Modulation of norepinephrine by cannabinoids

描述（由申请人提供）：内源性大麻素系统的存在，包括大麻素受体和内源性配体，现在已经得到了很好的认可。然而，大麻素受体的分布和大麻素激动剂对单胺能神经递质系统的影响只是慢慢开始出现。这一信息对于理解慢性娱乐性药物暴露后的细胞适应以及阐明大麻素基化合物的潜在治疗用途至关重要。大麻素受体激动剂的急性作用包括学习和记忆缺陷、感知扭曲、解决问题困难和协调性丧失。反复服用会导致应激反应系统的激活增加、焦虑、抑郁、认知障碍和精神病。问题仍然是大麻素在哪里起作用，诱导可能导致长期行为障碍的细胞适应。我们实验室的初步数据表明，一个潜在的靶点是去肾上腺素能蓝-皮质通路，这是一种参与调节高级认知功能和情绪的生物胺系统。这个系统与设置注意力模式有关，并作为促进觉醒的压力反应的一部分。我们的指导假设是，慢性大麻素管理导致一个增强的去甲肾上腺素能系统，可能有助于情感性障碍的病理生理。该研究综合了神经解剖学、神经化学和行为学方法，有望进一步了解大麻素受体调节蓝斑-额叶皮质通路的细胞基质，并揭示该回路在大麻素诱导的焦虑中的作用。提出了四个具体目标来回答以下问题：1)大麻素诱导的皮质去甲肾上腺素外排介导的细胞位点是什么？2) CB1受体在额叶皮层和LC中的神经解剖学分布如何？3)反复服用大麻素激动剂是否会对去甲肾上腺素能功能产生长期影响（通过酪氨酸羟化酶基因表达和释放的增加来检测）4)去甲肾上腺素能病变对大麻素诱导的焦虑有什么影响？通过完成提出的具体目标，我们将对大麻素对大脑去甲肾上腺素能功能的作用的细胞位点和慢性暴露于大麻素对去甲肾上腺素能系统的行为后果有一个坚定的理解。

DESCRIPTION (provided by applicant): The existence of an endogenous cannabinoid system, comprising cannabinoid receptors and endogenous ligands is now well recognized. However, the distribution of cannabinoid receptors and the impact of cannabinoid agonists on monoaminergic neurotransmitter systems is only slowly beginning to emerge. This information is essential for understanding cellular adaptations following chronic recreational drug exposure as well as elucidating potential therapeutic uses for cannabinoid-based compounds. Acute effects of cannabinoid receptor agonist administration include deficits in learning and memory, distorted perception, difficulty in problem solving and loss of coordination. Repeated administration leads to increases in the activation of the stress-response system, anxiety, depression, cognitive impairment, and psychosis. The question remains as to where cannabinoids act to induce cellular adaptations that may result in long term behavioral dysfunction. Preliminary data from our laboratories suggest that one potential target is the noradrenergic coeruleo-cortical pathway, a biogenic amine system involved in modulating higher cognitive function and mood. This system is implicated in setting the attentional mode, and is engaged as part of the stress response to facilitate arousal. Our guiding hypothesis is that chronic cannabinoid administration results in a potentiated noradrenergic system that may contribute to the pathophysiology of affective disorders. The proposed aims, which integrate neuroanatomical, neurochemical and behavioral approaches, promise to further our understanding of the cellular substrates for cannabinoid receptor modulation of the locus coeruleus (LC)-frontal cortex pathway and reveal the participation of this circuit in cannabinoid-induced anxiety. Four specific aims are proposed to answer the following questions: 1) What are the cellular sites mediating cortical norepinephrine efflux induced by cannabinoids ? 2) What is the neuroanatomical distribution of CB1 receptors in the frontal cortex and LC ? 3) Does repeated administration of cannabinoid agonists result in long term effects on noradrenergic function (as detected by increases in tyrosine hydroxylase gene express and release) 4) What are the effects of noradrenergic lesions on cannabinoid-induced anxiety ? By accomplishing the proposed specific aims, we will have a firm understanding of the cellular sites of action of cannabinoids on brain noradrenergic function and the behavioral consequences of chronic exposure to cannabinoids on the noradrenergic system.