MODEL OF SCHIZOPHRENIA--ROLE OF CORTICAL DOPAMINE

精神分裂症模型--皮质多巴胺的作用

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6187011
• 关键词: 6 hydroxydopamine; age difference; animal developmental psychology; animal food; appetite; axon; behavior test; behavioral /social science research tag; brain electrical activity; brain injury; disease /disorder model; dopamine; environmental stressor; experimental brain lesion; laboratory rat; neural degeneration; neurochemistry; neuropathology; neuropharmacology; neurotransmitter transport; nucleus accumbens; nutrition related tag; prefrontal lobe /cortex; schizophrenia; short term memory

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.

验尸研究表明，在精神分裂症受试者中，前额叶皮层（PFC）的多巴胺（DA）神经受到减少。此外，涉及中额外DA神经元的神经发育破坏被认为有助于精神分裂症的病理生理学，部分原因可能是随着个体成熟的症状的出现。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）中持续的前额叶皮层（PFC）中DA轴突的部分损失是否会差异地影响PFC在青春期前和成年大鼠中的功能。首先，我们将研究开发早期在发展前和成年大鼠PFC中局部细胞外DA的局部DA轴突的局部损失的影响（AIM 1）。我们最近的研究表明，在青春期（40天龄）之前，PFC中DA轴突损失60％，降低了成年大鼠PFC的基础和压力诱发的细胞外DA（68天龄）。因此，在精神分裂症受试者的PFC中观察到的DA纤维的中等损失可能足以损害PFC的功能。我还将研究开发早期持续的DA轴突在PFC中的部分损失对PFC调节皮层靶区域神经化学活性的能力的影响，即中等含量的DA投影（AIM 2）。以前，已经提出，中额乳突DA神经元的活性减少会增强皮质下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轴突的部分损失在成年大鼠的NAS壳中增加了压力引起的DA释放。最后，我们将研究在发育早期持续的DA轴突在PFC中的部分损失对被认为是被中脑和中胞菌神经元调节的行为的行为的影响（AIM 3）。有人提出，中颈和中牙神经元的功能障碍会导致精神分裂症的某些行为症状。以前，我们报告说，在青春期衰减NAS核心中的苯丙胺引起的DA释放之前，PFC中DA轴突的部分损失在成年大鼠的NAS核心和苯丙胺诱导的运动行为中释放。共同的发现共同表明，中皮质和中牙神经元之间的神经化学相互作用最终在行为表达中起作用。目前的研究将与中源和中牙神经元的活性变化与延迟的响应任务，运动行为以及对食欲和厌恶刺激的行为响应有关。