慢启动长效多巴胺受体抑制剂对药物依赖性潜在治疗作用的研究(英文)

POTENTIAL USE OF SLOW-ONSET LONG-ACTING DOPAMINE TRANSPORTER INHIBITORS IN THE TREATMENT OF DRUG DEPENDENCE

长效阿片受体激动剂美沙酮对阿片依赖的有效治疗提示,慢启动长效多巴胺受体(DAT)抑制剂很可能对精神兴奋剂成瘾具有潜在治疗作用。为验证此假设,我们成功地研制出慢启动长效DAT抑制剂CTDP32,476,并进一步研究其在成瘾性动物模型中的治疗作用。结果显示:(1)腹腔注射(ip)CTDP32,476(10 -20 mg.kg-1)可缓慢但长时间增高伏隔核内细胞外多巴胺浓度;(2)无药物史的老鼠不能自身给药CTDP32,476,但能自身给药可卡因;(3)将可卡因自身给药的老鼠转换为CTDP32,476自身给药后,自身给药行为表现为低频率、不规则、并随时间进行性降低;(4)与相同剂量的可卡因相比,CTDP32,476在累进比(progressive -ratio)的自身给药模式下,为获得药物的断点(break -point)明显较低;(5)将可卡因自身给药的老鼠给予CTDP32,476前处理后,CTDP32,476产生了剂量依赖性、长时间( -24 h)地抑制可卡因自身给药行为。研究提示,(1)慢启动长效DAT抑制剂CTDP32,476的成瘾性低于可卡因;(2) CTDP32,476对可卡因或其他精神兴奋剂的成瘾性有潜在治疗作用。

The successful use of methadone,a long-acting opiate receptor agonist,in the treatment of opiate dependence suggests a potential use of slow-onset long-acting dopamine （DA） transporter （DAT） inhibitors in the treatment of psychostimulant addiction. To test this hypothesis,we have successfully developed a slow-onset long-acting DAT inhibitor called CTDP32,467 （named by a NIDA Cocaine Treatment Development Program） and investigated its pharmacological action in animal models of addiction. We found that： （1） systemic administration of CTDP32,476 （ 10 - 20 mg · kg^-1,ip） produced a slow - onset long - lasting increase in extracellular DA in the nucleus accumbens （NAc） ; （ 2 ） drug naive rats did not self - administer CTDP32,476, but reliably self - administered cocaine ; （ 3 ） in cocaine self- administration rats, CTDP32,476 maintained a low rate and irregular self- administra- tion and displayed a distinction pattern of drug taking over time; （4） cocaine self - administration rats displayed lower break -point levels for CTDP32,476 than for cocaine under a progressive -ratio rein-forcement schedule; and finally; （5） pretreatment with the same doses of CTDP32,476 produced a long- time （ -24 h） reduction in cocaine self- administration in a dose- dependent manner. These findings suggest that： （1） CTDP32,476 has lower addictive properties than cocaine; and （2） this compound or other slow - onset long - acting DAT inhibitors may have potential use for the treatment of addiction to cocaine or other psychostimulants.