MECHANISMS OF MUSCARINIC RECEPTOR CROSS-TALK IN BRAIN

本建议的目的是加强候选人的发展， 膜受体领域的独立研究者， 脑内的细胞内信号。候选人的近期目标 是要开发一个研究项目，调查 毒蕈碱受体信号传导机制与其他受体相互作用 大脑不同区域的神经系统以及精神药物如何干扰 或调节这些相互作用。候选人的长期目标是 建立受体之间相互作用的功能意义 大脑中的信号机制，这些机制如何影响神经元 兴奋性、学习、记忆和行为。A的财政支持 研究职业发展奖将使主要研究者能够 花更多的时间做研究和学习新技术，以实现他的目标。 长期目标。作为药理学系的一员， 加州大学欧文分校的候选人将有充分的机会 与该领域的其他既定调查人员合作， 神经科学和心血管药理学。的具体目标 候选人的研究建议是调查的影响， 毒蕈碱受体激活对其他受体系统的能力， 刺激腺苷酸环化酶活性的完整细胞制备的 腮腺和大脑的各个区域。直接贡献 毒蕈碱受体介导的腺苷酸环化酶活性抑制 抑制性鸟嘌呤核苷酸结合蛋白将使用 百日咳毒素，以防止这种影响。的药理学亚型， 毒蕈碱受体介导磷酸肌醇水解和抑制 腺苷酸环化酶活性将在相同的制备物中定义。 纹状体和腮腺，使用药理学无效方法， 放射性配体结合方法来分析选择性 毒蕈碱激动剂和拮抗剂。类似的方法将用于 确定参与与之相互作用的毒蕈碱受体的亚型 其他刺激腺苷酸环化酶活性的受体。最后 各种精神药理学药物的作用机制 （神经安定药、三环类抗抑郁药、锂）干扰 将研究毒蕈碱受体偶联机制。结果 这些研究可能揭示大脑中新的胆碱能机制， 可能在阿尔茨海默病和其他精神疾病中受到损害， 胆碱能机能减退

The aims of this proposal are to enhance the candidate's development as an independent investigator in the field of membrane receptors and intracellular signalling within the brain. The candidate's immediate goals are to develop a research program investigating the mechanisms by which muscarinic receptor signalling mechanisms interact with other receptor systems in various regions of the brain and how psychiatric drugs interfere or modulate these interactions. The long range goals of the candidate are to establish the functional significance of interactions between receptor signalling mechanisms in the brain, how these mechanisms influence neuronal excitability, learning, memory and behavior. The financial support of a Research Career Development award will enable the principal investigator to spend more time doing research and learning new techniques to achieve his long range goals. As a member of the Department of Pharmacology at the University of California, Irvine, the candidate will have ample opportunity to collaborate with other established investigators within the field of neuroscience and cardiovascular pharmacology. The specific aims of the candidate's research proposal are to investigate the influence of muscarinic receptor activation on the ability of other receptor systems to stimulate adenylate cyclase activity in intact cell preparations of the parotid gland and various regions of the brain. The contribution of direct muscarinic receptor-mediated inhibition of adenylate cyclase activity via the inhibitory guanine nucleotide binding protein will be assessed using pertussis toxin to prevent this effect. The pharmacological subtypes of the muscarinic receptor mediating phosphoinositide hydrolysis and inhibition of adenylate cyclase activity will be defined in identical preparations of the corpus striatum and parotid gland using pharmacological null methods and radioligand binding methods to analyze the properties of selective muscarinic agonists and antagonists. Similar methods will be used to identify the subtype of the muscarinic receptor involved in cross-talk with other receptors that stimulate adenylate cyclase activity. Finally, the mechanisms by which various drugs of psychopharmacological interest (neuroleptics, tricyclic antidepressants, lithium) interfere with muscarinic receptor coupling mechanisms will be investigated. The results of these studies may reveal new cholinergic mechanisms in the brain which may be compromised in Alzheimer's disease and other mental disorders of cholinergic hypofunction.