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: 2902681
• 负责人: JANET M FINLAY
• 金额: $ 12.76万
• 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/2902681
• 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.

尸检研究表明，精神分裂症受试者前额叶皮质的多巴胺(DA)神经支配减弱。此外，涉及中前叶DA神经元的神经发育障碍被认为是精神分裂症的病理生理机制之一，并可能在一定程度上解释随着个体成熟而出现症状的原因。为了确定这种结构异常的潜在功能后果，我将研究发育早期(12日龄)前额叶皮质(PFC)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，我们将研究发育早期持续的DA轴突的部分丧失对青春期前和成年大鼠PFC局部细胞外DA的影响(目标1)。我们最近的研究表明，在青春期前(40d龄)，成年大鼠(68日龄)PFC内60%的DA轴突丢失，基础和应激诱发的PFC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纤维的适度丢失可能足以损害PFC的功能。我还将研究在发育早期持续的PFC中DA轴突的部分丧失对PFC调节皮质下靶区--中隔区DA投射的神经化学活动的影响(目标2)。以往的研究表明，中脑前额叶DA神经元的活动减弱增强了皮质下DA神经元的活动，这两个事件都参与了精神分裂症的病理生理过程。我们自己的研究表明，青春期前PFC中DA轴突的部分丢失，增加了应激诱导的成年大鼠NAS壳中DA的释放。最后，我们将研究在发育早期维持的PFC中DA轴突的部分丧失对青春期前和成年大鼠的被认为是由中前额和中伏隔DA神经元调制的行为的影响(目标3)。已有研究表明，精神分裂症的某些行为症状是由中脑前额叶和中脑伏隔核DA神经元功能障碍共同引起的。在此之前，我们报道了青春期前持续的PFC中DA轴突的部分缺失会减弱苯丙胺诱发的NAS核心的DA释放和苯丙胺诱导的成年大鼠的运动行为。综上所述，后者的发现表明，中皮质和中伏隔核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。本研究将在延迟反应任务的表现、运动行为以及对食欲和厌恶刺激的行为反应中，将中脑前额叶和中隔伏隔区DA神经元的活动变化联系起来。