Woodward J J, Compton D M, Balster R L, Martin B R
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond 23298, USA.
Eur J Pharmacol. 1995 Apr 13;277(1):7-13. doi: 10.1016/0014-2999(95)00042-j.
The effects of selected local anesthetics on in vitro and in vivo measurements of dopamine transporter activity were determined to investigate the role of local anesthetic activity in the neuronal actions of cocaine. Cocaine inhibited [3H]2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1.5-naphthalenedisulfonate (CFT) binding and [3H]dopamine uptake with estimated Ki and IC50 values of 0.6 microM and 0.7 micorM, respectively. Of the local anesthetics tested, only dimethocaine showed full displacement of CFT binding (0-30 microM tested) and full inhibition of dopamine uptake (0-100 microM tested). Dimethocaine was only slightly less potent than cocaine with an estimated Ki of 1.4 micorM and an IC50 value of 1.2 microM for [3H]CFT binding and dopamine uptake. At a maximum concentration of 100 microM, the ester containing local anesthetics procaine, tetracaine, piperocaine and the amide containing local anesthetic dibucaine and bupivacaine partially inhibited dopamine uptake by 47-70%. The ester containing local anesthetic propoxycaine and the amide containing local anesthetics prilocaine, etidocaine, procainamide, and lidocaine inhibited dopamine uptake by 8-30% at 100 microM. A 10 min administration of cocaine, dimethocaine, or procaine in the dialysis solution produced dose-dependent, reversible increases in endogenous dopamine efflux from the striata of awake rats. Cocaine and dimethocaine produced similar 12-fold increases in dialysate dopamine at concentrations of 0.1 mM and 1 mM respectively. Procaine (10 mM) produced a 6-fold increase in dialysate dopamine while lidocaine (1 mM) produced a reproducible and reversible decrease (30%). These results show that the cocaine-like actions of certain local anesthetics such as dimethocaine and procaine result from their direct actions of dopamine uptake inhibitors.
为了研究局部麻醉药活性在可卡因神经元作用中的角色，测定了所选局部麻醉药对多巴胺转运体活性的体外和体内测量的影响。可卡因抑制[3H]2-β-甲氧羰基-3-β-(4-氟苯基)托烷1,5-萘二磺酸盐（CFT）结合以及[3H]多巴胺摄取，其估计的Ki和IC50值分别为0.6微摩尔和0.7微摩尔。在所测试的局部麻醉药中，只有地美卡因能完全取代CFT结合（测试浓度为0 - 30微摩尔）并完全抑制多巴胺摄取（测试浓度为0 - 100微摩尔）。地美卡因的效力仅略低于可卡因，其对[3H]CFT结合和多巴胺摄取的估计Ki为1.4微摩尔，IC50值为1.2微摩尔。在最大浓度100微摩尔时，含酯类局部麻醉药普鲁卡因、丁卡因、哌罗卡因以及含酰胺类局部麻醉药丁哌卡因和布比卡因可部分抑制多巴胺摄取，抑制率为47% - 70%。含酯类局部麻醉药丙氧卡因以及含酰胺类局部麻醉药丙胺卡因、依替卡因、普鲁卡因胺和利多卡因在100微摩尔时可抑制多巴胺摄取8% - 30%。在透析液中给予可卡因、地美卡因或普鲁卡因10分钟，可使清醒大鼠纹状体中内源性多巴胺外流产生剂量依赖性、可逆性增加。可卡因和地美卡因分别在浓度为0.1毫摩尔和1毫摩尔时使透析液多巴胺增加了相似的12倍。普鲁卡因（10毫摩尔）使透析液多巴胺增加了6倍，而利多卡因（1毫摩尔）则产生了可重复且可逆的减少（30%）。这些结果表明，某些局部麻醉药如地美卡因和普鲁卡因的可卡因样作用是其作为多巴胺摄取抑制剂的直接作用所致。
