Witkin J M, Goldberg S R, Katz J L, Kuhar M J
Addiction Research Center, National Institute on Drug Abuse, Baltimore, MD 21224.
Life Sci. 1989;45(24):2295-301. doi: 10.1016/0024-3205(89)90111-2.
In view of the toxicity of cocaine and recent reports on the antimuscarinic properties of cocaine, the present study evaluated the effects of manipulations in cholinergic neurotransmission on the lethal effects of cocaine. Physostigmine pretreatment significantly altered the lethality of cocaine, increasing the LD 50 from 82.5 mg/kg to 96.9 mg/kg in male F344 rats. Atropine alone did not alter the lethal effects of cocaine at doses that are effective in preventing parasympathetic effects and lethality of oxotremorine. The prophylactic effect of physostigmine was not prevented by atropine. Neostigmine did not significantly affect the cocaine lethality dose-effect function. Both oxotremorine and (-)-nicotine were also devoid of protective actions. At higher doses, all of the cholinomimetics potentiated the lethal effects of cocaine. These results suggest that whereas cocaine lethality may be enhanced by stimulation of muscarinic receptors, low doses of physostigmine protect against lethality through actions at noncholinergic sites.
鉴于可卡因的毒性以及近期有关可卡因抗毒蕈碱特性的报道，本研究评估了胆碱能神经传递的调控对可卡因致死效应的影响。毒扁豆碱预处理显著改变了可卡因的致死性，使雄性F344大鼠的半数致死量（LD50）从82.5毫克/千克提高到96.9毫克/千克。单独使用阿托品在有效预防毒蕈震颤素的副交感效应和致死性的剂量下，并未改变可卡因的致死效应。毒扁豆碱的预防作用未被阿托品阻断。新斯的明对可卡因致死剂量效应函数无显著影响。毒蕈震颤素和（-）-尼古丁也均无保护作用。在较高剂量下，所有拟胆碱药均增强了可卡因的致死效应。这些结果表明，虽然刺激毒蕈碱受体会增强可卡因的致死性，但低剂量的毒扁豆碱通过作用于非胆碱能位点来预防致死性。
