Dopaminergic and Endocannabinoid Interactions in Nicotine Dependence

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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.