A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants
A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants
复制标题
DOI：
10.1038/sj.npp.1300795
复制
发表时间：
2006-02-01
影响因子：
7.6
通讯作者：
Woolverton, WL
中科院分区：
文献类型：
--
作者：
Wee, S;Carroll, FI;Woolverton, WL
据推测，缓慢的起效会削弱药物的强化作用。本研究评估了这一假设与缓慢发作的可卡因类似物，WIN 35428，RTI 31和RTI 51。当可卡因或可卡因类似物提供给恒河猴（n = 4或5）自我管理下的渐进比（PR）的时间表与1小时的注射之间的时间，所有的药物作为阳性药物。最大注射次数的顺序为可卡因>WIN 35428 >RTI 31 >RTI 51。在大鼠纹状体中的体内结合中，在静脉注射后5.8、22.4、30.8和44.1 min，估计等效剂量的可卡因、WIN 35428、RTI 31和RTI 51分别取代多巴胺转运体（DAT）处25%的[H-3] WIN 35428结合。此外，相对增强功效与DAT结合速率相关，使得[H-3] WIN 35428的较慢置换与较弱的增强效应相关。在猴脑组织中的体外结合中，可卡因类似物与可卡因相比对单胺转运体位点具有更高的亲和力，但对5-HTT/DAT的亲和力比相似。最后，RTI 31在固定比例1方案下在未用药恒河猴中显示出作为阳性药物的功能。总的来说，这些数据支持这样的假设，即DAT的缓慢发作与DAT配体的增强功效降低有关。然而，PR和FR时间表下的数据表明，DAT的缓慢起效仅在有限程度上影响强化效果。
A slow onset of action has been hypothesized to weaken the reinforcing effects of drugs. The present study evaluated this hypothesis with slow-onset cocaine analogs, WIN 35428, RTI 31, and RTI 51. When cocaine or a cocaine analog was made available to rhesus monkeys (n = 4 or 5) for self-administration under a progressive-ratio (PR) schedule with a 1-h time-out between injections, all the drugs functioned as positive reinforcers. The maximum number of injections was in the order of cocaine >WIN 35428 >RTI 31 >RTI 51. In in vivo binding in rat striatum, equipotent doses of cocaine, WIN 35428, RTI 31, and RTI 51 were estimated to displace 25% of [H-3] WIN 35428 binding at the dopamine transporters (DAT), respectively, 5.8, 22.4, 30.8, and 44.1 min after the intravenous injection. Further, relative reinforcing efficacy was correlated with rate of DAT binding such that slower displacement of [H-3] WIN 35428 was associated with a weaker reinforcing effect. In in vitro binding in monkey brain tissue, the cocaine analogs had higher affinity for monoamine transporter sites, but similar affinity ratios of 5-HTT/DAT, compared to cocaine. Lastly, RTI 31 was shown to function as a positive reinforcer in drug-naive rhesus monkeys under a fixed-ratio 1 schedule. Collectively, the data support the hypothesis that a slow onset at the DAT is associated with reduced reinforcing efficacy of DAT ligands. The data under both the PR and FR schedules, however, suggest that a slow onset at the DAT influence reinforcing effect only to a limited extent.