CHOLINERGIC MECHANISMS IN AGING AND AD

衰老和 AD 中的胆碱能机制

• 批准号: 2699747
• 负责人: Lincoln T. Potter
• 金额: $ 29.53万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-05-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2699747
• 关键词: Alzheimer's disease; acetylcholine; affinity chromatography; aging; anticholinergic agent; behavior test; cholinergic agents; confocal scanning microscopy; corpus striatum; dopamine receptor; hippocampus; laboratory rat; medulla oblongata; muscarinic receptor; neuroanatomy; neuropharmacology; neurotoxins; pain; receptor expression; reptile poison; spinal cord

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.

描述：（申请人的摘要）该实验室对 开发可能是人类脑疾病的新疗法 由针对M1，M2，M3，M4或M5毒蕈碱选择性的药物控制 受体。目前，许多小组对潜在用途感兴趣 M1激动剂用于记忆障碍，主要基于患病率 皮质和海马中的M1受体的失忆作用 西孢胺，以及阿尔茨海默氏病（AD）中乙酰胆碱的丧失。 实际上，我们不知道新的选择性激动剂或反对者如何 M1-M5受体可能起作用，因为我们没有这些药物 学习。实际上，毒蕈碱神经传递的领域仍在 最紧迫的阶段是了解个人如何 受体亚型调节神经元，电路和 特定行为。这个实验室发现了唯一的特定 M1和M4受体，M1毒素和M4毒素的拮抗剂。这些 毒素现在允许，我们建议进行精确和协调 解剖学，生理，生化和行为实验 建立新的M4和M1选择药物的细胞和电路 可能用于修改运动，记忆和痛苦。纹状体的研究 首先从一个前提开始，即M4对手将对 低迷疾病（例如帕金森氏病）和M4激动剂 基于超动力学疾病（例如，迟发性运动障碍） 纹状体M4受体的特殊患病率，较低水平5倍 在其他地方，以及东pol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 直接途径中的纹状体投影神经元，加上或减去 黑质病变。协作电生理研究与 两种毒素都将建立可以调节的细胞和电流。 两种毒素都将在体内用于研究激动剂诱导的转弯 患有多巴胺能或胆碱能受体的大鼠的反应 左右纹状体的水平。这些研究应提供 测试M4选择药物治疗的合理基础 运动障碍。海马研究基于特殊 M1受体的患病率和乙酰胆碱的重要性 记忆。 LSCM将用于测试M1和M4受体是 在不同的神经元上。两种毒素都将用于协作研究 确定M1和M4激活如何调节海马激发 和抑制。这些研究应有助于验证使用的想法 M1激动剂用于记忆，并披露了一些潜在的临床影响 M4选择药物。伤害感受的研究是基于证据 M1或M4受体的毒蕈碱激动剂减少大鼠的伤害感受 通过不受纳洛酮影响的机制。 LSCM将用于测试 关键受体在背脊髓和thostral中是M4的想法 腹侧髓质，两种毒素将用于确定哪个 受体调节镇痛。这些研究应该提供理性 开发新的非阿片类镇痛药的基础。更远 生化研究旨在披露 来自正常和广告大脑的M1受体的结构。