NEUROCHEMISTRY OF COCAINE DEPENDENCEE

可卡因依赖的神经化学

• 批准号: 6481206
• 负责人: IRWIN LUCKI
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6481206
• 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病非法使用者的需求增加 兴奋剂，需要了解其影响的神经基质 与药物戒断和残余渴望有关， 导致复发。 动物条件反射实验结果 模型和人类吸毒者都认为环境刺激 与注射兴奋剂有关的可能会引起类似的 反应与药物本身一样。 这些条件化的环境刺激 与药物管理相关的可能有助于药物渴望， 通过产生生理和神经化学变化最终复发 在停药后的关键时期。 的例子 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。 活体技术 微透析，可以直接测量神经递质 释放，提供了一种方法来检查神经基板， 条件性药物效应 当这些实验在清醒的 自由移动的动物，条件性药物作用的行为证据可以 同时检查相关的神经化学变化。 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的神经基质 这可能为理解药物复发或 设计可能治疗药物复发的潜在药物疗法。 的 将使用体内微透析技术来检测 多巴胺，去甲肾上腺素和血清素在脑桥核，大脑 该区域与可卡因的强化作用关系最密切， 安非他明，在三个不同系列的行为条件反射研究中 被认为是由丘脑核介导的。 重复给药 可卡因或安非他明使大鼠对它们对随后的 如果环境提示与药物相关， 管理保持不变。 第一系列研究将检查 试验环境对致敏性发展的影响 可卡因和安非他明的神经化学和行为效应 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， 条件性位置偏好的表达。 条件性位置偏爱 提供了一种被认为与奖励效应有关的行为， 药物让老鼠选择留在一个以前 与注射可卡因或安非他明有关 第三系列 研究将检查神经递质释放过程中的反应， 介绍了与《京都议定书》有关的次级议定书， 可卡因或安非他明的自我管理。 的呈现 二次刺激，如短暂的视觉刺激，与 注射可卡因或安非他明可以维持压杆行为 即使在药物注射的主要强化作用已经被 熄灭了 这些研究将提供重要的新的 关于大鼠的条件性药物作用及其 脑桥核中的神经基质足够坚固， 持续为吸毒成瘾者的残余药物渴求提供模型。 条件性药物效应及其神经化学底物可能会 认为药物干预的靶点是 在治疗期间导致复发的药物成瘾。