Modulation of norepinephrine by cannabinoids

描述(申请人提供)：去甲肾上腺素系统仍然是开发焦虑症新疗法的重要靶点，因为它在调节情绪状态和调节唤醒和压力反应方面起着关键作用。合成的大麻素受体激动剂/拮抗剂和以脑内内源性大麻素合成/代谢为靶点的化合物已受到广泛关注，因为这些方法可能具有治疗精神疾病的潜力。在之前的资助期间，我们证明了蓝斑-皮质通路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，这与大脑去甲肾上腺素能活动的多个指数的增加有关。我们还首次提供了几种肾上腺素能受体亚型在大脑皮层和边缘的表达水平改变的证据。 急性和反复暴露于大麻素受体激动剂后的区域。最后，我们确定去甲肾上腺素能在边缘回路的传递对于大麻诱导的特定行为至关重要。在竞争性更新应用中，电路和细胞水平的研究被提出以完善我们的模型，即在应激条件下去甲肾上腺素系统是如何被内源性大麻素系统调节的。目标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。目的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研究的基础上。目标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将确定应激诱导的分子和细胞适应在大麻素对蓝斑皮质通路的调制中。了解这一整合系统的状态依赖改变的性质，可能为治疗应激诱导的焦虑症提供新的底物。

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.