Review
Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis

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There is a well-established connection between smoking and depression. Depressed individuals are over-represented among smokers, and ex-smokers often experience increased depressive symptoms immediately after stopping smoking. Nicotine in tobacco binds, activates and desensitizes nicotinic acetylcholine receptors (nAChRs), but it is not known whether activation or desensitization is more important for the effects of nicotine on depressive symptoms. Here we review, based on clinical and preclinical studies of nicotinic drugs, the hypothesis that blockade (rather than activation) of neuronal nAChRs might be important for the effects of nicotinic agents on depressive symptoms. The endogenous neurotransmitter for nAChRs is acetylcholine, and the effects of nicotine on depression-like behaviors support the idea that dysregulation of the cholinergic system might contribute to the etiology of major depressive disorder. Thus, pharmacological agents that limit acetylcholine signaling through neuronal nAChRs might be promising for the development of novel antidepressant medications.

Section snippets

Smoking and depression: self-medication or a vicious cycle?

The link between smoking and depression is more than just anecdotal. The connection between smoking and depression has been well established in the literature. Estimates of the prevalence of nicotine dependence in patients with major depression range from 50% to 60%, compared with ∼25% in the general population [1]. Furthermore, smokers with a history of major depression are 2–3-times more likely to have failed attempts to stop smoking compared with non-depressed smokers [2]. Smoking cessation

The hypercholinergic hypothesis of depression

The hypothesis that too much acetylcholine might lead to depression was put forward >30 years ago by Janowsky and colleagues, who suggested that depression is associated with hyperactivation of the cholinergic system and decreased activity of the noradrenergic system [14]. This hypothesis is consistent with early observations that organophosphate poisoning (which leads to profound inhibition of acetylcholinesterase (AChE) and therefore elevates acetylcholine levels throughout the brain and

Signaling through cholinergic receptors modulates the affective state

The receptors for acetylcholine can be divided into two broad classes: nAChRs and muscarinic acetylcholine receptors (mAChRs). If alterations in acetylcholine levels lead to depressive symptoms, a change in the activity of nAChRs and mAChRs is probably the mechanism transducing the altered acetylcholine signal. Authors have proposed that mAChRs are involved in mood control because scopolamine was shown to induce rapid-onset antidepressant effects in clinical trials 27, 28. In addition, mAChRs

Nicotinic blockers and partial agonists have antidepressant-like effects in animal models

If smoking relieves depressive symptoms due to desensitization of nAChRs, then it should be possible to test this by pharmacological means by determining if drugs that decrease nAChR function or interfere with acetylcholine signaling through these receptors have antidepressant effects. In support of this hypothesis, preclinical studies have demonstrated that the non-selective, non-competitive nicotinic antagonist mecamylamine (Inversine®; see Table 1 for structure) has antidepressant-like

Antidepressant effects of nicotinic blockers and partial agonists in human subjects

Mecamylamine is approved for use in human subjects and was originally used to treat hypertension. Interest in mecamylamine as a potential therapy for affective disorders was first raised when it was used in subjects with Tourette's disorder and showed significant ability to decrease depression-like symptoms in these patients 58, 59. There are now several published clinical trials of nicotinic blockers or partial agonists in human subjects with major depressive disorder. In Tourette's patients

Varenicline and suicidality

Numerous recent reports have suggested that some smokers taking varenicline experience an increase in suicidal ideation. This has led to a black box warning by the Food and Drug Administration (FDA) in the USA, and resulted in considerable concern from patients and physicians. This seems paradoxical if varenicline also has antidepressant effects [65]. A recent report on patients in primary care in the UK suggests that there was no increase in suicidal ideation in a cohort of >80,000 smokers

Augmentation strategies and future clinical practice

Studies in rodents 42, 53 and humans 62, 65 show that mecamylamine and varenicline can induce antidepressant-like effects in subjects administered an ineffective dose of a classical antidepressant such as an SSRI. In a review in 1986, Dilsaver noted that the cholinergic hypothesis should more accurately be termed the ‘cholinergic–monoaminergic interaction theory’ because manipulation of one neurotransmitter system in the brain also has extensive consequences on several other systems [72].

Activation or desensitization? An ongoing controversy in modulation of mood by smoking

Although the primary hypothesis explored in this review is that decreasing endogenous acetylcholine signaling through nAChRs can be antidepressant, whether inhibition or activation (or both) of nAChRs results in antidepressant effects is controversial. For example, mecamylamine does not show antidepressant-like properties in FSL rats and it can block the antidepressant-like effects of nicotine in the forced swim test in rats [19]. In addition, mecamylamine is used to induce withdrawal after

Conclusion

Numerous clinical and preclinical studies have established that decreasing acetylcholine transmission at specific nAChRs can positively affect mood, although the data also suggest that a fine balance between the activation and desensitization of receptors is required to yield relevant antidepressant-like effects [10]. Though the exact neurobiological basis for the antidepressant-like effects of nicotinic agents remains to be clarified, alteration of nAChR function alone or in combination with

Disclosure

The authors report that Yale University (New Haven, CT, USA) and the University of Bonn (Bonn, Germany) have a patent on novel cytisine derivatives for use as potential antidepressant medications.

Acknowledgements

This work was supported by the State of Connecticut, Department of Mental Health and Addiction Services, and National Institutes of Health grants MH77681 and DA00436.

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