Effective Reduction in High Ethanol Drinking by Semisynthetic Tetracycline Derivatives.
Effective Reduction in High Ethanol Drinking by Semisynthetic Tetracycline Derivatives.
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通过半合成四环素衍生物有效降低高乙醇饮用。
DOI：
10.1111/acer.13253
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Bergeson SE
中科院分区：
文献类型：
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作者：
Syapin PJ;Martinez JM;Curtis DC;Marquardt PC;Allison CL;Groot JA;Baby C;Al-Hasan YM;Segura I;Scheible MJ;Nicholson KT;Redondo JL;Trotter DRM;Edwards DS;Bergeson SE
New pharmacotherapies to treat Alcohol Use Disorders (AUD) are needed. Given the complex nature of AUD, there likely exist multiple novel drug targets. We, and others, have shown that the tetracycline drugs, minocycline and doxycycline, reduced ethanol drinking in mice. To test the hypothesis that suppression of high ethanol consumption is a general property of tetracyclines, we screened several derivatives for anti-drinking activity using the Drinking-In-the-Dark (DID) paradigm. Active drugs were studied further using the dose-response relationship. Adult female and male C57BL/6J mice were singly housed and the DID paradigm was performed using 20% ethanol over a 4-day period. Mice were administered a tetracycline or its vehicle 20 h prior to drinking. Water and ethanol consumption was measured daily. Body weight was measured at the start of drug injections and after the final day of the experiment. Blood was collected for ethanol content measurement immediately following the final bout of drinking. Seven tetracyclines were tested at a 50 mg/kg dose. Only minocycline and tigecycline significantly reduced ethanol drinking, and doxycycline showed a strong effect-size trend towards reduced drinking. Subsequent studies with these three drugs revealed a dose-dependent decrease in ethanol consumption for both female and male mice, with sex differences in efficacy. Minocycline and doxycycline reduced water intake at higher doses, although to a lesser degree than their effects on ethanol drinking. Tigecycline did not negatively affect water intake. The rank order of potency for reduction in ethanol consumption was minocycline > doxycycline > tigecycline, indicating efficacy was not strictly related to their partition-coefficients (LogP) or distribution constants (LogD). Due to its effectiveness in reducing high ethanol consumption coupled without an effect on water intake, tigecycline was found to be the most promising lead tetracycline compound for further study toward the development of a new pharmacotherapy for the treatment of AUD.
