CHOLINERGIC MECHANISMS IN AGING AND AD

描述：（申请人的摘要）本实验室感兴趣的是 开发新的治疗人类大脑疾病的方法， 由对m1、m2、m3、m4或m5毒蕈碱有选择性的药物控制 受体。目前，许多团体对潜在的用途感兴趣， 记忆障碍的m1激动剂，主要基于 大脑皮层和海马体中的m1受体， 东莨菪碱和阿尔茨海默病（AD）中乙酰胆碱的丢失。 事实上，我们不知道新的选择性激动剂或拮抗剂如何 m1-m5受体可能会起作用，因为我们还没有这些药物， study.事实上，毒蕈碱神经传递领域仍处于 在这个阶段，最迫切的需要是了解个人 受体亚型调节神经元、回路和 具体行为。这个实验室发现了唯一一个 M1和M4受体拮抗剂，M1-毒素和M4-毒素。这些 毒素现在允许，我们建议进行，精确和协调 解剖学、生理学、生物化学和行为实验， 建立新的m4和m1选择性药物 可用于改变运动、记忆和疼痛。纹状体的研究 开始的前提是，M4拮抗剂将是有用的， 运动机能减退障碍（例如，帕金森氏病）和用于治疗帕金森氏病的m4激动剂 运动过度障碍（例如，迟发性运动障碍），基于 纹状体m4受体异常普遍，水平低5倍 其他地方，以及东莨菪碱对运动的影响。荧光 毒素和激光扫描共聚焦显微镜（LSCM）将用于 测试M4受体优先位于大鼠上的想法 直接通路中的纹状体投射神经元，正负 黑质纹状体病变协同电生理研究， 这两种毒素将建立到可以被调节的细胞和电流。 这两种毒素将在体内用于研究激动剂诱导的转向 多巴胺能或胆碱能受体不等的大鼠的反应 左右纹状体的水平这些研究将提供一个 测试m4选择性药物治疗的合理依据 运动障碍海马体的研究是基于 m1受体的流行和乙酰胆碱的重要性， 记忆LSCM将被用来测试的想法，m1和m4受体是 在不同的神经元上。两种毒素都将用于合作研究 为了确定m1和m4激活如何调节海马兴奋， 和抑制。这些研究应该有助于验证使用 M1激动剂用于记忆，并公开了 M4选择性药物伤害感受的研究是基于以下证据： M1或M4受体的毒蕈碱激动剂减少大鼠的伤害感受 通过一种不受纳洛酮影响的机制LSCM将用于测试 认为脊髓背侧和喙侧的关键受体是m4， 腹侧髓质，这两种毒素将被用来确定 受体调节镇痛。这些研究应该提供一个合理的 为开发新的非阿片类镇痛药奠定了基础。进一步 生物化学研究旨在揭示新的特点， 来自正常和AD脑的M1受体的结构。

DESCRIPTION: (Applicant's Abstract) This laboratory is interested in the development of new therapies for human brain diseases that can be controlled by drugs selective for m1, m2, m3, m4, or m5 muscarinic receptors. At present many groups are interested in the potential use of an m1 agonist for memory disorders, based largely on the prevalence of m1 receptors in the cortex and hippocampus, the amnesic effects of scopolamine, and the loss of acetylcholine in Alzheimer's disease (AD). In reality, we don't know how new selective agonists or antagonists for m1-m5 receptors might work, because we have not had these drugs to study. In fact, the field of muscarinic neurotransmission is still at the stage where the most pressing need is to understand how individual receptor subtypes regulate the functions of neurons, circuits and specific behaviors. This lab has discovered the only specific antagonists for m1 and m4 receptors, m1-toxin and m4-toxin. These toxins now permit, and we propose to carry out, precise and coordinated anatomical, physiological, biochemical and behavioral experiments to establish the cells and circuits at which new m4- and m1-selective drugs may be use to modify movement, memory and pain. Studies of the striatum begin with the premise that an m4 antagonist will be useful for hypokinetic disorders (e.g., Parkinson's disease) and an m4 agonist for hyperkinetic disorders (e.g., tardive dyskinesia), based on the exceptional prevalence of striatal m4 receptors, 5-fold lower levels elsewhere, and the effects of scopolamine on movement. Fluorescent toxins and laser scanning confocal microscopy (LSCM) will be used to test the idea that m4 receptors are located preferentially on rat striatal projection neurons in the direct pathway, plus or minus nigrostriatal lesions. Collaborative electrophysiological studies with both toxins will establish to cells and currents that can be regulated. Both toxins will be used in vivo to study the agonist-induced turning responses of rats having unequal dopaminergic or cholinergic receptor levels in the right and left striata. These studies should provide a rational basis for testing m4-selective drugs for the treatment of movement disorders. Studies of hippocampus are based on the exceptional prevalence of m1 receptors and the importance of acetylcholine for memory. LSCM will be used to test the idea that m1 and m4 receptors are on different neurons. Both toxins will be used in collaborative studies to establish how m1 and m4 activation modulate hippocampal excitation and inhibition. These studies should help validate the idea of using m1 agonists for memory, and disclose some potential clinical effects of m4-selective drugs. Studies of nociception are based on evidence that muscarinic agonists for m1 or m4 receptors diminish nociception in rats by a mechanism unaffected by naloxone. LSCM will be used to test the idea that the key receptors are m4 in the dorsal spinal cord and rostral ventral medulla, and both toxins will be used to establish which receptor modulates analgesia. These studies should provide a rational basis for the development of new non-opioid analgesics. Further biochemical studies are designed to disclose new features of the structure of m1 receptors from normal and AD brains.