BEHAVIORAL MECHANISMS OF DRUG EFFECTS

药物作用的行为机制

• 批准号: 6431937
• 负责人: Stephen J. Heishman
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6431937
• 关键词: Cannabis; alprazolam; amphetamines; attention; blood chemistry; clinical research; cocaine; codeine; cognition; dosage; drug abuse; drug administration routes; ethanol; human subject; memory; motivation; neuropsychological tests; performance; psychological reinforcement; psychopharmacology

The mechanisms by which drugs affect human behavior are complex, involving the interaction between the direct actions of the drug (e.g., impaired coordination) and the functional behavioral effects such as altered motivation. Specific determinants of drug response include the drug dose, the route of administration, the persons physiological and psychological state, the particular environmental conditions, and the nature of the behavior or test being measured. One approach that we are pursuing is to vary the environmental conditions by manipulating the reinforcement (monetary) contingencies under which subjects perform various tasks. This can be thought of as manipulating a subjects motivation to perform. By also varying drug dose and using tests that measure different aspects of performance (e.g., psychomotor vs. cognitive), we can begin to explore the complex interactions underlying the effects of drugs on behavior. In one such study, the experimental design was a factorial crossing of three marijuana doses with two reinforcement contingency conditions. In one condition, subjects earned $.01 for every three correct responses on the performance tests, and in the other, they earned $.15 per three correct responses. Testing occurred at predrug baseline and 5 min and 2 hr postdrug (word recall) and 5, 45 min, 2, 4, 10 hr postdrug (psychomotor tests). High dose marijuana decreased the number of correctly recalled words in the delayed free recall test. There was a significant dose X reinforcement contingency interaction with respect to intrusion errors on the memory test. Under the low contingency condition, intrusion errors increased in a dose-dependent manner. However, under the high contingency condition, intrusion errors showed an inverted-U dose function, such that errors were reduced to placebo levels after high dose marijuana. These data indicate that marijuana-induced impairment in reflective cognition can be influenced by reinforcement contingency. Another approach to investigating the mechanisms by which drugs influence behavior is to focus on performance impairment produced by psychoactive drugs. The performance-impairing effects of drugs of abuse produce a large toll on the nation each year in terms of traffic injuries and fatalities and lost productivity in the workplace. However, for most drugs, we lack basic knowledge about the behavioral mechanisms underlying their impairment of human performance. A series of studies is being conducted that will address such questions. A battery of physiological, behavioral, and performance measures designed to determine whether an individual is behaviorally impaired as the result of taking a drug has been tested with ethanol, marijuana, and cocaine. A second study investigated the effects of marijuana, amphetamine, codeine, and alprazolam on this same test battery as well as a cognitive test of attention and memory. By also collecting blood samples during these studies, we are able to gain valuable information concerning the relationship between plasma concentrations of drugs and degree of performance impairment. In two studies, we investigated the effect of smoked marijuana on four standardized field sobriety tests (FST) that are used to determine whether a person can safely operate a motor vehicle. Subjective effects and delta-9-tetrahydrocannabinol (THC) plasma concentrations were also measured to correlate with behavioral impairment. In a residential study, 12 volunteers participated in six experimental sessions. At each session, subjects smoked ad lib two half- cigarettes containing 0 or 3.58% THC. Placebo, low, and high doses consisted of two placebo half-cigarettes, one placebo and one active half-cigarette, and two active half-cigarettes, respectively. Subjects received each marijuana dose twice in random order. Marijuana impaired performance on only one FST, the One Leg Stand, by increasing number of hops and times the elevated foot touched the floor to maintain balance. In a nonresidential study, 20 subjects participated in three experimental sessions. At each session, subjects smoked two cigarettes (16 paced puffs) containing 0, 1.75, or 3.55% THC. Marijuana impaired performance on two FST, One Leg Stand and Finger to Nose. The number of times subjects put their foot down and raised their arms to maintain balance and amount of body sway were increased by marijuana in the One Leg Stand test. A dose-dependent increase in number of misses was observed in the Finger to Nose test. In both studies, marijuana produced orderly dose-related increases in subjective ratings of intoxication. THC plasma concentrations peaked immediately after smoking and had declined to 15-28 ng/ml at time of FST testing (15 min postsmoking). These data suggest a threshold plasma THC level in the 20-25 ng/ml range for marijuana to impair behaviors critical for safe driving.

