NEUROCHEMISTRY OF COCAINE DEPENDENCEE

可卡因依赖的神经化学

• 批准号: 6327615
• 负责人: IRWIN LUCKI
• 金额: $ 40.27万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6327615
• 关键词: alcoholism /alcohol abuse; behavior test; brain metabolism; cocaine; craving; dopamine; drug addiction; drug interactions; drug withdrawal; heroin; laboratory rat; microdialysis; model design /development; neurochemistry; neuropharmacology; nucleus accumbens; operant conditionings; reinforcer; serotonin; stimulus /response

The increased need to treat illicit users of cocaine, and other psychomotor stimulants, requires understanding the neural substrates of its effects that are associated with drug withdrawal and residual craving that could lead to relapse. The results of conditioning experiments with animal models and human drug users have suggested that environmental stimuli associated with the injection of stimulants may come to elicit similar responses as the drug itself. these conditioned environmental stimuli associated with drug administration may contribute to drug craving and eventual relapse by producing physiological and neurochemical changes during a critical period following drug withdrawal. Examples of such stimuli in human addicts include drug-taking paraphernalia or the sight of a bar of place associated with taking drugs. The technique of in vivo microdialysis, which allows the direct measurement of neurotransmitter release, provides a method to examine the neural substrates that underlie conditioned drug effects. When these experiments are carried out in awake freely-moving animals, behavioral evidence for conditioned drug effects can be examined simultaneously with associated neurochemical changes. Although the pharmacology of cocaine has been studied extensively, little is known about the neural substrates underlying the conditioned effects of cocaine, which may provide important targets for understanding drug relapse or for designing potential pharmacotherapies that may treat drug relapse. The technique of in vivo microdialysis will be used to examine the release of dopamine, norepinephrine and serotonin in the nucleus accumbens, the brain region most implicated in the reinforcing effects of cocaine and amphetamine, in three different series of behavioral conditioning studies thought to be mediated by the nucleus accumbens. Repeated administration of cocaine or amphetamine sensitizes rats to their effects on subsequent injections provided that the environment cues associated with drug administration remain constant. The first series of studies will examine the influence of testing environment on the development of sensitization to the neurochemical and behavioral effects of cocaine and amphetamine following their repeated administration. The second series of studies will examine neurotransmitter release following the training and during the expression of conditioned place preference. Conditioned place preference provides a behavior thought to be associated with the rewarding effects of drugs where rats choose to remain n an environment that has previously been associated with injections of cocaine or amphetamine. The third series of studies will examine neurotransmitter release during responding for the presentation of secondary reinforcers that have been associated with the self-administration of cocaine or amphetamine. The presentation of secondary reinforcers, such as brief visual stimulus, associated with injections of cocaine or amphetamine can maintain lever pressing behavior even after the primary reinforcing effects of drug injections have been extinguished. These studies taken together will provide important new information concerning whether conditioned drug effects in rats and their neural substrates in the nucleus accumbens are sufficiently robust and persistent to provide a model for residual drug craving in drug addicts. Conditioned drug effects and their neurochemical substrates may then be considered targets for pharmacological intervention as residual effects of drug addiction that contribute to relapse during therapy.

治疗可卡因和其他精神运动非法使用者的需求增加 兴奋剂，需要了解其作用的神经基础 与药物戒断和残留渴望有关，可能会 导致复发。 动物调理实验结果 模型和人类吸毒者都认为环境刺激 与注射兴奋剂相关的可能会引起类似的反应 反应如药物本身。 这些条件性环境刺激 与药物管理相关的可能会导致药物渴望和 通过产生生理和神经化学变化最终复发 停药后的关键时期。 此类的例子 对人类成瘾者的刺激包括吸毒用具或看到 与吸毒有关的酒吧。 体内技术 微透析，可以直接测量神经递质 释放，提供了一种检查神经底物的方法 条件药物作用。 当这些实验在清醒的情况下进行时 自由活动的动物，条件药物作用的行为证据可以 与相关的神经化学变化同时进行检查。 虽然 可卡因的药理学已被广泛研究，但知之甚少 关于可卡因条件作用背后的神经基质， 这可能为了解药物复发或 设计可能治疗药物复发的潜在药物疗法。 这 体内微透析技术将用于检查释放 大脑伏隔核中的多巴胺、去甲肾上腺素和血清素 受可卡因强化作用影响最大的地区 安非他明，在三个不同系列的行为调节研究中 被认为是由伏隔核介导的。 重复给药 可卡因或安非他明使大鼠对其对后续的影响敏感 注射提供与药物相关的环境线索 行政管理保持不变。 第一系列研究将考察 测试环境对敏感性发展的影响 可卡因和安非他明的神经化学和行为影响 经过反复的管理。 第二系列研究将 检查训练后和训练期间神经递质的释放 条件性地点偏好的表达。 条件性地点偏好 提供了一种被认为与奖励效果相关的行为 老鼠选择留在以前已经存在的环境中的药物 与注射可卡因或安非他明有关。 第三个系列 研究将检查在响应过程中神经递质的释放 与相关的次要强化物的呈现 自行服用可卡因或安非他明。 的介绍 次要强化物，例如短暂的视觉刺激，与 注射可卡因或安非他明可以维持杠杆按压行为 即使在药物注射的主要强化作用已经消失之后 熄灭了。 这些研究结合在一起将提供重要的新 关于条件药物是否对大鼠及其动物产生影响的信息 伏隔核中的神经基质足够坚固 坚持不懈地为吸毒者残留的药物渴望提供模型。 然后，条件药物效应及其神经化学底物可能被 将药物干预的目标视为残留效应 导致治疗期间复发的药物成瘾。