COGNITIVE DYSFUNCTION AFTER CHRONIC PCP, THC AND COCAINE

描述：(申请人摘要) 拟议的研究将提供对 反复吸毒对认知功能和行为的影响 大脑皮层腹内侧额叶的神经化学研究 非人灵长类动物。我们在猴子身上有了令人兴奋的新数据，这表明 重复服用苯环利定(PCP)可诱导长时间的多巴胺 (Da)大脑皮层缺乏。这种DA缺陷表现为， 并与行为去抑制和增强的冲动相关， 已知的功能依赖于这个皮质区域。我们观察到 慢性暴露停止后的缺陷，因此神经的变化 与冲动有关的回路似乎是持久的。在……里面 此外，我们有啮齿动物的行为和生化数据表明 慢性PCP或大麻素后大脑皮层功能的平行变化 (THC)管理。前庭DA功能障碍后的冲动性 皮质可能与进行性脑损伤相伴而生，甚至增强。 慢性药物暴露诱导的中脑边缘DA传递增强， 假设的影响，以削弱对奖励效应的敏感性 滥用药物。大脑皮层致密地支配着细胞核。 伏隔核(NAC)，因此这种皮质边缘回路的功能障碍可能 抑制增强的冲动和药物介导的强化。使用中 在老鼠和猴子身上的体内和体外技术，这个项目将检验 重复引起神经生物学变化的假说 对可卡因、THC和五氯苯酚等滥用药物的管理将导致 与前言相关的常见适应和认知功能障碍 大脑皮层。 研究计划将调查以下假设：(1)重复 暴露于滥用药物可导致大脑皮层类似的变化 DA和认知功能是长期的，可以由以下特征来表征 冲动的增加。(2)初级DA神经支配功能障碍 导致无法控制或调节激励奖励的变化 依赖于NAC的行为。因此，反复接触毒品会导致 在与认知和奖励相关的神经回路的变化中， 已知两者都严重依赖于多巴胺的神经支配。 大脑皮层和NAC。这些研究的总体目标是阐明 与高血压相关的神经基质的神经生物学改变 冲动和回报。针对DA功能障碍的新型治疗药物 可能为发育的新途径提供新的途径 缓解与药物渴求相关的冲动的疗法。

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.