Cepeda-Benito Antonio, Davis Kristina W, Reynoso Jose T, Harraid James H
Department of Psychology, Texas A&M University, College Station, TX 77943-4235, USA.
Psychopharmacology (Berl). 2005 Jul;180(2):224-33. doi: 10.1007/s00213-005-2151-4. Epub 2005 Feb 5.
Theories of drug tolerance differentiate between associative and behavioral (instrumental) drug tolerance. However, there is little research comparing these two forms of drug tolerance beyond alcohol and morphine.
We examined the time course development of associative and behavioral tolerance to the analgesic effects of nicotine.
Associative tolerance was investigated by giving independent groups of rats one, five, 15, ten or 20 administrations of nicotine either explicitly paired or unpaired with a distinctive context. Associative tolerance, assessed in the tail flick, developed more rapidly and reached greater magnitude when nicotine and distinctive context were explicitly paired than when they were unpaired. This effect was evidenced after the fifth conditioning session and was maintained through the tenth, 15th, and 20th sessions. Contextual tolerance, assessed in the hot plate, was first evident after ten sessions. However, this effect disappeared safter 15 and 20 sessions. A second study examined the acquisition of behavioral tolerance to the disruptive effects of nicotine on the hot-plate response. Animals that practiced the test response while drugged developed greater tolerance than animals receiving as much nicotine and hot-plate practice but with these two conditions explicitly unpaired. This effect was evident in two different environments but did not generalize to the tail-flick test.
The findings suggest that contextual tolerance to drug effects is test specific, with tail-flick responses depending on cue-associative tolerance processes and hot-plate responses requiring procedures that allow the animal to practice the test response while drugged.
药物耐受性理论区分了关联性药物耐受性和行为（工具性）药物耐受性。然而，除了酒精和吗啡之外，很少有研究比较这两种药物耐受性形式。
我们研究了对尼古丁镇痛作用的关联性和行为耐受性的时间进程发展。
通过给予独立的大鼠组1次、5次、15次、10次或20次尼古丁给药来研究关联性耐受性，给药时尼古丁要么与独特环境明确配对，要么不配对。在甩尾试验中评估，当尼古丁与独特环境明确配对时，关联性耐受性发展得更快且达到更大程度，而不配对时则不然。这种效应在第5次条件反射训练后得到证实，并在第10次、15次和20次训练中持续存在。在热板试验中评估的情境耐受性在第10次训练后首次显现。然而，这种效应在第15次和20次训练后消失。第二项研究考察了对尼古丁干扰热板反应作用的行为耐受性的习得情况。在给药时练习测试反应的动物比接受相同剂量尼古丁和热板练习但这两个条件明确不配对的动物产生了更大的耐受性。这种效应在两种不同环境中都很明显，但并未推广到甩尾试验中。
研究结果表明，对药物效应的情境耐受性具有测试特异性，甩尾反应依赖于线索关联耐受性过程，而热板反应需要让动物在给药时练习测试反应的程序。
