COGNITIVE DYSFUNCTION AFTER CHRONIC PCP, THC AND COCAINE

慢性五氯苯酚、四氢大麻酚和可卡因后的认知功能障碍

• 批准号: 6164477
• 负责人: Jane R Taylor
• 金额: $ 25.36万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164477
• 关键词: Cercopithecidae; behavior; behavior test; cannabinoids; cocaine; cognition; conditioning; dopamine; dopamine receptor; drug abuse; drug administration rate /duration; high performance liquid chromatography; impulsive behavior; innervation; laboratory rat; limbic system; microdialysis; neuroanatomy; nucleus accumbens; phencyclidine; reinforcer

DESCRIPTION: (Applicant's Abstract) The proposed research will provide the first intensive examination of the effects of repeated exposure to drugs abuse on the cognitive function and neurochemistry of the ventromedial frontal, i.e. prelimbic cortex, in the non-human primate. We have exciting new data in monkeys which suggests that repeated administration of phencyclidine (PCP) induces a long-term dopamine (DA) deficiency in the prelimbic cortex. This DA deficiency is manifest as, and correlated with, behavioral disinhibition and increased impulsivity, functions known to be dependent on this cortical region. We observed deficits after cessation of chronic exposure so changes in the neural circuitry associated with impulsivity appear to be long-lasting. In addition, we have behavioral and biochemical data in the rodent that suggest parallel functional changes in the cortex after chronic PCP or cannabinoid (THC) administration. Impulsivity following DA dysfunction in the prelimbic cortex may be concomitant with, and indeed enhance, the progressive augmentation of mesolimbic DA transmission induced by chronic drug exposure, effects postulated to subserve the sensitization of the rewarding effects of drugs of abuse. The prelimbic cortex densely innervates the nucleus accumbens (NAc) and therefore dysfunction of this corticolimbic circuit may subserve increased impulsivity and drug-mediated reinforcement. Using in vivo and ex vivo techniques in rats and monkeys, this project will examine the hypothesis that neurobiological changes induced by repeated administration of such drugs of abuse as cocaine, THC and PCP will result in common adaptations and cognitive dysfunctions associated with the prelimbic cortex. The research plan will investigate the following hypotheses: (1) Repeated exposure to drugs of abuse induces analogous changes in prelimbic cortical DA and cognitive function that are long-term and can be characterized by increases in impulsivity. (2) Dysfunction of the prelimbic DA innervation results in an inability to gate or modulate changes in reward motivated behaviors that are dependent on NAc. Thus, repeated drug exposures result in changes in the neural circuitry associated with cognition and reward, both of which are known to be critically dependent on DA innervation of the prelimbic cortex and NAc. The overall goal of these studies is to elucidate neurobiological alterations in the neural substrates associated with impulsivity and reward. Novel therapeutic agents that target DA dysfunction in the prelimbic cortex may provide new avenues for the development of therapies to ameliorate impulsivity associated with drug craving.

描述：（申请人摘要） 拟议的研究将提供第一次深入检查 重复暴露于药物滥用对认知功能的影响， 神经化学的腹内侧额叶，即前边缘皮层，在 非人类灵长类动物 我们在猴子身上得到了令人兴奋的新数据， 苯环利定（PCP）的重复给药诱导长期多巴胺 (DA)前边缘皮层的缺陷 这种多巴胺缺乏症表现为， 与行为抑制解除和冲动性增加相关， 这些功能都依赖于这个皮层区域。 我们观察到 停止慢性暴露后的缺陷， 与冲动有关的回路似乎是持久的。 在 此外，我们在啮齿动物中的行为和生化数据表明， 慢性PCP或大麻素后皮质的平行功能变化 (THC)局 前边缘系统DA功能障碍后的冲动性 皮质可能伴随着，并且确实增强， 慢性药物暴露诱导的中脑边缘DA传递增强， 假设有助于提高奖励效应的敏感性的效应 滥用药物。 前边缘皮质密集地支配着核 因此，这种皮质边缘回路的功能障碍可能 有助于增加冲动和药物介导的强化。 使用in 在大鼠和猴子的体内和体外技术，该项目将研究 这一假说认为，反复的 服用可卡因、四氢大麻酚和五氯苯酚等滥用药物会导致 与前边缘系统相关的常见适应和认知功能障碍 皮层 研究计划将探讨以下假设：（1）重复 暴露于滥用药物诱导类似的变化， DA和认知功能是长期的，其特征可以是 冲动的增加。 (2)边缘前DA神经支配功能障碍 导致无法门控或调节奖励激励的变化 依赖于NAC的行为。 因此，重复的药物暴露导致 与认知和奖励相关的神经回路的变化， 这两种都是已知的严重依赖于DA神经支配的， 前边缘皮层和NAc。 这些研究的总体目标是阐明 神经基质的神经生物学改变与 冲动和奖励 靶向DA功能障碍的新型治疗剂 在前边缘皮层可能提供新的途径， 改善与药物渴望相关的冲动性的疗法。