Cannabinoid Regulation of CB1 Receptor Function

描述（由申请人提供）：CB1受体（CB1R）介导δ 9-四氢大麻酚（THC）（大麻中的主要精神活性成分）的精神活性作用和大麻素（CB）在CNS中的治疗作用。然而，CB的治疗用途受到不期望的副作用以及长期使用的耐受性和依赖性的发展的限制。这些影响是介导的CB1R在不同的脑回路，但了解的功能神经元和原子的CB已被限制使用传统的放射自显影图像分析。慢性CB效应通过G蛋白受体激酶/β-抑制蛋白介导的CB1R与G蛋白解偶联（脱敏）和/或CB1R密度降低（下调）发生。这些适应性变化的区域在中枢神经系统方面的因素，如发展和恢复的幅度和时间过程。很少有研究调查区域特定的适应所产生的慢性管理不同的CB。此外，用内源性大麻素或稳定类似物治疗的慢性效应尚不清楚。广泛的中枢神经系统分布的CB1R和它们的不同的神经调节作用表明一个更复杂的配置文件的区域适应比以前认识到的。此外，适应的区域差异可能是由于CB1R与调节蛋白（如β-arrestin-2）的差异共定位。这些研究将检验慢性给予CB激动剂产生CB1R适应的不同区域模式的假设。此外，由于区域特异性适应依赖于与不同调控蛋白的相互作用，基于它们与CB1 R的解剖学共分布，我们假设CB1 R适应将在β-抑制蛋白-2缺失小鼠中降低。我们建议使用一种新的基于三维体素的成像分析在重建小鼠大脑中检查CB1R适应，这将提供前所未有的放射自显影数据解剖分析水平。这将在无偏倚的全脑基础上进行检查，使用激动剂刺激的[35S] GTP γ S和[3H]配体放射自显影术分别评估CB 1介导的G蛋白活性和受体。因为我们将研究CB1R在整个大脑中的适应性，并在体素水平上建立显着的变化，我们预测，我们提出的研究将提供CB1R功能的全面功能解剖学研究，这将为CB系统提供新的见解。我们预测，这些适应性也将与大麻模拟效应的耐受性的发展。 公共卫生相关性：CB在管理许多使人衰弱的医疗状况方面为公共卫生提供了潜在的治疗益处。对于对现有治疗无反应的患者，基于CB的治疗为他们的临床管理提供了替代方案。

DESCRIPTION (provided by applicant): CB1 receptors (CB1R) mediate the psychoactive effects of delta9-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana, and therapeutic effects of cannabinoids (CBs) in the CNS. However, therapeutic use of CBs is limited by undesirable side effects and development of tolerance and dependence with chronic use. These effects are mediated by CB1R in diverse brain circuits, but understanding of the functional n euro an an atomy of CBs has been limited using conventional autoradiographic image analysis. Chronic CB effects occur by G-protein receptor kinase/beta-arrestin mediated uncoupling of CB1R from Gproteins (desensitization) and/or reduction in CB1R density (downregulation). These adaptations vary regionally in the CNS with regard to factors such as magnitude and time course for development and recovery. Few studies have investigated region-specific adaption produced by chronic administration of different CBs. Moreover, the chronic effect of treatment with endocannabinoids or stable analogs is unclear. The widespread CNS distribution of CB1R and their diverse neuromodulatory roles suggest a more intricate profile of regional adaptation than previously appreciated. In addition, regional differences in adaptation likely result from differential co-localization of CB1R with regulatory proteins, such as beta-arrestin-2. These studies will test the hypothesis that chronic administration of CB agonists produces differential regional patterns of CB1R adaptation. Further, because region-specific adaptation is dependent on interaction with different regulatory proteins, based on their anatomical co-distribution with CB1 R, we hypothesize that CB1R adaptation will be decreased in Beta-arrestin-2 null mice. We propose to examine CB1R adaptation using a novel 3D voxel-based imaging analysis in reconstructed mouse brains, which will provide an unprecedented level of anatomical analysis of autoradiographic data. This will be examined on an unbiased whole-brain basis, using agonist-stimulated [35S]GTPgammaS and [3H]ligand autoradiography to assess CB1-mediated G-protein activity and receptors, respectively. Because we will investigate CB1R adaptations in the whole brain and establish significant changes at the voxel level, we predict that our proposed studies will provide a comprehensive functional anatomical study of CB1R function that will offer new insight into the CB system. We predict that these adaptations will also be associated with the development of tolerance to cannabimimetic effects. PUBLIC HEALTH RELEVANCE: CBs offer potential therapeutic benefits to public health in the management of many debilitating medical conditions. For patients who are unresponsive to existing treatments, CB-based therapy offers alternatives in their clinical management.