CAJ | 학술논문

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.
장효아편수체격동제미사동대아편의뢰적유효치료제시,만계동장효다파알수체(DAT)억제제흔가능대정신흥강제성은구유잠재치료작용.위험증차가설,아문성공지연제출만계동장효DAT억제제CTDP32,476, 병진일보연구기재성은성동물모형중적치료작용.결과현시:(1)복강주사(ip)CTDP32,476(10-20 mg·kg-1)가완만단장시간증고복격핵내세포외다파알농도;(2)무약물사적로서불능자신급약CTDP32,476,단능자신급약가잡인;(3)장가잡인자신급약적로서전환위CTDP32,476자신급약후,자신급약행위표현위저빈솔、불규칙、병수시간진행성강저;(4) 여상동제량적가잡인상비,CTDP32,476재루진비(progressive-ratio) 적자신급약모식하,위획득약물적단점(break-point) 명현교저;(5)장가잡인자신급약적로서급여CTDP32,476전처리후,CTDP32,476산생료제량의뢰성、장시간(-24 h)지억제가잡인자신급약행위.연구제시,(1)만계동장효DAT억제제CTDP32,476적성은성저우가잡인;(2) CTDP32,476대가잡인혹기타정신흥강제적성은성유잠재치료작용.
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-administration 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 reinforcement 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.