An exciting area of human health R&D for positron emission tomography (PET) is its application to the study of drug actions in humans both centrally and peripherally. During the previous grant period, the unexpected and remarkable discovery was made that cigarette smokers have lower brain monoamine oxidase (MAO) than non-smokers and former smokers, an effect not caused by nicotine. Compelled by this discovery, the applicant has expanded studies of brain MAO in smokers and initiated the development of radiotracer methods to measure peripheral MAO. Peripheral MAO levels in smokers are of relevance because MAO is a crucial enzyme for detoxifying vasoactive amines in foods or those released by many substances including nicotine. Advances in radiotracer chemistry made over the previous 26-year history of this grant will be exploited along with the ability to merge them with the unique characteristics of human PET imaging. Cigarette smoking is a massive public health problem worldwide. Yet surprisingly little is known about the pharmacologic effects of smoke on the human body, or their relationships to smoking epidemiology and to evidence that components of tobacco smoke including nicotine may be neuroprotective. Building on novel approaches to measure brain MAO and recent progress in the synthesis of radiotracers to measure brain nicotinic acetylcholine receptors (nAChR), the study of the effects of tobacco smoke in humans on these two important molecular targets is proposed. Having shown reduced brain MAO in smokers, the effects of smoking on peripheral MAO will be studied exploiting the deuterium isotope effect with [C-11]clorgyline and [C-11]L-deprenyl and deuterium substituted derivatives as radiotracers (Specific Aim 1). In order to examine the functional significance of brain MAO B inhibition is smokers, radiotracers for studying phenethylamine (PEA), an endogenous neuromodulator of dopamine and a specific MAO B substrate will be developed using [N-13]PEA to track PEA metabolism (Specific Aim 2). Finally, a safe radiotracer for examining the effects of smoking on central nAChR (the major molecular target of nicotine) in humans (Specific Aim 3) will be developed. Hypotheses to be tested are that smokers have: 1) reduced peripheral MAO; 2) reduced metabolism of PEA; and 3) elevated nAChR. New studies in the applicant's laboratory and emerging knowledge in the neurosciences support the feasibility of the proposed studies. The overarching view is that that PET, coupled with sophisticated radiotracer methods and a commitment to translating the fruits of basic radiotracer research into scientific tools for human neuroscience, is well posed to characterize the molecular targets underlying the addictive, protective, and toxic effects of tobacco smoke.
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