Effects of CNS Lesions on Drug Action

描述(由申请人提供)：5-羟色胺5-HT2A受体在精神分裂症和情感障碍的发病机制中的作用日益受到重视。特别是，抗精神病药物的治疗作用被认为是由于它们在5-HT2A受体上的作用，导致受体密度的变化。然而，这种受体变化的功能后果还没有得到充分的研究。这项提议的创新方面来自：1)我们使用了一个动物模型，在该模型中，联想学习(精神分裂症中的一个异常过程)由5-HT2A受体调节，2)我们检测由于成人大脑中5-HT2A受体密度变化而导致的学习变化的能力，以及3)我们的初步证据表明5-HT2A受体在结构上是活跃的。我们现在建议详细研究边缘皮质5-HT2A受体的上调和下调如何改变学习速度、这些脑区内的神经元电路、长时程增强的发展(学习的体外模型)、受体的构成活性以及受体介导的第二信使信号。学习是在兔的眨眼反应的经典跟踪条件作用下进行测量的，这是一种受5-HT2A受体调节的学习形式，依赖于边缘皮质(海马体和额叶皮质)的完整性。值得注意的是，精神分裂症患者的眨眼条件反射也会受到损害。脑内注射药物将被用来识别5-HT2A受体调节学习的关键大脑部位。大脑5-羟色胺的耗竭将被用来确定5-HT2A受体的构成活性的程度，通过基础和激动剂刺激的第二信使信号来衡量。这一研究结果将为精神分裂症的治疗提供新的治疗策略。此外，这项研究将为学习的神经生物学提供一个新的视角和新的见解。

DESCRIPTION (provided by applicant): Increasing emphasis has been placed on the role of the serotonin 5-HT2A receptor in the pathogenesis of schizophrenia and affective disorders. In particular, the therapeutic effects of antipsychotic drugs have been suggested to be due to their actions at the 5-HT2A receptor that lead to changes in receptor density. However, the functional consequences of such receptor changes have not been fully examined. The innovative aspect of this proposal derives from: 1) our use of an animal model in which associative learning (a process that is abnormal in schizophrenia) is regulated by the 5-HT2A receptor, 2) our ability to detect changes in learning that result from alterations in the density of the 5-HT2A receptor in the adult brain, and 3) our preliminary evidence that the 5-HT2A receptor is constitutively active. We now propose to examine in detail how both the up- and down- regulation of the 5-HT2A receptor in limbic cortex, brain regions that are thought to be affected in schizophrenia, alters the rate of learning, the neuronal circuitry within those brain regions, the development of long-term potentiation (an in vitro model of learning), the constitutive activity of the receptor, and receptor mediated second messenger signaling. Learning is measured during classical trace conditioning of the rabbit's eye-blink response, a form of learning that is regulated by the 5-HT2A receptor, and is dependent on the integrity of limbic cortex (hippocampus and frontal cortex). It is important to note that eyeblink conditioning is also impaired in schizophrenia. Intracerebral injections of drugs will be used to identify the critical brain loci at which the 5-HT2A receptors regulate learning. Depletions of brain serotonin will be employed to determine the extent of constitutive activity at the 5-HT2A receptor as measured by basal and agonist stimulated second messenger signalling. The results of this research should provide novel therapeutic strategies in the treatment of schizophrenia. In addition, this research will provide a new perspective and new insights into the neurobiology of learning.