NEUROCHEMISTRY OF COCAINE DEPENDENCEE

可卡因依赖的神经化学

• 批准号: 6433729
• 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: 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/6433729
• 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.

越来越多的人需要治疗非法吸食可卡因的人和其他精神病人 兴奋剂，需要了解其影响的神经基础 与戒毒和残留的渴望有关，这可能 导致故态复萌。动物条件反射实验结果 模型和人类吸毒者认为环境刺激 与注射兴奋剂相关的可能会引起类似的 作为药物本身的反应。这些有条件的环境刺激 与吸毒有关的人可能会导致对毒品的渴望和 通过产生生理和神经化学变化而最终复发 在戒毒后的关键时期。这样的例子 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。活体技术 微透析，允许直接测量神经递质 Release，提供了一种检查底层神经基质的方法 条件性药物效应。当这些实验在清醒状态下进行时 自由活动的动物，条件药物效应的行为证据可以 与相关的神经化学变化同时进行检查。虽然 可卡因的药理作用已被广泛研究，但知之甚少 关于可卡因条件性作用的神经底物， 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。这个 体内微渗析技术将被用于检测药物的释放 伏隔核脑中的多巴胺、去甲肾上腺素和5-羟色胺 与可卡因和可卡因的增强作用最相关的区域 安非他明，在三个不同的行为条件研究系列中 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随后的 注射提供了与药物有关的环境线索 行政管理保持不变。第一系列研究将检查 测试环境对敏感度发展的影响 可卡因和苯丙胺对神经化学和行为的影响 在他们反复管理之后。第二系列研究将 在训练后和训练期间检查神经递质的释放 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 老鼠选择留在以前的环境中的药物 与注射可卡因或安非他明有关。第三个系列 研究将检查在反应过程中神经递质的释放 介绍了与该病毒相关的次级增强剂 自行注射可卡因或安非他明。介绍了 辅助增强剂，如短暂的视觉刺激，与 注射可卡因或安非他明可以保持杠杆按压行为 即使在注射毒品的主要强化作用已经 熄灭了。这些研究加在一起将提供重要的新的 关于条件性药物对大鼠是否有作用及其影响的信息 伏隔核中的神经基质足够健壮， 坚持不懈地为吸毒者的残留药物渴求提供一个模式。 条件性药物效应及其神经化学底物可能 被认为是药物干预的目标，作为药物残留效应 在治疗过程中导致复发的毒瘾。