Sally R.;Muccigrosso, Megan M.;Haydon, Philip G.
已知神经炎症会引起脑生理学的许多变化，并与各种病理学相关，包括神经退行性疾病和行为，如睡眠和急性疾病。此外，越来越多的证据表明，对酒精的行为反应受到神经免疫系统扰动的影响。最近的研究表明，促炎介质的管理增加酒精消费，而抗炎药物，如米诺环素，减少消费。多西环素是一种抗炎介质和四环素衍生物，通常用于四环素调控系统，这是一种因其诱导性和可逆性而被广泛认可的转基因方法。鉴于抗炎药与酒精反应和酒精消耗之间的联系，并且由于四环素调控系统越来越多地用于遗传操作和行为表型分析，我们研究了多西环素给药对酒精敏感性和消耗的影响。使用两个独立的含有四环素反式激活因子转基因或四环素操纵基因启动子插入的转基因系，沿着野生型同窝小鼠（C57 BI/6 J），测量多西环素给药（40 mg/kg，在食物中）时酒精消耗、酒精诱导的运动障碍和镇静以及血液酒精浓度的变化。使用重复的会议在黑暗中饮酒的范例，我们发现，强力霉素一贯减少消耗20%的酒精在两个和四个小时的访问。多西环素还增加了对酒精（2 g/kg）的运动损伤效应的敏感性，以及乙醇注射（3.5 g/kg）后翻正反射丧失的持续时间，而不会引起血液酒精水平的显著变化。尽管使用四环素调控的转基因方法有许多优点，但重要的是要考虑多西环素给药对可能受神经炎症影响的行为（包括酒精行为）的影响。
Neuroinflammation is known to elicit numerous changes in brain physiology and is associated with various pathologies, including neurodegenerative diseases, and behaviors, such as sleep and acute illness. In addition, there is accumulating evidence that the behavioral response to alcohol is affected by perturbations to the neuroimmune system. Recent studies have shown that administration of proinflammatory mediators increases alcohol consumption, while anti-inflammatory drugs, such as minocycline, decrease consumption. Doxycycline is an anti-inflammatory mediator and a tetracycline derivative, and is commonly used in the tetracycline regulatory system, a transgenic approach widely accredited for its inducible and reversible nature. Given the established link between anti-inflammatory agents and response to and consumption of alcohol, and because the tetracycline regulatory system is becoming increasingly employed for genetic manipulations and behavioral phenotyping, we investigated the effect of doxycycline administration on alcohol sensitivity and consumption. Two independent transgenic lines containing a tetracycline transactivator transgene or the tetracycline operator promoter insertion, along with wild-type littermate mice (C57BI/6J), were used to measure changes in alcohol consumption, alcohol-induced motor impairment and sedation, and blood alcohol concentration with doxycycline administration (40 mg/kg in chow). Using repeated sessions of the drinking-in-the-dark paradigm, we found that doxycycline consistently reduced consumption of 20% alcohol during two- and four-hour access. Doxycyline also increased sensitivity to the motor-impairing effects of alcohol (2 g/kg), and the duration of loss of righting reflex after ethanol injection (3.5 g/kg), without causing a significant alteration in blood alcohol levels. Despite the many advantages of using a tetracycline-regulated transgenic approach, it is important to consider the effects of doxycycline administration in behaviors that may be influenced by neuroinflammation, including alcohol behaviors.