Locke K W, Gorney B, Cornfeldt M, Fielding S
Department of Biological Research, Hoechst-Roussel Pharmaceuticals, Inc., Somerville, New Jersey.
J Pharmacol Exp Ther. 1989 Jul;250(1):241-6.
Rats were trained to discriminate physostigmine (0.1 mg/kg s.c.) from saline in a two-choice, discrete-trial avoidance paradigm. Stimulus generalization curves for physostigmine were steep; complete generalization with physostigmine occurred only at the 0.1 mg/kg training dose. The muscarinic cholinergic agonists oxotremorine, pilocarpine and arecoline were evaluated for physostigmine-like discriminative effects. Oxotremorine generalized with physostigmine at a dose of 0.1 mg/kg in four of six rats tested; partial generalization was engendered by this dose in the remaining two animals. Complete generalization with physostigmine was produced in only one of six rats treated with pilocarpine. However, pilocarpine (3.0-10 mg/kg) did engender some physostigmine-appropriate responding in all rats tested. Arecoline (1.0 mg/kg) produced primarily saline-appropriate responding in all animals tested. Neostigmine, eseroline and nicotine were tested for physostigmine-like discriminative effects in order to assess the specificity of the physostigmine cue. Eseroline (1.0 mg/kg), an opioid-like derivative of physostigmine, and neostigmine (0.1 mg/kg) engendered saline-appropriate responding. Similarly, nicotine failed to generalize with physostigmine at doses up to 1.0 mg/kg. The discriminative stimulus effects of physostigmine were sensitive to antagonism by atropine. Complete blockade of the stimulus effects of the training dose of physostigmine was produced by 1.0 to 3.0 mg/kg of atropine. In contrast, a 10-fold higher dose of the quaternary antagonist homatropine methylbromide was necessary to block the discriminative effects of physostigmine. The discriminative effects of physostigmine were not blocked or were only partially blocked by mecamylamine at doses up to 10 mg/kg. The results of these experiments suggest that the discriminative stimulus effects of physostigmine are selective and probably centrally mediated.(ABSTRACT TRUNCATED AT 250 WORDS)
在两选择、离散试验回避范式中，训练大鼠区分毒扁豆碱（0.1毫克/千克，皮下注射）和生理盐水。毒扁豆碱的刺激泛化曲线很陡；只有在0.1毫克/千克的训练剂量下才会出现与毒扁豆碱的完全泛化。对毒蕈碱胆碱能激动剂氧化震颤素、毛果芸香碱和槟榔碱进行了类似毒扁豆碱的辨别效应评估。在测试的6只大鼠中，有4只在剂量为0.1毫克/千克时氧化震颤素与毒扁豆碱产生泛化；该剂量在其余2只动物中产生部分泛化。用毛果芸香碱处理的6只大鼠中只有1只产生了与毒扁豆碱的完全泛化。然而，毛果芸香碱（3.0 - 10毫克/千克）在所有测试大鼠中确实产生了一些与毒扁豆碱相符的反应。槟榔碱（1.0毫克/千克）在所有测试动物中主要产生与生理盐水相符的反应。测试了新斯的明、依色林和尼古丁的类似毒扁豆碱的辨别效应，以评估毒扁豆碱线索的特异性。依色林（1.0毫克/千克）是毒扁豆碱的一种阿片样衍生物，新斯的明（0.1毫克/千克）产生与生理盐水相符的反应。同样，尼古丁在剂量高达1.0毫克/千克时未能与毒扁豆碱产生泛化。毒扁豆碱的辨别刺激效应易受阿托品拮抗作用的影响。1.0至3.0毫克/千克的阿托品可完全阻断训练剂量毒扁豆碱的刺激效应。相比之下，需要高10倍剂量的季铵拮抗剂甲基溴东莨菪碱才能阻断毒扁豆碱的辨别效应。在剂量高达10毫克/千克时，美加明对毒扁豆碱的辨别效应没有阻断或只是部分阻断。这些实验结果表明，毒扁豆碱的辨别刺激效应具有选择性，可能是由中枢介导的。（摘要截断于250字）
