MODEL OF SCHIZOPHRENIA--ROLE OF CORTICAL DOPAMINE

精神分裂症模型--皮质多巴胺的作用

基本信息

批准号：
6187011
负责人：
JANET M FINLAY
金额：
$ 13.9万
依托单位：
WESTERN WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-01 至 2003-05-31
项目状态：
已结题

项目摘要

Postmortem studies indicate that the dopamine (DA) innervation of prefrontal cortex (PFC) is diminished in schizophrenic subjects. Furthermore, neurodevelopmental disruptions involving mesoprefrontal DA neurons are thought to contribute to the pathophysiology of schizophrenia and could, in part, account for the emergence of symptoms as the individual matures. To determine the potential functional consequences of this structural abnormality, I will examine whether partial loss of DA axons in the prefrontal cortex (PFC) sustained early in development (12 days of age) differentially affect function of PFC in the prepubertal and adult rat. First, we will examine the effect of partial loss of DA axons sustained early in development on local extracellular DA in PFC of the prepubertal and adult rat (Aim 1). Our recent studies indicate that 60% loss of DA axons in PFC sustained immediately prior to puberty (40 days of age), decreased basal and stress- evoked extracellular DA in PFC of the adult rat (68 days of age). Thus, moderate loss of DA fibers as recently observed in PFC of schizophrenic subjects, may be sufficient to impair the function of PFC. I will also examine the effects of partial loss of DA axons in PFC sustained early in development on the ability of the PFC to regulate the neurochemical activity of a subcortical target area, the mesoaccumbens DA projection (Aim 2). Previously, it has been suggested that diminished activity of mesoprefrontal DA neurons augments the activity of subcortical DA neurons and that both events contribute to the pathophysiology of schizophrenia. Our own studies indicate that partial loss of DA axons in PFC sustained immediately prior to puberty, increased stress-evoked DA release in the NAS shell of adult rats. Finally, we will examine the impact of partial loss of DA axons in PFC sustained early in development on behaviors thought to be modulated by mesoprefrontal and mesoaccumbens DA neurons in the prepubertal and adult rat (Aim 3). It has been suggested that dysfunction of mesoprefrontal and mesoaccumbens DA neurons together give rise to some of the behavioral symptoms of schizophrenia. Previously, we reported that partial loss of DA axons in PFC sustained immediately prior to puberty attenuated amphetamine-evoked DA release in the NAS core and amphetamine-induced motor behavior in adult rats. Together, the latter findings suggest that neurochemical interactions between mesocortical and mesoaccumbens DA neurons ultimately play a role in the expression of behavior. The present studies will correlate changes in the activity of mesoprefrontai and mesoaccumbens DA neurons with performance on a delayed response task, motor behavior, and the behavioral response to appetitive and aversive stimuli.

尸检研究表明，精神分裂症患者前额皮质 (PFC) 的多巴胺 (DA) 神经支配减弱。此外，涉及中前额叶 DA 神经元的神经发育障碍被认为与精神分裂症的病理生理学有关，并且可以部分解释随着个体成熟而出现的症状。为了确定这种结构异常的潜在功能后果，我将检查在发育早期（12 天龄）前额皮质 (PFC) 中 DA 轴突的部分丧失是否对青春期前和成年大鼠的 PFC 功能产生不同的影响。首先，我们将检查发育早期持续的 DA 轴突部分缺失对青春期前和成年大鼠 PFC 中局部细胞外 DA 的影响（目标 1）。我们最近的研究表明，在青春期（40 天龄）之前，PFC 中 DA 轴突持续损失 60%，成年大鼠（68 天龄）PFC 中基础和应激诱发的细胞外 DA 减少。因此，最近在精神分裂症受试者的 PFC 中观察到的 DA 纤维的中度损失可能足以损害 PFC 的功能。我还将研究 PFC 发育早期持续的 DA 轴突部分缺失对 PFC 调节皮层下目标区域（中伏隔肌 DA 投射）神经化学活动的能力的影响（目标 2）。此前，有人提出，中前额叶 DA 神经元活性减弱会增强皮质下 DA 神经元的活性，并且这两种事件都有助于精神分裂症的病理生理学。我们自己的研究表明，在青春期之前，PFC 中 DA 轴突的部分丢失持续存在，成年大鼠 NAS 壳中应激诱发的 DA 释放增加。最后，我们将研究发育早期 PFC 中 DA 轴突的部分缺失对青春期前和成年大鼠中被认为是由中前额叶和中伏隔 DA 神经元调节的行为的影响（目标 3）。有人提出，中前额叶和中伏本DA神经元的功能障碍共同引起精神分裂症的一些行为症状。此前，我们报道了在青春期前，PFC 中 DA 轴突的部分缺失会减弱 NAS 核心中苯丙胺诱发的 DA 释放以及成年大鼠苯丙胺诱导的运动行为。总之，后一项研究结果表明，中皮质和中伏隔 DA 神经元之间的神经化学相互作用最终在行为表达中发挥作用。目前的研究将把中前额和中伏本DA神经元的活动变化与延迟反应任务、运动行为以及对食欲和厌恶刺激的行为反应的表现联系起来。