DaveFoster
Member
Dr. Peat has written of nicotine's neuroprotective effects. Nicotine itself inhibits Histone deacetylases (HDAC), which protects the brain from stress and can support the brain in its recovery from stress. HDAC inhibitors have been shown to oppose some of the toxic effects of nicotinic acetylcholine receptors (nAChRs) on the brain's nerves. Taking another HDAC inhibitor can actually decrease one's craving for nicotine, so a supplement like vitamin B3 (niacinamide) can aid smoking cessation.
Some brain receptors increase anxiety, such as β2 subunit containing nicotinic ACh receptors (β2*nAChRs.) Nicotine opposes β2*nAChRs in smaller amounts, but larger amounts of nicotine actually increases the number of β2*nAChRs, which can result in greater anxiety, eventually increasing anxiety past baseline levels.
In place of a multitude of smaller studies, researchers have compiled many of these findings within a single paper, which lies below as an excerpt with a link to the main article on PubMed.
Some brain receptors increase anxiety, such as β2 subunit containing nicotinic ACh receptors (β2*nAChRs.) Nicotine opposes β2*nAChRs in smaller amounts, but larger amounts of nicotine actually increases the number of β2*nAChRs, which can result in greater anxiety, eventually increasing anxiety past baseline levels.
In place of a multitude of smaller studies, researchers have compiled many of these findings within a single paper, which lies below as an excerpt with a link to the main article on PubMed.
"Preclinical studies of nicotine on mood, anxiety, and aggression-related behavioral states
i. 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 persistently desensitized in the presence of nicotine, whereas α7 nAChRs can maintain their activity (Mansvelder et al., 2002). These data suggest there is decreased ACh signaling through some nAChR subtypes during ongoing smoking, but likely to be restored and potentially increased over time (because high affinity nAChRs are upregulated by chronic nicotine use as experienced by smokers (Fenster et al., 1999) as nicotine is cleared during withdrawal. This phenomenon could also underlie the cyclical mood dysregulation experienced by smokers between smoking episodes, and could therefore perpetuate smoking behavior (Watkins et al., 2000). For example, one group has proposed that a single puff of a cigarette results in occupancy of 50% of α4β2* nAChRs for more than 3 hours, that blood levels of nicotine in a smoker would saturate almost 90% of these nAChRs for hours and that desensitization of these receptors can suppress craving (Brody et al., 2006). This could explain why nicotinic signaling has seemingly paradoxical effects: low dose chronic nicotine has a comparable effect to an antagonist of high affinity β2 subunit-containing (β2*) nAChRs in a conditioned emotional response task in mice (Anderson and Brunzell, 2012), and both nicotine and the nicotinic antagonist mecamylamine can increase serotonin release in the hippocampus (Kenny et al., 2000). Several pharmacological studies have confirmed that nicotinic blockers (antagonists or partial agonists) can alleviate depression-like behaviors in mice, either alone or in combination with monoaminergic drugs (Andreasen et al., 2009; Bacher et al., 2009; Mineur et al., 2009; Mineur et al., 2011; Rollema et al., 2009). Interestingly, commonly used antidepressants can also act as α4β2* nAChR antagonists in cell-based assays (Shytle et al., 2002; Slemmer et al., 2000), suggesting that these medications might also act in synergy with nAChR signaling to be fully effective. Rodent studies have further demonstrated that the effects of selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs) in models of depression-like behaviors can be potentiated by nAChR antagonists or partial agonists (Andreasen et al., 2009; Andreasen and Redrobe, 2009; Rollema et al., 2009), and that β2* nAChRs are required for antidepressant efficacy of at least one antidepressant medication (Caldarone et al., 2004). Conversely, mice with increased activity of α4β2* nAChRs as a result of a point mutation in the α4 subunit show increased anxiety-like behaviors (Labarca et al., 2001)."
Reference: Mood and anxiety regulation by nicotinic acetylcholine receptors: a potential pathway to modulate aggression and related behavioral statesi. 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 persistently desensitized in the presence of nicotine, whereas α7 nAChRs can maintain their activity (Mansvelder et al., 2002). These data suggest there is decreased ACh signaling through some nAChR subtypes during ongoing smoking, but likely to be restored and potentially increased over time (because high affinity nAChRs are upregulated by chronic nicotine use as experienced by smokers (Fenster et al., 1999) as nicotine is cleared during withdrawal. This phenomenon could also underlie the cyclical mood dysregulation experienced by smokers between smoking episodes, and could therefore perpetuate smoking behavior (Watkins et al., 2000). For example, one group has proposed that a single puff of a cigarette results in occupancy of 50% of α4β2* nAChRs for more than 3 hours, that blood levels of nicotine in a smoker would saturate almost 90% of these nAChRs for hours and that desensitization of these receptors can suppress craving (Brody et al., 2006). This could explain why nicotinic signaling has seemingly paradoxical effects: low dose chronic nicotine has a comparable effect to an antagonist of high affinity β2 subunit-containing (β2*) nAChRs in a conditioned emotional response task in mice (Anderson and Brunzell, 2012), and both nicotine and the nicotinic antagonist mecamylamine can increase serotonin release in the hippocampus (Kenny et al., 2000). Several pharmacological studies have confirmed that nicotinic blockers (antagonists or partial agonists) can alleviate depression-like behaviors in mice, either alone or in combination with monoaminergic drugs (Andreasen et al., 2009; Bacher et al., 2009; Mineur et al., 2009; Mineur et al., 2011; Rollema et al., 2009). Interestingly, commonly used antidepressants can also act as α4β2* nAChR antagonists in cell-based assays (Shytle et al., 2002; Slemmer et al., 2000), suggesting that these medications might also act in synergy with nAChR signaling to be fully effective. Rodent studies have further demonstrated that the effects of selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs) in models of depression-like behaviors can be potentiated by nAChR antagonists or partial agonists (Andreasen et al., 2009; Andreasen and Redrobe, 2009; Rollema et al., 2009), and that β2* nAChRs are required for antidepressant efficacy of at least one antidepressant medication (Caldarone et al., 2004). Conversely, mice with increased activity of α4β2* nAChRs as a result of a point mutation in the α4 subunit show increased anxiety-like behaviors (Labarca et al., 2001)."
