Cholinergic transmission abnormalities associated with smoking behavior in humans

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT In recent decades, the prevalence of cigarette smoking has plummeted in the general population of the United States, but a subset of smokers has been unable to quit. As nicotine acts at receptors that form part of the brain cholinergic system, medications that modulate cholinergic receptor signaling have been developed, implemented, and shown to be efficacious for smoking cessation. Yet, little is known in human smokers about the integrity of the cholinergic system in vivo beyond postsynaptic receptor functioning, due to a lack of tools for imaging cholinergic transmission specifically. A better understanding of presynaptic cholinergic integrity could provide novel medication targets that can be used adjunctively with currently approved medications acting at postsynaptic receptors. This strategy could be especially fruitful among chronic smokers for whom available therapeutics have been insufficient to accomplish complete cessation. Here, we will use the newly-developed radiotracer [18F]VAT in conjunction with positron emission tomography (PET) to image a different molecular target, the vesicular acetylcholine transporter (VAChT); VAChT is presynaptic and specific to cholinergic vesicles, and therefore can provide a measure of cholinergic storage in terminals that directly relates to transmission. Our preliminary data demonstrate that [18F]VAT: is currently in routine use at Stony Brook University, shows initial evidence for test-retest reproducibility, and has sufficient sensitivity to detect group differences between healthy and clinical populations, including drug addiction. In this application, we satisfy the Cutting-Edge Basic Research Awards (CEBRA) criteria by testing the innovative and significant hypothesis, for which there is little available human data due to the previous unavailability of presynaptic cholinergic tracers, that smokers have lower cholinergic transmission compared with non-smokers. We will study 14 smokers and 14 matched non-smokers with [18F]VAT, and we will correlate the resulting presynaptic cholinergic integrity data, indexed as [18F]VAT total distribution volume (VT) in striatal and select prefrontal cortical regions, with the amount and speed of cigarette smoking in a laboratory self-administration paradigm, and with measures of chronic smoking severity. Results of this study will also provide the foundational data needed to take on larger smoking investigations as well as potentially apply this new tracer for use in other addictions, consistent with the goals of the CEBRA mechanism. Finally, results can potentially inform new avenues for medication development to help addicted smokers achieve lasting cigarette abstinence.