Invited reviewMood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states
Introduction
Nicotine consumption through tobacco products is highly co-morbid with mood disorders, including depression, anxiety and irritability; however the connection between nicotine use and behavioral regulation remains unclear and is still debated (Moylan et al., 2012). For instance, the overall incidence of smoking in depressed patients is twice as high as in the general population (Glassman et al., 1990) and the rate of smoking relapse is greater in patients with depression (Covey et al., 1998). The underlying mechanisms mediating the connection between smoking and mood alterations are not yet understood, however. Tobacco use could precipitate mood dysregulation, potentially explaining the higher incidence of depression in smokers (Boden et al., 2010); however, many studies have reported that nicotine can improve symptoms of depression under some conditions (Salin-Pascual et al., 1995, Tizabi et al., 1999). It has therefore been suggested that nicotine in tobacco is used in an effort to self-medicate symptoms of depression and other psychiatric disorders (Markou et al., 1998). In addition, smoking cessation and nicotine withdrawal can be accompanied by depressive episodes, stress-induced anger, and increased tension (al'Absi et al., 2007, Hatsukami et al., 1985). Taken together, these associations suggest that alterations in signaling through nicotinic acetylcholine receptors (nAChRs) might be involved in mood regulation. In this review we discuss potential mechanisms underlying the association between nAChRs and depression and anxiety.
Mood dysregulation, especially depressed mood and co-morbid anxiety states, is influential in regulating the constructs of aggression, irritability, and agitation, an interrelated triad we refer to as aggression-related behavioral states (ARBS). We review studies from both pre-clinical and clinical studies that demonstrate a key role for nAChRs in ARBS, and suggest that nAChR modulation of mood and/or anxiety might account, in part, for its effects on ARBS. Finally, we propose that further study at the pre-clinical and clinical levels might encourage development of novel nicotinic-based agents for treating mood dysregulation as well as ARBS.
Section snippets
Depression and anxiety
While there are variable effects of nicotinic signaling on behaviors related to depression, numerous studies suggest that decreasing activity of α4β2* nAChRs can improve symptoms of depression (for reviews see Mineur and Picciotto, 2009, Picciotto et al., 2008). Chronic nicotine exposure induces up-regulation of nAChRs, but also profound desensitization of these receptors in vitro (Fenster et al., 1997, Grady et al., 1994). Studies in slices have shown that α4β2* nAChRs can be rapidly and
Depression and anxiety
The relevance of nicotine in both depression and anxiety has been studied extensively (Laje et al., 2001, Morissette et al., 2007, Picciotto et al., 2002). Recent imaging studies have shown that availability of β2* nAChRs for tracer binding was greatly decreased in actively depressed patients but was intermediate in remitted subjects (Saricicek et al., 2012). Post-mortem studies confirmed that a higher level of acetylcholine competing for receptor binding was the likely reason for the decrease
Conclusions
The mechanisms underlying nicotinic modulation of mood and anxiety regulation are only beginning to be understood, due to the complex pharmacology of nAChRs, their broad distribution, their desensitization in response to agonists, and the multiple neural systems modulated by nAChRs. However, changes in nAChRs could provide relevant biomarkers for at least a subset of depressive symptoms, and may help with the diagnosis and characterization of the pathophysiology of depression.
Clinical
Acknowledgments
This work was supported by grants MH077681, MH19961, MH014276, DA033945 and DA14241 from the National Institutes of Health.
References (148)
- et al.
Anger and psychobiological changes during smoking abstinence and in response to acute stress: prediction of smoking relapse
Int. J. Psychophysiol.
(2007) Optogenetics, sex, and violence in the brain: implications for psychiatry
Biol. Psychiatry
(2012)- et al.
Combined alpha7 nicotinic acetylcholine receptor agonism and partial serotonin transporter inhibition produce antidepressant-like effects in the mouse forced swim and tail suspension tests: a comparison of SSR180711 and PNU-282987
Pharmacol. Biochem. Behav.
(2012) - et al.
A combined alpha7 nicotinic acetylcholine receptor agonist and monoamine reuptake inhibitor, NS9775, represents a novel profile with potential benefits in emotional and cognitive disturbances
Neuropharmacology
(2013) Cholinergic synapses in the lateral hypothalamus for the control of predatory aggression in the rat
Brain Res.
(1970)- et al.
Afferent projections to the preoptic area and hypothalamic regions in the rat brain
Neuroscience
(1981) - et al.
Effects of nicotinic and muscarinic compounds on biting attack in the cat
Pharmacol. Biochem. Behav.
(1976) - et al.
The impact of depression on smoking cessation in women
Am. J. Prev. Med.
(1996) - et al.
High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation
Biol. Psychiatry
(2004) - et al.
Adjunctive transdermal nicotine reduced behavioral agitation in severe dementia
Am. J. Geriatr. Psychiatry
(2007)