Mechanisms mediating the attention-enhancing effects of nicotinic receptor agents

烟碱受体药物增强注意力作用的介导机制

基本信息

  • 批准号:
    8649926
  • 负责人:
  • 金额:
    $ 42.79万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-03-15 至 2019-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Diseases such as schizophrenia and Alzheimer's disease are marked by cognitive deficits for which there are to date no effective treatments. Drugs that activate the nicotinic acetylcholine receptor (nAChR) en- hance cognition, most robustly attentional functions. Non-selective nAChR agonists such as the prototypical agonist nicotine have a broad effects profile that includes unwanted side effects. The development of nAChR agonists selective for subtypes of the nAChR has had limited success in maximizing therapeutic and reducing side effects. The overall goal of the present proposal is to generate the knowledge upon which to base a more targeted development of nAChR agents with clinically significant cognitive-enhancing effects. Previous drug development efforts have focused on agonists of the two most widely expressed nAChR subtypes, reflecting the fact that the specific systems and mechanisms mediating the sought-after effects are largely unknown. This project is aimed at identifying the systems and mechanisms through which nAChR agents enhance attentional functions. Employing analogous human and rodent paradigms that we have shown to be reliably sensitive to the attention-enhancing effects of nicotine, this project consists of a series of mutually informative pharmacological characterization studies in healthy human never-smokers and rats. Aim 1 is to potentiate the attention-enhancing effects of nAChR agonism with Allosteric Poten- tiating Ligands (APLs). Interaction studies with low-dose nicotine (as a model agonist) and galantamine will be conducted in humans and rats, and in rats with novel, more selective APLs. Aim 2 is to evaluate the attention-enhancing properties of ultra low-dose nAChR antagonism, suggested by our previous preclinical findings. Studies in humans and rats with the nAChR antagonist mecamylamine will be accompanied by preclinical experiments employing more selective nAChR antagonists, and followed by pharmacological interaction studies to determine the secondary neurotransmitter system(s) involved. Aim 3 is to determine the secondary system(s) mediating the attention-enhancing properties of nAChR agonists. Following our previous preclinical findings, we will aim at antagonizing the attention-enhancing effects of nicotine in humans with a β-adrenoceptor antagonist. Concurrent preclinical experiments will aim at reversing attentional effects of nicotine with noradrenergic, glutamatergic, GABAergic, glycinergic, and histaminergic antagonists at doses devoid of effects by themselves. The resulting knowledge would enable drug development efforts to focus on nAChR subtypes expressed more selectively on those system(s) that mediate effects on attention. Such agents would have reduced unwanted and potentially larger therapeutic effects. Evaluating benefits of APLs and ultra low-dose antagonism diversifies strategies of nAChR modulation with the aim of producing larger effects. The integration of human and rodent findings will facilitate their translation into clinical practice. Overall, the project is expectedto result in nAChR agents with greater clinical potential.
描述(由申请人提供):精神分裂症和阿尔茨海默病等疾病的特征是认知缺陷,迄今为止还没有有效的治疗方法。激活烟碱乙酰胆碱受体(nAChR)的药物增强认知能力,尤其是注意力功能。非选择性nAChR激动剂如原型激动剂尼古丁具有广泛的作用特征,包括不需要的副作用。对nAChR亚型具有选择性的nAChR激动剂的开发在最大化治疗和减少副作用方面取得了有限的成功。本提案的总体目标是获得知识,以作为更有针对性地开发具有临床显着认知增强作用的nAChR药物的基础。以前的药物开发工作主要集中在两种最广泛表达的nAChR亚型的激动剂上,这反映了这样一个事实,即介导所追求的效果的特定系统和机制在很大程度上是未知的。该项目旨在确定nAChR试剂增强注意力功能的系统和机制。采用我们已经证明对尼古丁的注意力增强作用可靠敏感的类似人类和啮齿动物范例,该项目包括一系列在健康人类从不吸烟者和大鼠中进行的相互信息的药理学表征研究。目的1是增强nAChR激动剂与别构电位配体(APLs)的注意增强效应。将在人类和大鼠以及具有新型、更具选择性的APL的大鼠中进行低剂量尼古丁(作为模型激动剂)和加兰他敏的相互作用研究。目的2是评估超低剂量nAChR拮抗作用的注意力增强特性,这是我们以前的临床前研究结果所建议的。在人类和大鼠中使用nAChR拮抗剂美加明的研究将伴随使用更具选择性的nAChR拮抗剂的临床前实验,然后进行药理学相互作用研究,以确定所涉及的次级神经递质系统。目的3是确定介导nAChR激动剂的注意力增强特性的次级系统。根据我们之前的临床前研究结果,我们将致力于用β-肾上腺素受体拮抗剂拮抗尼古丁在人体中的注意力增强作用。同时进行的临床前实验旨在逆转尼古丁与去甲肾上腺素能、多巴胺能、GABA能、甘氨酸能和组胺能拮抗剂在自身无作用剂量下的注意力效应。由此产生的知识将使药物开发工作能够集中在nAChR亚型上,这些亚型在介导注意力影响的系统上更有选择性地表达。这样的药剂将具有减少的不想要的和潜在的更大的治疗效果。评估APLs和超低剂量拮抗作用的益处使nAChR调节策略多样化,目的是产生更大的效果。人类和啮齿动物研究结果的整合将有助于将其转化为临床实践。总的来说,该项目有望产生具有更大临床潜力的nAChR药物。

项目成果

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Britta Hahn其他文献

Britta Hahn的其他文献

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{{ truncateString('Britta Hahn', 18)}}的其他基金

Nicotine Insensitivity and Cue-Controlled Smoking Behavior in People with Schizophrenia
精神分裂症患者的尼古丁不敏感性和提示控制吸烟行为
  • 批准号:
    9892179
  • 财政年份:
    2020
  • 资助金额:
    $ 42.79万
  • 项目类别:
Effects of nicotine on dependence-related associative learning processes
尼古丁对依赖相关联想学习过程的影响
  • 批准号:
    8824263
  • 财政年份:
    2015
  • 资助金额:
    $ 42.79万
  • 项目类别:
Effects of nicotine on dependence-related associative learning processes
尼古丁对依赖相关联想学习过程的影响
  • 批准号:
    9037633
  • 财政年份:
    2015
  • 资助金额:
    $ 42.79万
  • 项目类别:
Nicotinic enhancement of cognitive remediation training in schizophrenia
烟碱增强精神分裂症认知矫正训练
  • 批准号:
    8699480
  • 财政年份:
    2014
  • 资助金额:
    $ 42.79万
  • 项目类别:
Nicotinic modulation of the default network of resting brain function
静息大脑功能默认网络的烟碱调节
  • 批准号:
    7772183
  • 财政年份:
    2010
  • 资助金额:
    $ 42.79万
  • 项目类别:
Nicotinic modulation of the default network of resting brain function
静息大脑功能默认网络的烟碱调节
  • 批准号:
    8035480
  • 财政年份:
    2010
  • 资助金额:
    $ 42.79万
  • 项目类别:

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