Department of Neuroscience, Tufts University, 136 Harrison Avenue, Boston, MA 02111, USA.
Exp Biol Med (Maywood). 2012 Oct;237(10):1129-33. doi: 10.1258/ebm.2012.012029. Epub 2012 Sep 27.
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 (C57Bl/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. Doxycycline 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.
神经炎症会引起大脑生理的诸多变化，并与多种病理学相关，包括神经退行性疾病，以及睡眠和急性疾病等行为。此外，越来越多的证据表明，神经免疫系统的紊乱会影响对酒精的行为反应。最近的研究表明，促炎介质的给药会增加酒精的消耗，而抗炎药物，如米诺环素，则会减少消耗。强力霉素是一种抗炎介质和四环素衍生物，常用于四环素调控系统，该系统作为一种遗传操作和行为表型广泛认可的诱导和可逆性方法。鉴于抗炎剂与对酒精的反应和消耗之间的既定联系，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，我们研究了强力霉素给药对酒精敏感性和消耗的影响。使用包含四环素转录激活物转基因或四环素操纵子启动子插入的两个独立的转基因系，以及野生型同窝仔鼠（C57Bl/6J），来测量酒精消耗、酒精引起的运动障碍和镇静以及强力霉素给药时的血液酒精浓度的变化（在饲料中给予 40mg/kg）。使用暗室饮酒范式的重复疗程，我们发现强力霉素一致减少了 20%酒精的消耗，在两小时和四小时的访问期间。强力霉素还增加了对酒精运动障碍效应的敏感性（2g/kg），以及乙醇注射后翻正反射丧失的持续时间（3.5g/kg），而不会导致血液酒精水平的显著改变。尽管使用四环素调控的转基因方法有许多优点，但在可能受神经炎症影响的行为中，包括酒精行为，考虑强力霉素给药的影响是很重要的。
