Currently, it is unknown how menthol may play a role in the addiction to nicotine. Despite this, it is clear that people who smoke menthol cigarettes exhibit poorer quit rates compared to those who smoke non- menthol cigarettes. I have a unique opportunity at Caltech to gain understanding of menthol's effects as I have access to unique tools that will facilitate the in vivo characterization of menthol's effect on the addiction to nicotine. I plan to combine multiple in vivo techniques to look specifically at how menthol alters nicotine reward, dopamine release, and neurobiology. These include: 1) behavioral assays with conditioned place preference and self-administration; 2) in vivo and ex vivo voltammetry assays; 3) electrophysiology using mouse brain slices; and 4) microscopy to study changes in neurobiology. I, along with NIDA, hold a strong interest in menthol and how menthol plays a role in nicotine addiction. I have preliminary data showing that menthol enhances nicotine reward-related behavior in mice in a conditioned place preference assay. Despite this, there is much that we need to know concerning menthol. This proposal aims to address many of the concerns issued recently by NIDA concerning menthol. The assays (behavior, voltammetry, microscopy, and electrophysiology) are planned to be synergistic. Doses of nicotine and menthol found to be efficacious in behavior assays will be used in both microscopy and electrophysiology assays. Through these proposed assays, my goal is to collect data that will further the aims of NIDA by providing the basic research that will improve public health and encourage new science that will reduce tobacco dependence. To accomplish this proposed research plan, I will pursue two years of additional postdoctoral training in animal behavioral assays and fast scan cyclic voltammetry under the supervision and direction of my mentors. Henry Lester, PhD (Caltech), my primary mentor is an expert in neuroscience, neurobiology, and biophysics. Marina Picciotto, PhD (Yale) and Nii Addy, PhD (Yale) are both experts in neuropharmacology, rodent behavior, rodent genetics, and mechanisms in reward, learning, and memory. At Caltech and Yale, I will have all the necessary guidance, tools, and resources to be adequately trained in the new assays and successfully complete this project. With the skills attained from my additional training, I will transition to an academic faculty position as a independent investigator.

Public Health Relevance

Nicotine, the primary addictive component of tobacco products, is one of the most heavily used drugs of abuse in the United States. It is estimated that a third of the U.S. population uses cigarettes, cigars and or chewing tobacco products. This results in ~440,000 premature deaths each year and an annual cost of more than $75 billion in direct medical charges. Menthol is the only remaining legal cigarette flavorant; but menthol cigarettes have lower quit rates. This has suggested that menthol may enhance nicotine reward; but how this occurs is unknown. I have found that menthol enhances nicotine reward-related behavior in mice. Therefore, I aim to characterize menthol's effect on nicotine reward and dopamine release. Furthermore, I aim to characterize menthol's effect on midbrain dopamine neurons of the nigrostriatal reward pathway. This research will be of benefit to public safety as i will provide novel science that may aid the FDA in regulating menthol in tobacco products.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Sorensen, Roger
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Marshall University
Other Basic Sciences
Other Domestic Higher Education
United States
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Henderson, Brandon J; Wall, Teagan R; Henley, Beverley M et al. (2017) Menthol Enhances Nicotine Reward-Related Behavior by Potentiating Nicotine-Induced Changes in nAChR Function, nAChR Upregulation, and DA Neuron Excitability. Neuropsychopharmacology 42:2285-2291
Fox-Loe, Ashley M; Henderson, Brandon J; Richards, Christopher I (2017) Utilizing pHluorin-tagged Receptors to Monitor Subcellular Localization and Trafficking. J Vis Exp :