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.