Anti-cocaine antibody and butyrylcholinesterase-derived cocaine hydrolase exert cooperative effects on cocaine pharmacokinetics and cocaine-induced locomotor activity in mice
Anti-cocaine antibody and butyrylcholinesterase-derived cocaine hydrolase exert cooperative effects on cocaine pharmacokinetics and cocaine-induced locomotor activity in mice
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DOI：
10.1016/j.cbi.2012.08.015
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发表时间：
2013-03-25
影响因子：
5.1
通讯作者：
Gao, Yang
中科院分区：
文献类型：
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作者：
Brimijoin, Stephen;Orson, Frank;Gao, Yang
我们正在研究基于病毒基因转移的可卡因水解酶（CocH）的可卡因滥用的治疗方法，该水解酶来源于人丁酰胆碱酯酶，可以减少可卡因刺激的运动和可卡因引发的大鼠觅药行为的恢复数月。在这里，在小鼠中，我们探索了抗可卡因抗体可以补充CocH的作用以减少大脑中的可卡因摄取并阻断中枢诱发的运动刺激的可能性。测试蛋白的直接注射显示CocH（0.3或1 mg/kg）本身在降低给予可卡因（10 mg/kg，s.c.，或20 mg/kg，i.p）。以低剂量（8 mg/kg，i. p.）对可卡因的分布几乎没有影响。然而，较高剂量的抗体（12 mg/kg）引起外周捕获（血浆药物水平增加），导致CocH对可卡因的代谢增加，如血浆苯甲酸升高6倍所证明。用小剂量的CocH和抗体（分别为1和8 mg/kg）进行的行为测试表明，单独使用这两种药物都不能降低由非常大剂量的可卡因（100 mg/kg，腹膜内）引发的小鼠运动活动。然而，双重治疗完全抑制了运动刺激。总之，我们发现合作和可能的协同作用，值得进一步探索双重疗法治疗可卡因滥用。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
We are investigating treatments for cocaine abuse based on viral gene transfer of a cocaine hydrolase (CocH) derived from human butyrylcholinesterase, which can reduce cocaine-stimulated locomotion and cocaine-primed reinstatement of drug-seeking behavior in rats for many months. Here, in mice, we explored the possibility that anti-cocaine antibodies can complement the actions of CocH to reduce cocaine uptake in brain and block centrally-evoked locomotor stimulation. Direct injections of test proteins showed that CocH (0.3 or 1 mg/kg) was effective by itself in reducing drug levels in plasma and brain of mice given cocaine (10 mg/kg, s.c., or 20 mg/kg, i.p). Administration of cocaine antibody per se at a low dose (8 mg/kg, i.p.) exerted little effect on cocaine distribution. However, a higher dose of antibody (12 mg/kg) caused peripheral trapping (increased plasma drug levels), which led to increased cocaine metabolism by CocH, as evidenced by a 6-fold rise in plasma benzoic acid. Behavioral tests with small doses of CocH and antibody (1 and 8 mg/kg, respectively) showed that neither agent alone reduced mouse locomotor activity triggered by a very large cocaine dose (100 mg/kg, i.p.). However, dual treatment completely suppressed the locomotor stimulation. Altogether, we found cooperative and possibly synergistic actions that warrant further exploration of dual therapies for treatment of cocaine abuse. (C) 2012 Elsevier Ireland Ltd. All rights reserved.