Dopaminergic and Endocannabinoid Interactions in Nicotine Dependence

描述(由申请人提供)：吸烟仍然是一个主要的健康问题，现有的药物疗法比安慰剂只有轻微的效果。烟草烟雾最初的强化作用和持续使用可能部分是由尼古丁诱导的多巴胺释放驱动的。然而，关于用PET脑成像准确测量尼古丁诱导的多巴胺释放的能力，文献中仍然存在不一致之处。多巴胺D2/3放射性示踪剂[11C]PHNO的开发比其他多巴胺D2受体配体具有优势，因为它是一种激动剂，可以测量高亲和力、功能活性的D2受体，而不是低亲和力的D2受体。最近的研究表明，与其他的PET配体相比，这能提高测量突触多巴胺水平变化的灵敏度，从而为研究尼古丁诱导的多巴胺释放提供了一种新的范式。此外，大麻素受体拮抗剂利莫那班在临床前和临床上都显示出作为戒烟药物的前景。研究多巴胺能系统和内源性大麻素系统之间的关系，对于扩大我们对烟草依赖的理解，并利用这种关系的知识开发新的药物疗法至关重要。为了开始解决这种关系，我们提出了以下目标。在目标1中，我们建议使用激动剂放射性示踪剂[11C]PHNO和PET脑成像来检测尼古丁诱导的多巴胺释放。具体地说，6个非人类灵长类动物将参与[11C]PHNO PET扫描，在扫描中，他们将被注射尼古丁(0.06 mg/kg，IV)，并将测量多巴胺的释放。我们假设尼古丁将导致显著的多巴胺释放，例如，等于或大于10%的配体结合变化。在目标2中，我们建议使用CB1受体拮抗剂利莫那班来阻断尼古丁对多巴胺释放的影响。来自AIM 1的相同的6个非人类灵长类动物将参加[11C]PHNO PET扫描，在扫描中，他们首先被给予利莫那班(1 mg/kg，IV)，然后被注射尼古丁(0.06 mg/kg，IV)。我们假设利莫那班将完全阻断(例如，大约80%)尼古丁诱导的多巴胺释放。这项研究的发现将促进对烟草吸烟背后的神经化学机制的理解。拟议中的实验将通过描绘一种可能对戒烟有用的药物背后的大脑机制，直接影响公众健康。公共卫生相关性：拟议的实验将通过开发一种新的范式来研究尼古丁在体内诱导的多巴胺释放，从而直接影响公共健康。这些研究将检查尼古丁和治疗药物利莫那班在大脑中的影响，以确定这些药物对大脑化学的相互作用。这些研究最终将为如何更有效地治疗吸烟提供信息。

DESCRIPTION (provided by applicant): Tobacco smoking continues to be a major health problem, and existing pharmacotherapies have only modest effects over placebo. The initial reinforcing effects and continued use of tobacco smoke are likely driven in part by nicotine-induced dopamine release. However, there remains inconsistency in the literature regarding the ability to accurately measure nicotine-induced dopamine release with PET brain imaging. The development of the dopamine D2/3 radiotracer [11C]PHNO has advantages over other dopamine D2 receptor ligands because it is an agonist and measures the high affinity, functionally active D2 receptors and not the low affinity D2 receptors. This has been recently shown to produce an increased sensitivity over other PET ligands to measure changes in synaptic dopamine levels and thus provides a novel paradigm to investigate nicotine-induced dopamine release. Additionally, rimonabant, a cannabinoid receptor antagonist, has shown promise both preclinically and clinically as a smoking cessation medication. Research investigating the relationship between the dopaminergic and endocannabinoid systems will be critical to expand our understanding of tobacco dependence, and to develop novel pharmacotherapies that utilize the knowledge of this relationship. To begin to address this relationship, we propose the following Aims. In Aim 1, we propose to examine nicotine-induced dopamine release with the agonist radiotracer [11C]PHNO and PET brain imaging. Specifically, 6 nonhuman primates will participate in [11C]PHNO PET scans in which they will be given an injection of nicotine (0.06 mg/kg, IV) and dopamine release will be measured. We hypothesize that nicotine will result in significant dopamine release, e.g., equal to or greater than a 10% change in ligand binding. In Aim 2, we propose to use the CB1 receptor antagonist, rimonabant, to block the effect of nicotine on dopamine release. The same 6 nonhuman primates from Aim 1 will participate in [11C]PHNO PET scans in which they will first be given rimonabant (1 mg/kg, IV), and then given an injection of nicotine (0.06 mg/kg, IV). We hypothesize that rimonabant will fully block (e.g., by approximately 80%) the nicotine-induced dopamine release. The findings from this study will advance the understanding of the neurochemical mechanisms that underlie tobacco smoking. The proposed experiments will directly impact public health by delineating a brain mechanism underlying a medication that may be useful in smoking cessation. PUBLIC HEALTH RELEVANCE: The proposed experiments will directly impact public health by developing a novel paradigm to investigate nicotine-induced dopamine release in vivo. These studies will examine the effects of nicotine and the treatment drug rimonabant in the brain to determine the interaction of these drugs on brain chemistry. These studies will ultimately provide information on how to more successfully treat tobacco smoking.