Brain Region-Specific nAChR and Associated Protein Abundance Alterations Following Chronic Nicotine and/or Menthol Exposure

Abstract

The identification of biomarkers that are altered following nicotine/tobacco exposure can facilitate the investigation of tobacco-related diseases. Nicotinic acetylcholine receptors (nAChRs) are pentameric cation channels expressed in the mammalian central and peripheral nervous systems and the neuromuscular junction. Neuronal nAChR subunits (11) have been identified in mammals (α2-7, α9-10, β2-4). We examined changes in β2 nAChR subunit protein levels after chronic nicotine, (±)-menthol, or nicotine co-administered with (±)-menthol in nine murine brain regions. Our investigation of β2 nAChR subunit level changes identified the hypothalamus as a novel region of interest for menthol exposure that demonstrated increased β2 nAChR levels after (±)-*

Protein profiling in the habenula after chronic (–)‐menthol exposure in mice

“…No predetermined sample size calculation was performed. The sample size was based on previous studies of a similar nature (Alsharari et al, 2015; Mulcahy et al, 2020).…”

“…Chronic nicotine exposure up‐regulates β2* nAChRs on the subunit, receptor, and functional levels in a region‐specific manner (Govind et al, 2009; Marks et al, 2011; Mulcahy et al, 2020). Like the effects of nicotine, the effects of menthol on either receptor or subunit levels are highly CNS region‐specific and are stereoisomer specific (i.e.…”

“…Like the effects of nicotine, the effects of menthol on either receptor or subunit levels are highly CNS region‐specific and are stereoisomer specific (i.e. (+)‐menthol vs. (–)‐menthol) (Henderson et al 2018; Mulcahy et al, 2020). We previously investigated the effects of chronic nicotine, (±)‐menthol, and nicotine plus (±)‐menthol co‐application administered via osmotic minipump on β2 subunits and total membrane proteins (Mulcahy et al, 2020).…”

“…(+)‐menthol vs. (–)‐menthol) (Henderson et al 2018; Mulcahy et al, 2020). We previously investigated the effects of chronic nicotine, (±)‐menthol, and nicotine plus (±)‐menthol co‐application administered via osmotic minipump on β2 subunits and total membrane proteins (Mulcahy et al, 2020). Of the nine regions investigated, we identified two brain regions, the cortex and hypothalamus, that had altered β2 subunit levels when nicotine was co‐applied with (±)‐menthol (a model of mentholated cigarette smoke exposure) compared to nicotine alone (a model of non‐mentholated cigarette exposure).…”

Multidimensional Intersection of Nicotine, Gene Expression, and Behavior

“…For instance, menthol is a common additive found both in tobacco cigarettes and e-cigarette vape solutions. When menthol and nicotine are co-administered, a significant upregulation of α4α6β2 nAChRs is found in the VTA, substantia nigra, and hypothalamus, as compared to nicotine alone (Henderson et al, 2017 ; Mulcahy et al, 2020 ), which is positively correlated with dopaminergic neuron excitability and increased drug reward (Henderson et al, 2017 ). Therefore, a bidirectional relationship is present between behavior and gene expression, in which drug consumption causes upregulation of nAChRs, which can subsequently affect neural responsiveness in brain regions that mediate aversion or reinforcement signaling that regulate later drug intake.…”