Multidimensional Intersection of Nicotine, Gene Expression, and Behavior

Abstract

The cholinergic system plays a crucial role in nervous system function with important effects on developmental processes, cognition, attention, motivation, reward, learning, and memory. Nicotine, the reinforcing component of tobacco and e-cigarettes, directly acts on the cholinergic system by targeting nicotinic acetylcholine receptors (nAChRs) in the brain. Activation of nAChRs leads to a multitude of immediate and long-lasting effects in specific cellular populations, thereby affecting the addictive properties of the drug. In addition to the direct actions of nicotine in binding to and opening nAChRs, the subsequent activation of circuits and downstream signaling cascades leads to a wide range of changes in gene expression, which can subsequently alter further behavioral expression. In this review, we provide an overview of the actions of nicotine that lead to changes in gene expression and further highlight evidence supporting how these changes can often be bidirectional, thereby inducing subsequent changes in behaviors associated with further drug intake.

Multifactorial Etiology of Adolescent Nicotine Addiction: A Review of the Neurobiology of Nicotine Addiction and Its Implications for Smoking Cessation Pharmacotherapy

“…The transcriptional profile associated with immune activation is significantly different in adolescent microglia as compared to adult microglia ( 148 ). Nicotine treatment showed age-dependent effects on microglial marker Iba1 expression in the NAc and BLA which are actively maturing brain region during adolescence responsible for reward ( 66 ).…”

Sex and diet-dependent gene alterations in human and rat brains with a history of nicotine exposure

“…Thus, experiencing the pleasurable effects of nicotine and avoiding withdrawal symptoms that contribute to maintained use and relapse behavior (4). Long-term nicotine use leads to gene expression alterations that promote the development of the trajectory of nicotine dependence (6). Chronic nicotine exposure also induces epigenetic modifications, including DNA methylation of several genes in different areas of the brain, such as in the medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (dLPFC), orbitofrontal cortex (OFC), and nucleus accumbens (NAc) (7).…”

“…Smoking induces DNA methylation and changes in gene expression in the brain and widespread alterations in pulmonary, cardiovascular, hepatic, and adipose tissue (12). Several studies have demonstrated that DNA methylation can be used as a predictor in human behavior for nicotine dependence, withdrawal, or relapse (6). Numerous factors affect epigenetic modifications in human smokers, including the duration of nicotine exposure, brain region, sex, and diet (6).…”

“…Several studies have demonstrated that DNA methylation can be used as a predictor in human behavior for nicotine dependence, withdrawal, or relapse (6). Numerous factors affect epigenetic modifications in human smokers, including the duration of nicotine exposure, brain region, sex, and diet (6). Chronic nicotine exposure may also alter the expression of a variety of other nicotinic acetylcholine receptors (nAChR)-interacting genes, proteins, and micro RNA (miRNA) in a sex-dependent manner (6).…”

Differential Expression Patterns of Lynx Proteins and Involvement of Lynx1 in Prepulse Inhibition

“…The cholinergic system controls a variety of complex cognitive processes, such as attention, sensorimotor gating, cognitive flexibility, reinforcement, learning, and memory ( Court et al, 1999 ; Miwa et al, 2006 , 2011 ; Tekinay et al, 2009 ; Zhang et al, 2010 ; de la Salle et al, 2013 ; Freitas et al, 2013 ; Chen et al, 2018 , 2020 ; Solari and Hangya, 2018 ; Anderson et al, 2020 ; Sherafat et al, 2021 ). Integral to the cholinergic system are the nicotinic acetylcholine receptors (nAChRs).…”