Modulation of norepinephrine by cannabinoids

说明(申请人提供)：目前已充分认识到存在内源性大麻素系统，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才刚刚开始缓慢地出现。这一信息对于了解慢性娱乐药物暴露后的细胞适应以及阐明基于大麻素的化合物的潜在治疗用途至关重要。服用大麻素受体激动剂的急性影响包括学习和记忆障碍、知觉扭曲、解决问题困难和协调能力丧失。反复给药会导致压力反应系统的激活、焦虑、抑郁、认知障碍和精神病的增加。问题仍然是大麻类物质在哪里作用于诱导细胞适应，这可能导致长期的行为障碍。我们实验室的初步数据表明，一个潜在的靶点是去甲肾上腺素能蓝斑皮质通路，这是一种参与调节高级认知功能和情绪的生物胺系统。这一系统与设置注意模式有关，并作为促进唤醒的应激反应的一部分。我们的指导性假设是，长期服用大麻素会导致去甲肾上腺素系统的增强，这可能有助于情感性障碍的病理生理学。结合神经解剖学、神经化学和行为学方法提出的AIMS，有望加深我们对蓝斑(LC)-额叶皮质通路中大麻素受体调节的细胞底物的理解，并揭示这一回路在大麻素诱导的焦虑中的参与。提出了四个具体的目标来回答以下问题：1)介导大麻素诱导的皮质去甲肾上腺素外流的细胞部位是什么？2)CB1受体在额叶皮质和LC中的神经解剖学分布是什么？3)重复使用大麻素激动剂是否会对去甲肾上腺素功能产生长期影响(通过增加酪氨酸羟基酶基因的表达和释放来检测)4)去甲肾上腺素能损害对大麻素诱导的焦虑有什么影响？通过实现所提出的特定目标，我们将对大麻素对脑去甲肾上腺素能功能的细胞作用部位以及长期暴露于大麻素对去甲肾上腺素能系统的行为后果有一个明确的了解。

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.