Modulation of norepinephrine by cannabinoids

大麻素对去甲肾上腺素的调节

• 批准号: 8739959
• 负责人: ELISABETH J VAN BOCKSTAELE
• 金额: $ 14.16万
• 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/8739959
• 关键词: Acute; Adaptive Behaviors; Adrenergic Agents; Adrenergic Receptor; Affect; Agonist; Anxiety; Anxiety Disorders; Area; Arousal; Attention; Behavior; Brain; Cannabinoids; Cell surface; Chronic stress; Cognitive; Data; Development; 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; Mus; 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; adrenergic; biological adaptation to stress; cannabinoid receptor; flexibility; improved; indexing; interest; locus ceruleus structure; mouse model; neurochemistry; noradrenergic; norepinephrine system; novel; preclinical study; receptor; receptor expression; receptor function; response; 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目标，因为它在调节情绪状态以及调节唤醒和应激反应中发挥着关键作用。合成大麻素受体激动剂/拮抗剂和针对大脑内源性大麻素合成/代谢的化合物已受到广泛关注，因为这些方法可能对精神疾病具有一定的治疗潜力。在之前的资助期间，我们证明了蓝皮质通路是大麻素作用的重要目标。我们提供的证据表明，在基础条件下，接触合成大麻素受体激动剂会增加焦虑样行为，这与大脑去甲肾上腺素能活动的多个指数的增加相关。我们还提供了皮质和边缘中几种肾上腺素能受体亚型表达水平变化的第一个证据 急性和反复接触大麻素受体激动剂后的区域。最后，我们确定边缘回路中的去甲肾上腺素能传输对于选定的大麻诱导的行为至关重要。在竞争性的更新应用中，提出了电路和细胞水平的研究，以完善我们的模型，即在压力条件下内源性大麻素系统如何调节去甲肾上腺素能系统。 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皮层通路。 AIM 2 建立在 AIM 1 研究的基础上，通过研究去甲肾上腺素能电路对皮质内源性大麻素水平的调节。 AIM 3 将确定删除 1 型大麻素受体是否会改变 去甲肾上腺素能活性的分子和电生理指标。最后，AIM 4 将识别大麻素对蓝皮层通路的调节中压力诱导的分子和细胞适应。了解这种整合系统的状态依赖性改变的本质可能为治疗压力引起的焦虑症提供新的基础。