CHARACTERISTICS OF TETRAHYDROCANNABINOL TOLERANCE *
CHARACTERISTICS OF TETRAHYDROCANNABINOL TOLERANCE *
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四氢大麻酚耐受性的特征 *
DOI：
10.1111/j.1749-6632.1971.tb13990.x
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发表时间：
1971
影响因子：
5.2
通讯作者：
L. Harris
中科院分区：
文献类型：
--
作者：
D. McMillan;W. Dewey;L. Harris
据说，“当重复给药后，给定剂量的药物产生的效果逐渐减弱，或者相反，必须服用越来越大的剂量才能获得原始剂量所观察到的效果时”，就会产生对药物的耐受性。有证据表明，在动物和人类中，大麻及其活性成分的作用产生了耐受性。 7 然而，许多研究人员尚未观察到动物和人类对大麻或其活性成分的耐受性，也没有提出建议。重复吸食大麻可能会导致人类对大麻主观影响的敏感性增加。12 有许多因素可能导致关于大麻耐受性发展的相互矛盾的发现。其中最严重的因素是难以控制大麻中活性成分的剂量水平，因为植物材料制剂的纯度各不相同。I3由于对药物的耐受性是根据对恒定剂量的递减反应或对剂量分级增加的恒定反应来定义的，因此未能充分控制剂量会使耐受性的证明变得困难。证明对大麻及其活性成分的耐受性的其他问题可能源于评估耐受性的方法的差异和物种差异。我们试图通过仅使用那些已被证明在 man14-17 中具有活性并且以相对纯净的形式提供的大麻成分，并通过使用标准化程序来测量几个物种的耐受性发展来尽量减少这些问题。最近，日程控制行为已被用作敏感且稳定的基线，用于评估几个物种对多种 d r ~ g s ~ * ~ J ~ ~ ~ 的耐受性的发展。研究日程控制行为的基本技术是众所周知的。22 在我们的实验中，鸽子被训练啄食半透明的塑料响应键，以便在四秒钟内获得混合谷物。每次啄击都会破坏电路，从而可以对啄击进行计数和记录。有时，根据食物奖励的时间表，啄食会产生获得谷物的机会。在宽容标准中最常使用的鸽子奖励计划是多重固定比例 30 响应、固定间隔五分钟（multi FR 30 FI 5）食物呈现计划。在此时间表下，当半透明按键后面的蓝灯亮起时，需要 30 次按键才能产生食物（FR 30 组件），而当按键后面的红灯亮起时，五分钟后第一次按键就会产生食物（FI 5 组件）。两个时间表组成部分在整个训练过程中交替进行，时间表的两个组成部分都有 40 秒的时间限制，这样，如果鸽子在食物可用时没有做出反应，时间表可以自动从一个组成部分更改为另一个组成部分。在这些时间表参数下，鸽子通常在 FR 成分下以高稳定速率做出反应，而在 FI 5 成分下的反应特点是在间隔早期暂停，然后随着食物的可用性增加反应率。2~
Tolerance to a drug is said to have developed “when, after repeated administration, a given dose of a drug produces a decreasing effect, or conversely when increasingly larger doses must be administered to obtain the effects observed with the original dose.”’ There is evidenv that tolerance develops to the effects of marijuana and its active constituents in animaW6 and in man.7 However, many investigators have not observed tolerance to marijuana or its active constituents in animalss and in mang-lls or have suggested that the repeated administration of marijuana may result in an increased sensitivity to the subjective effects of marijuana in man.12 There are many factors that might have contributed to the conflicting findings concerning the development of tolerance to marijuana. Among the most serious of these factors has been the difficulty in controlling the dose level of the active constituents in marijuana, due to the varying purity of the preparations from the plant material.I3 Since tolerance to a drug is defined either in terms of a diminishing response to a constant dose or in terms of a constant response to graded increases in the dose, failure to control the dose adequately makes the demonstration of tolerance difficult. Other problems in demonstrating tolerance to marijuana and its active constituents may arise from differences in the methods used to assess tolerance and from species differences. We have attempted to minimize these problems by using only those constituents of marijuana that have been shown to have activity in man14-17 and are available in relatively pure form,ls and by using standardized procedures for measuring the development of tolerance in several species. Recently, schedule-controlled behavior has been used as a sensitive and stable baseline for assessing the development of tolerance to a number of d r ~ g s ~ * ~ J ~ ~ ~ in several species. The basic techniques for studying schedule-controlled behavior are well known.22 In our experiments, pigeons are trained to peck a translucent plastic response key in order to obtain a four-second access to mixed grain. Each peck breaks an electrical circuit, which permits the peck to be counted and recorded. Occasionally, depending on the schedule of food reward, pecks produce access to grain. The reward schedule for pigeons that has been used most often in tolerance s t ~ d i e s ~ ~ J ~ is the multiple fixed-ratio 30-response, fixed-interval fiveminute (mult FR 30 FI 5) schedule of food presentation. Under this schedule, when a blue light behind the translucent key is on, 30 key pecks are required to produce food (FR 30 component), and when a red light behind the key is on, the first key peck after five minutes produces food (FI 5 component). The two schedule components alternate throughout a session, with a 40-second time limit applying to both components of the schedule, so that the schedule can change automatically from one component to the other component if the pigeon is not responding at the time food is available. At these schedule parameters, pigeons usually respond at a high steady rate under the FR component, while responding under the FI 5 component is characterized by a pause early in the interval, followed by an increasing rate of responding as the availability of food appr0aches.2~