Modulation of norepinephrine by cannabinoids

描述（由申请人提供）：由于去甲肾上腺素能系统在情绪状态的调节以及觉醒和应激反应的调节中起着关键作用，因此它一直是焦虑症新疗法发展的重要靶点。合成大麻素受体激动剂/拮抗剂和靶向脑内源性大麻素合成/代谢的化合物已受到广泛关注，因为这些方法可能具有治疗精神疾病的潜力。在之前的资助期间，我们证明蓝核-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，暴露于合成大麻素受体激动剂会增加焦虑样行为，这种行为与大脑去甲肾上腺素能活性的多个指标的增加相关。我们还提供了皮层和边缘几种肾上腺素能受体亚型表达水平改变的第一个证据

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.