MODEL OF SCHIZOPHRENIA--ROLE OF CORTICAL DOPAMINE

死后研究表明，精神分裂症患者前额叶皮层（PFC）的多巴胺（DA）神经支配减少。此外，涉及中前额叶DA神经元的神经发育中断被认为有助于精神分裂症的病理生理学，并可能部分解释个体成熟时症状的出现。为了确定这种结构异常的潜在功能后果，我将研究在发育早期（12日龄）持续的前额皮质（PFC） DA轴突的部分丢失是否会对青春期前和成年大鼠的前额皮质（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轴突部分缺失对青春期前和成年大鼠PFC局部细胞外DA的影响（目的1）。我们最近的研究表明，在青春期（40日龄）之前，PFC中60%的DA轴突持续丢失，成年大鼠（68日龄）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在发育早期持续的DA轴突部分损失对PFC调节皮层下靶区（伏隔中脑DA投射）神经化学活动的能力的影响（目的2）。在此之前，有研究表明，前额叶间叶DA神经元活性的减弱会增强皮层下DA神经元的活性，这两个事件都有助于精神分裂症的病理生理。我们自己的研究表明，青春期前PFC中DA轴突的部分缺失持续存在，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轴突的部分缺失对被认为是由青春期前和成年大鼠前额叶和伏隔叶DA神经元调节的行为的影响（目的3）。有人认为，中前额叶和中伏核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。在此之前，我们报道了青春期前PFC中DA轴突的部分缺失，减弱了安非他明诱发的NAS核心DA释放和安非他明诱导的成年大鼠运动行为。总之，后一项研究结果表明，中皮层和中伏隔皮层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。本研究将中额叶和伏隔中脑DA神经元的活动变化与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联系起来。

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.