CHOLINERGIC MECHANISMS IN AGING AND AD

描述：(申请人摘要)本实验室对 开发治疗人类脑部疾病的新疗法 由选择m1、m2、m3、m4或m5毒鼠强的药物控制 感受器。目前，许多团体都对它的潜在用途感兴趣 一种治疗记忆障碍的M1激动剂，主要基于 在大脑皮层和海马区的M1受体中， 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是如何 M1-M5受体可能起作用，因为我们还没有这些药物来 学习。事实上，毒扁豆碱类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如何 受体亚型调节神经元、回路和 特定的行为。这个实验室已经发现了唯一特定的 M1和M4受体拮抗剂，M1毒素和M4毒素拮抗剂。这些 现在毒素允许，我们建议进行精确和协调的 解剖学、生理学、生化和行为学实验 建立新的M4和M1选择性药物的细胞和回路 可用于改变运动、记忆和疼痛。纹状体的研究 首先，假设M4拮抗剂将对 运动障碍(如帕金森氏病)和一种M4激动剂 多动症(如迟发性运动障碍)，基于 纹状体M4受体的异常流行，水平降低了5倍 在其他地方，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 验证M4受体在大鼠体内优先定位的观点 直接通路中的纹状体投射神经元，正负 黑质纹状体损伤。协作性电生理研究 这两种毒素都会对细胞和电流产生可调节的影响。 这两种毒素都将在体内用于研究激动剂诱导的转归。 多巴胺能或胆碱能不等受体大鼠的反应 左侧和右侧纹状体的水平。这些研究应该提供一个 检测M4选择性药物治疗骨肉瘤的合理依据 运动障碍。对海马体的研究是基于例外 M1受体的患病率及乙酰胆碱对脑功能的影响 记忆。LSCM将被用来测试M1和M4受体是 在不同的神经元上。这两种毒素都将用于合作研究 确定M1和M4激活是如何调节海马区兴奋的 和抑制。这些研究应该有助于验证使用 M1激动剂用于记忆，并揭示了一些潜在的临床效果 M4-选择性药物。对伤害性感受的研究是基于以下证据 M_1或M_4受体激动剂减少大鼠的伤害性感受 通过一种不受纳洛酮影响的机制。LSCM将用于测试 认为脊髓背侧和吻侧的关键受体是M4 延髓腹侧，两种毒素都将被用来确定 受体调节止痛作用。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 正常和AD脑中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.