PHARMACOLOGY OF NICOTINIC RECEPTORS

该项目将复制和扩展CHRNA 7基因多态性与抑制功能障碍表型的关系，通过抑制P50对重复听觉刺激的反应来测量精神分裂症和对照受试者。alpha7特异性激动剂将在精神分裂症患者中进行测试，以确定它们是否使P50反应正常化，以及它们在多大程度上影响精神分裂症的神经认知特征和临床症状。我们已经获得美国食品药品监督管理局（FDA）的批准，可以给药3,4 -二甲氧基苯基苯基猪巴aseine给药，并在初步实验中证明该药物可以改善P50抑制缺陷。α 7烟碱受体不仅在神经传递中发挥作用，我们通过P50抑制证明了这一点，而且我们通过观察acra7变异体动物模型海马中间神经元区域分布的差异来表征它还具有重要的发育作用。由于纠正与alpha7受体相关的神经传递缺陷并不能解决这一发育作用，我们还将采用小鼠动物模型

This project will replicate and extend the relationship of genetic polymorphisms in CHRNA 7 to the phenotype of inhibitory dysfunction as measured by inhibition of the P50 response to repeated auditory stimuli in schizophrenic and control subjects. Alpha7-specific agonists will be tested in schizophrenics to determine if they normalize P50 response and to what extent they also affect the neurocognitive features and clinical symptoms of schizophrenia. We have received FDA approval for the administration of 3-2,4 dimethoxybenzylidene anabaseine to humans and in an initial experiment demonstrated that the drug improves deficient P50 inhibition. The alpha7 nicotinic receptor not only has a role in neurotransmission, which we demonstrate by P50 inhibition, but it also has a major developmental role that we have characterized by observing differences in the regional distribution of hippocampal interneurons in animal models with acra7 variants. Because correction of neurotransmission deficits related to alpha7 receptors does not address this developmental role, we will also employ mouse animal models to determine if alpha7 agonist treatment in the perinatal period affects the development of interneurons. To extend the hippocampal pathophysiology we have postulated to include the deficits in learning and memory found in schizophrenia, we now show deficits in learning in mice with the acra7 (murine CHRNA 7) null mutation, as well as evidence in humans that P50 abnormalities correlate with decreased declarative memory. We present new data that perinatal choline supplementation to mice with acra7 polymorphisms results in offspring with normal inhibition of the hippocampal response to repeated sounds. In conjunction with Project by Restrepo, we will measure olfactory function in schizophrenics. For Project by Ross, we will record P50 inhibition as a basic measure of inhibitory function to be related to their measurements in children and adults.