Modulation of norepinephrine by cannabinoids

大麻素对去甲肾上腺素的调节

• 批准号: 9271435
• 负责人: ELISABETH J VAN BOCKSTAELE
• 金额: $ 0.58万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271435
• 关键词: Acute; Adaptive Behaviors; Adrenergic Agents; Adrenergic Receptor; Affect; Agonist; Anxiety Disorders; Area; Arousal; Attention; Behavior; Brain; CNR1 gene; Cannabinoids; Cell surface; Chronic stress; Cognitive; DSP 4; Data; Development; Electrophysiology (science); Elements; Emotional; Endocannabinoids; Environment; Exposure to; Fire - disasters; Funding; Health; Immunotoxins; Knockout Mice; Knowledge; Lesion; Measures; Medial; Mediating; Mental disorders; Messenger RNA; Metabolism; Modeling; Molecular; Nature; Neurons; Norepinephrine; Pathway interactions; Pattern; Physiology; Positioning Attribute; Prefrontal Cortex; Prosencephalon; Rattus; Recording of previous events; Regulation; Resolution; Role; Site; Slice; Source; Stress; Symptoms; Synapses; System; Testing; Therapeutic; Tyrosine 3-Monooxygenase; acute stress; anxiety-like behavior; biological adaptation to stress; brain circuitry; cannabinoid receptor; endogenous cannabinoid system; flexibility; improved; indexing; interest; locus ceruleus structure; mouse model; neurochemistry; noradrenergic; norepinephrine system; novel; novel therapeutics; preclinical study; receptor; receptor expression; receptor function; response; synthetic cannabinoid; transmission process

DESCRIPTION (provided by applicant): The noradrenergic system continues to be an important target in the development of new therapies for anxiety disorders because of its critical role in the modulation of emotional state and regulation of arousal and stress responses. Synthetic cannabinoid receptor agonists/antagonists and compounds targeting endocannabinoid synthesis/metabolism in brain have received widespread attention as these approaches may hold some therapeutic potential for psychiatric disorders. Over the prior funding period, we demonstrated that the coeruleo-cortical pathway is an important target of cannabinoid actions. We provided evidence that, under basal conditions, exposure to a synthetic cannabinoid receptor agonist increases anxiety- like behaviors that correlate with increases in multiple indices of brain noradrenergic activity. We also provided the first evidence of alterations in expression levels for several adrenergic receptor subtypes in cortical and limbic areas following acute and repeated exposure to cannabinoid receptor agonists. Finally, we established that noradrenergic transmission in limbic circuitry is critical for selected cannabinoi-induced behaviors. In the competing renewal application, circuit and cellular level studies are proposed to refine our model of how the noradrenergic system is regulated by the endocannabinoid system under conditions of stress. AIM 1 will define how molecular elements of the endocannabinoid system are positioned to impact the coeruleo-cortical pathway. AIM 2 builds on studies in AIM 1 by investigating the regulation of cortical endocannabinoid levels by noradrenergic circuitry. AIM 3 will determine if deletion of the cannabinoid type 1 receptor alters molecular and electrophysiological indices of noradrenergic activity. Finally, AIM 4 will identify stress-induced molecular and cellular adaptations in cannabinoid modulation of the coeruleo-cortical pathway. Understanding the nature of state dependent alterations of this integrative system may provide a novel substrate for the treatment of stress-induced anxiety disorders.

描述（由申请人提供）：去甲肾上腺素能系统仍然是开发焦虑症新疗法的重要靶点，因为其在调节情绪状态和调节唤醒和应激反应中发挥关键作用。合成大麻素受体激动剂/拮抗剂和靶向脑中内源性大麻素合成/代谢的化合物已经受到广泛关注，因为这些方法可能对精神障碍具有一定的治疗潜力。在之前的资助期内，我们证明了蓝斑-皮质途径是大麻素作用的重要靶点。我们提供的证据表明，在基础条件下，暴露于合成大麻素受体激动剂会增加焦虑样行为，这些行为与大脑去甲肾上腺素能活性的多个指数增加相关。我们还提供了第一个证据表明，在大脑皮层和边缘系统中， 急性和反复暴露于大麻素受体激动剂后的区域。最后，我们确定了去甲肾上腺素能传递在边缘电路是至关重要的选择大麻素诱导的行为。在竞争的更新应用，电路和细胞水平的研究，提出了完善我们的模型，去甲肾上腺素能系统是如何调节内源性大麻素系统的条件下的压力。AIM 1将定义内源性大麻素系统的分子元件如何定位以影响蓝斑-皮质通路。AIM 2通过研究去甲肾上腺素能回路对皮质内源性大麻素水平的调节，建立在AIM 1的研究基础上。AIM 3将确定大麻素1型受体的缺失是否会改变 去甲肾上腺素能活动的分子和电生理指标。最后，AIM 4将确定压力诱导的分子和细胞适应大麻素调制的蓝斑皮质途径。了解这种整合系统的状态依赖性改变的性质可能为治疗应激诱导的焦虑症提供一种新的底物。