Nicotine modulation of fear memories and anxiety: Implications for learning and anxiety disorders

Abstract

Anxiety disorders are a group of crippling mental diseases affecting millions of Americans with a 30% lifetime prevalence and costs associated with healthcare of $42.3 billion. While anxiety disorders show high levels of co-morbidity with smoking (45.3% vs. 22.5% in healthy individuals), anxiety disorders are also more common among the smoking population (22% vs. 11.1% in the non-smoking population). Moreover, there is clear evidence that smoking modulates symptom severity in patients with anxiety disorders. In order to better understand this relationship, several animal paradigms are used to model several key symptoms of anxiety disorders; these include fear conditioning and measures of anxiety. Studies clearly demonstrate that nicotine mediates acquisition and extinction of fear as well as anxiety through the modulation of specific subtypes of nicotinic acetylcholine receptors (nAChRs) in brain regions involved in emotion processing such as the hippocampus. However, the direction of nicotine’s effects on these behaviors is determined by several factors that include the length of administration, hippocampus-dependency of the fear learning task, and source of anxiety (novelty-driven vs. social anxiety). Overall, the studies reviewed here suggest that nicotine alters behaviors related to fear and anxiety and that nicotine contributes to the development, maintenance, and reoccurrence of anxiety disorders.

Impairment of contextual fear extinction by chronic nicotine and withdrawal from chronic nicotine is associated with hippocampal nAChR upregulation

“…While the increase in nicotine consumption can be explained by its anxiolytic properties (Ericson et al, 2000; O’Neill and Brioni, 1994), there is also evidence suggesting that nicotine may aggravate PTSD symptomatology as studies found that nicotine intake increased trauma-related intrusive memories (Hawkins and Cougle, 2013) and fear response to trauma-related scripts (Calhoun et al, 2011). In line with human studies, studies using animal models of fear learning have also shown that nicotine alters fear memory (see Kutlu and Gould, 2015 for a review). These studies repeatedly demonstrated that acute nicotine selectively enhanced hippocampus-dependent forms of fear conditioning, such as contextual and trace fear conditioning, but does not affect hippocampus-independent cued fear conditioning (Gould and Wehner, 1999; Gould, 2003; Gould and Stephen Higgins, 2003; Gould and Lommock, 2003; Gould et al, 2004; Davis et al, 2005, 2006; Davis and Gould, 2006).…”

Attenuation of Compulsive-Like Behavior Through Positive Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors in Non-Induced Compulsive-Like Mice

“…In contrast, anxiogenic effects of nicotine withdrawal are enhanced by stimulation of α7 nAChRs and decreased by inhibition of these nAChRs receptors (Kutlu and Gould, 2015). Allosteric modulation of α4β2 nAChRs by dFBr did not affect anxiety-like behavior in the OF test in the BIG mice, suggesting that these nAChRs receptors may not be involved in the control of anxiety in nicotine-naïve mice.…”

Acute nicotine enhances spontaneous recovery of contextual fear and changes c-fos early gene expression in infralimbic cortex, hippocampus, and amygdala

“…In addition, there is evidence showing that acute nicotine intake increases the likelihood of intrusive traumatic memories in healthy nonsmokers (Hawkins and Cougle 2013). Moreover, evidence from multiple animal studies showed that acute nicotine enhances contextual fear learning (Gould and Higgins 2003;Gould and Lommock 2003;Davis et al 2006) and disrupts extinction of fear memories Kutlu et al 2016; for review, see Kutlu and Gould 2015). Therefore, given the higher rates of smoking initiation in PTSD patients, the period of acute nicotine intake following a traumatic event may be especially critical for the development and relapse of fear in PTSD.…”