DOPAMINE MODULATION OF LIMBIC CORTICOACCUMBENS SYSTEM

边缘皮质伏隔系统的多巴胺调节

• 批准号: 6392956
• 负责人: Shao-Pii Onn
• 金额: $ 22.8万
• 依托单位: MCP HAHNEMANN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-09 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6392956
• 关键词: amphetamines; chemical stimulation; dopamine; dopamine receptor; drug addiction; electrophysiology; evoked potentials; immunocytochemistry; immunofluorescence technique; laboratory rat; limbic system; microelectrodes; neural transmission; neurons; neurophysiology; neuroregulation; nucleus accumbens; organ culture; prefrontal lobe /cortex; synapses

DESCRIPTION: (Adapted from the Investigator's Abstract) Psychostimulant abuse in humans is known to produce states similar to both positive and negative symptoms of schizophrenia. Studies in rats have suggested that hyper-dopaminergic activity in subcortical structures such as nucleus accumbens leads to behavioral abnormality that may have relevance to positive symptoms. Emotional and cognitive deficits that characterize negative symptoms have been recently demonstrated in monkeys similarly treated with low doses of amphetamine and that in many ways resemble those identified in human amphetamine abusers. These cognitive deficits are believed to result from a dysfunction in the prefrontal cortex, thus linking to a clinical state of hypofrontality. A basic dysfunction of prefrontal-accumbens circuits is thought to be critical to the cognitive dysfunction, negative affect and abnormal reward-related behavior that is characteristic of schizophrenia and drug abuse. My working hypotheses is that in amphetamine treated rats there exists deficits in the excitatory drive from the limbic afferents from the entorhinal cortex and the mediodorsal thalamus to the prefrontal cortex and/or deficits in the dopamine modulation of these excitatory afferents. Thus the proposed experiments using in vivo intracellular recording and labeling techniques will compare and contrast information arising intracortically (eg entorhinal cortex; aim 1) and subcortically (eg mediodorsal thalamus; aim 2), the latter of which transmits basal ganglia outflow back to the prefrontal cortex. Lastly cortical processing in influencing basal ganglia outflow from the nucleus accumbens. I predict attenuated intracortical processing (aim 1) to occur in conjunction with an augmented basal ganglia feedback circuit, as marked by increases in both mediodorsal thalamus-evoked activity in prefrontal cortex neurons (aim 2) and prefrontal cortex-evoked activity in nucleus accumbens neurons (aim 3), in amphetamine treated rats. The proposed study is of particular interest with respect to the deficit syndrome in schizophrenia and possibly other mental disorders such as drug addiction associated with negative affect and depression.

描述：（改编自研究者摘要）精神兴奋剂滥用 已知人类会产生类似于积极和消极的状态 精神分裂症的症状。对大鼠的研究表明 皮质下结构（如伏隔核）的多巴胺能亢进活动 导致可能与阳性症状相关的行为异常。 以阴性症状为特征的情绪和认知缺陷已被 最近在用低剂量的类似方法治疗的猴子中得到了证实 安非他明和在许多方面类似于人类中发现的安非他明 安非他明滥用者。这些认知缺陷被认为是由 前额皮质功能障碍，从而与临床状态相关 额叶不足。人们认为前额叶伏隔环路的基本功能障碍 对认知功能障碍、负面情绪和异常至关重要 奖励相关行为是精神分裂症和药物滥用的特征。 我的工作假设是，在安非他明治疗的大鼠中存在缺陷 来自内嗅皮层边缘传入神经的兴奋性驱动 和内侧丘脑到前额皮质和/或缺陷 多巴胺对这些兴奋性传入的调节。因此提出的 使用体内细胞内记录和标记技术的实验将 比较和对比皮质内产生的信息（例如内嗅皮质； 目标 1）和皮质下（例如内侧丘脑；目标 2），后者 将基底神经节的流出传输回前额皮质。最后是皮质 影响基底神经节从伏隔核流出的处理。我 预测减弱的皮质内处理（目标 1）同时发生 具有增强的基底神经节反馈电路，其特征是 前额皮质神经元中背侧丘脑诱发的活动（目标 2） 以及伏隔核神经元前额皮质诱发的活动（目标 3）， 安非他明治疗大鼠。拟议的研究特别令人感兴趣 关于精神分裂症和其他可能的精神缺陷综合症 与负面情绪相关的疾病，例如毒瘾和 沮丧。