Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase.
Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase.
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可卡因水解酶产生的可卡因代谢物的奖励和毒性。
DOI：
10.1007/s10571-015-0175-9
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发表时间：
2015
影响因子：
4
通讯作者：
Brimijoin,Stephen
中科院分区：
文献类型：
--
作者：
Murthy,Vishakantha;Geng,Liyi;Gao,Yang;Zhang,Bin;Miller,JordanD;Reyes,Santiago;Brimijoin,Stephen
丁酰胆碱酯酶（BChE）基因治疗是治疗可卡因成瘾的一个有前途的概念。基因转移后的BChE水平可以比未经治疗的小鼠高出1000倍，使这种酶成为第二丰富的血浆蛋白。在数月或数年的时间里，将BChE突变为可卡因水解酶（CocH）的基因转移可以维持在血液中出现后几秒钟内破坏可卡因的酶水平，使其几乎无法到达大脑。快速的酶作用导致两种可卡因代谢物苯甲酸（BA）和芽子碱甲酯（EME）的血浆水平急剧上升，这是一种平滑肌松弛剂，具有轻微的扩张作用，充其量也只有微弱的奖励作用。本研究，利用Balb/c小鼠，测试奖励效应和心血管效应的管理EME和BA一起在摩尔水平相当于由给定剂量的可卡因所产生的。奖励采用条件性位置偏爱评价。在这个范例中，可卡因（20毫克/公斤）诱导了一个强大的积极响应，但等效的EME + BA组合剂量未能诱导位置偏好或厌恶。同样，接受小鼠CocH基因转移（mCocH）的小鼠在重复接受接近致死的80 mg/kg可卡因剂量治疗后，没有表现出位置偏好或厌恶。此外，单次给予相同的高剂量可卡因未能影响使用非侵入性尾套法测量的血压。这些观察结果证实，CocH基因转移治疗后产生的药物代谢物是安全的，即使在通常致命的可卡因剂量后。
Butyrylcholinesterase (BChE) gene therapy is emerging as a promising concept for treatment of cocaine addiction. BChE levels after gene transfer can rise 1000-fold above those in untreated mice, making this enzyme the second most abundant plasma protein. For months or years, gene transfer of a BChE mutated into a cocaine hydrolase (CocH) can maintain enzyme levels that destroy cocaine within seconds after appearance in the blood stream, allowing little to reach the brain. Rapid enzyme action causes a sharp rise in plasma levels of two cocaine metabolites, benzoic acid (BA) and ecgonine methyl ester (EME), a smooth muscle relaxant that is mildly hypotensive and, at best, only weakly rewarding. The present study, utilizing Balb/c mice, tested reward effects and cardiovascular effects of administering EME and BA together at molar levels equivalent to those generated by a given dose of cocaine. Reward was evaluated by conditioned place preference. In this paradigm, cocaine (20 mg/kg) induced a robust positive response but the equivalent combined dose of EME + BA failed to induce either place preference or aversion. Likewise, mice that had undergone gene transfer with mouse CocH (mCocH) showed no place preference or aversion after repeated treatments with a near-lethal 80 mg/kg cocaine dose. Furthermore, a single administration of that same high cocaine dose failed to affect blood pressure as measured using the noninvasive tail-cuff method. These observations confirm that the drug metabolites generated after CocH gene transfer therapy are safe even after a dose of cocaine that would ordinarily be lethal.