Modulation of norepinephrine by cannabinoids

描述（由申请人提供）：现在已充分认识到内源性大麻素系统的存在，该系统包括大麻素受体和内源性配体。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。这些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化合物的潜在治疗用途至关重要。大麻素受体激动剂给药的急性效应包括学习和记忆缺陷、感知扭曲、解决问题困难和协调能力丧失。重复给药导致应激反应系统、焦虑、抑郁、认知障碍和精神病的激活增加。问题仍然是大麻素在哪里起作用来诱导可能导致长期行为功能障碍的细胞适应。来自我们实验室的初步数据表明，一个潜在的目标是去甲肾上腺素能蓝斑皮质通路，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，并作为压力反应的一部分参与促进唤醒。我们的指导性假设是，慢性大麻素管理的结果在一个增强的去甲肾上腺素能系统，可能有助于情感障碍的病理生理。所提出的目标，它集成了神经解剖学，神经化学和行为的方法，承诺进一步了解大麻素受体调制的蓝斑（LC）-额叶皮层通路的细胞底物，并揭示该电路在大麻素诱导的焦虑的参与。提出了四个具体的目标，以回答以下问题：1）哪些细胞的网站介导的皮质去甲肾上腺素流出大麻素诱导？2)CB 1受体在额叶皮层和LC中的神经解剖学分布是什么？3)大麻素激动剂的重复给药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）去甲肾上腺素能损伤对大麻素诱导的焦虑有什么影响？通过实现提出的具体目标，我们将有一个坚定的理解大麻素对大脑去甲肾上腺素能功能的细胞作用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。

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.