药物影响人类行为的机制是复杂的， 涉及药物的直接作用之间的相互作用 （例如，协调受损）和功能行为效应 例如改变动力。药物反应的特定决定因素 包括毒品剂量，行政途径，人 生理和心理状态，特定的环境 条件，行为或测试的性质。 我们追求的一种方法是改变环境 通过操纵加固的条件（货币） 受试者执行各种任务的意外事件。这可以 被认为是操纵主题的动机。经过 还改变了药物剂量和使用测量不同的测试 表现的各个方面（例如，精神运动与认知），我们可以 开始探索效果的基础的复杂互动 关于行为的毒品。在一项研究中，实验设计是 三种大麻剂量的阶乘穿越两种加固 应急条件。在一个条件下，受试者为0.01 $ 01 每三个正确的绩效测试中的正确响应 其他，他们每三个正确的答复赚了$ .15。测试 发生在Predrug基线和5分钟和2小时的Postdrug（单词） 召回）和5、45分钟，2、4、10小时后药物（心理运动测试）。 高剂量大麻减少了正确召回单词的数量 在延迟的免费召回测试中。有明显的剂量x 相对于入侵 内存测试中的错误。在低应变条件下， 侵入误差以剂量依赖性方式增加。然而， 在高应变条件下，入侵错误显示 倒立剂量功能，使错误减少到安慰剂 高剂量大麻后的水平。这些数据表明 大麻引起的反射认知损害可能是 受强化应急的影响。另一种方法 研究药物影响行为的机制是 专注于精神药物产生的性能障碍。这 滥用药物的性能障碍影响会造成巨大的损失 每年在交通伤害和死亡方面 并失去了工作场所的生产力。但是，对于大多数药物，我们 缺乏有关行为机制的基本知识 他们对人类绩效的损害。一系列研究正在 进行了这些问题。电池 旨在的生理，行为和绩效指标 确定一个人是否在行为上受到行为障碍 服用药物的结果已通过乙醇，大麻和 可卡因。第二项研究调查了大麻的影响， 苯丙胺，可待因和阿普唑仑在同一测试电池上 以及对注意力和记忆的认知测试。通过也收集 在这些研究期间，我们能够获得宝贵的血液样本 有关等离子体之间关系的信息 药物的浓度和性能障碍程度。一两个 研究，我们研究了烟熏大麻对四种的影响 用于确定的标准化现场清醒测试（FST） 一个人是否可以安全操作机动车。主观 效应和Delta-9-四氢大麻醇（THC）血浆浓度 还测量了与行为障碍相关的。在 住宅研究，12名志愿者参加了六个实验 会议。在每个会议上，受试者吸烟ad lib两个半 - 含有0或3.58％THC的香烟。安慰剂，低剂量 由两个安慰剂半烟，一个安慰剂和一个活跃 半烟和两个活跃的半烟。 受试者以随机顺序两次接受每种大麻剂量。 大麻仅在一个FST上的一条腿摊位上的性能受损， 通过增加啤酒花数量和时代，高高的脚触摸了 地板以保持平衡。在一项非住宅研究中，有20位受试者 参加了三个实验会议。在每个会话中， 受试者抽两支香烟（16个节奏的泡芙），其中包含0、1.75， 或3.55％THC。大麻在两个FST，一条腿上的性能受损 站在鼻子上。受试者的次数 脚下并举起手臂以保持平衡和数量 大麻在一个腿架测试中增加了身体摇摆。一个 在剂量依赖性误差数量的增加中被观察到 手指进行鼻子测试。在这两项研究中，大麻都有序 剂量相关的中毒主观评级增加。 THC 吸烟后立即达到血浆浓度，并有 在FST测试时（15分钟后发掘），拒绝降至15-28 ng/ml。 这些数据表明在20-25 ng/ml中的阈值等离子体THC水平 大麻损害对安全驾驶至关重要的行为的范围。