Nicotinic acetylcholine receptors as targets for antidepressants


While the monoamine deficiency hypothesis of depression is still most commonly used to explain the actions of antidepressant drugs, a growing body of evidence has accumulated that is not adequately explained by the hypothesis. This article draws attention to contributions from another apparently common pharmacological property of antidepressant medications—the inhibition of nicotinic acetylcholine receptors (nAChR). Evidence is presented suggesting the hypercholinergic neurotransmission, which is associated with depressed mood states, may be mediated through excessive neuronal nicotinic receptor activation and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors. In support of this hypothesis, preliminary evidence is presented suggesting that the potent, centrally acting nAChR antagonist, mecamylamine, which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder. If this hypothesis is supported by further preclinical and clinical research, nicotinic acetylcholine receptor antagonists may represent a novel class of therapeutic agents for treating mood disorders.


Currently accepted hypotheses regarding the etiology of depression originated over 30 years ago following serendipitous clinical observations that monoamine-elevating medications improved mood in patients with depression. The pharmacological actions of these drugs formed the basis for the monoamine hypothesis of depression postulating a functional deficiency of monoaminergic neurotransmission in the affected brain. However, various anomalous findings and recent discoveries have led to consideration of alternative hypotheses regarding the mechanism of action of antidepressants. The purpose of the present article is to highlight another apparently common pharmacological characteristic of many antidepressant medications—the inhibition of nicotinic acetylcholine receptors (nAChR). Evidence will be presented suggesting that hypercholinergic neurotransmission, which is associated with depressed mood states, may be partially mediated through excessive activation of nAChR and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors.

Limitations of the monoamine deficiency hypothesis of depression

The hypothesis that depression is associated with a relative deficiency of the monoamines, norepinephrine (NE) and serotonin (5-HT), which most antidepressants are known to elevate,1,2,3 continues to be widely held. However, evidence is growing which increasingly exposes the limitations of this hypothesis.4 For example, cerebral spinal fluid levels of 5-HT in unmedicated depressed patients have been reported to be elevated two-to-four times above levels in normal controls.5 The tryptophan hydroxylase activation inhibitor, AGN2979, which would be expected to reduce 5-HT levels, actually reduces depression clinically.6 Moreover, the clinically effective and marketed antidepressant, tianeptine, enhances the reuptake of 5-HT,7 the exact opposite effect of selective serotonin reuptake inhibitors (SSRIs). Finally, the potent centrally active monoamine reuptake inhibitor, EXP561, which was predicted to be superior to imipramine preclinically, was completely devoid of clinical antidepressant activity in humans.8 These findings do not support the hypothesis that depression is caused only by a deficiency of monoamines, in particular serotonin. In fact, some have even argued that enhanced NE and 5-HT levels induced by antidepressants may be responsible for their delayed onset of action, sexual dysfunction, and tendency to produce mania in patients predisposed to bipolarity.4

The anomalous findings outlined above, and the long standing recognition of the discordance between the rapid monoaminergic effects of antidepressants and their delayed therapeutic onset of action, have led to consideration of alternative hypotheses regarding the mechanism of action of antidepressants. For example, recent reports suggest that chronic antidepressant treatment produces neurotropic-like effects such as enhanced regeneration of catecholamine axon terminals in the cerebral cortex, enhanced hippocampal synaptic plasticity, and the attenuation of stress-induced atrophy of the hippocampal CA3 pyramidal neurons. These downstream neurotropic effects of antidepressants are thought to explain their delayed onset of action and ultimate therapeutic actions in the treatment of depression.9,10 Another recently proposed hypothesis maintains that therapeutic properties of antidepressants are primarily mediated through inhibition of neuronal potassium (K+) channels and subsequent interference with the stress-induced activation of tryptophan hydroxylase responsible for excessive elevations of 5-HT.4 While not discounting these potentially important effects of antidepressant drugs, it is also worthwhile to consider how other common pharmacological properties of antidepressants may contribute to their overall therapeutic mode of action. One such property shared by many antidepressants is the inhibition of nAChRs.

Antidepressants as nicotinic acetylcholine receptor antagonists

Over the past 20 years, several independent groups have reported on the nAChR inhibitory actions of classic tricyclic antidepressants including imipramine,11,12,13 nortriptyline, amitriptyline,14,15 and desipramine.13,16 More recent studies have characterized newer, more selective monoamine reuptake inhibitors including fluoxetine,17,18,19 sertraline, paroxetine, nefazodone,20 nisoxetine, citalopram, nomifensine,21 and GBR-1290922 as nAChR antagonists. Perhaps one of the most interesting antidepressants demonstrated to have nAChR inhibitory activity is the atypical antidepressant, bupropion.20,23,24 Bupropion is unique because it is a relatively weak reuptake inhibitor of both NE and DA, with little or no direct action on serotoninergic neurotransmission. Moreover, like the potent nicotinic receptor antagonist, mecamylamine,25,26 bupropion blocks the acute effects of nicotine in animals23 and is an effective smoking cessation drug (Zyban®).27

As shown in Table 1, the concentrations of antidepressants that inhibit nAChRs are consistently in the low micromolar range as reported from different laboratories employing different methodological approaches. While the prominent monoaminergic effects of these drugs occur at much lower concentrations, it has been argued that concentrations required to inhibit nAChRs are comparable to the antidepressant concentrations accumulated in the brain at about the time that these drugs begin to be therapeutically active.20,21 If antidepressants reduce depression, in part, through nAChR inhibition, the question remains as to how this might occur.

Table 1 Inhibition of nicotinic receptor function by various antidepressants and mecamylamine*

The cholinergic-adrenergic theory of depression

One of the most consistent findings in neuropsychiatry is that patients with depression have dysfunctional neuroendocrine systems possibly resulting from prolonged responses to stress.28,29 The available evidence suggests that acetylcholine (ACh) plays a significant role in mediating neuroendocrine, emotional, and physiological responses to stress. For example, central acetylcholine turnover is increased following stress30 and ACh facilitates the release of several stress-sensitive neurohormones and peptides including corticosterone, ACTH, and CRF.31

The cholinergic-adrenergic theory of depression hypothesizes a balance between cholinergic and adrenergic systems, suggesting that overactivity of the cholinergic system over the adrenergic system could lead to depressive symptoms.32 Consistent with this hypothesis, strong evidence supports the presence of exaggerated responses (behavioral, neurochemical, sleep) to cholinergic agents in affective disorder patients relative to controls.33 For example, the indirect ACh agonist, physostigmine, when administered to normal subjects, causes an increase in heart rate and blood pressure and produces symptoms of dysphoria, depression, anxiety, irritability, aggressiveness and hostility. When physostigmine was administered to patients with affective disorders, the symptoms of negative affect were more pronounced and longer lasting.31,34 Depression-like symptoms have also been observed in normal subjects receiving i.v. physostigmine or arecoline,35,36 and physostigmine was reported to induce depression in a majority of euthymic bipolar patients maintained on lithium.37

Cholinergic hyperactivity or hypersensitivity may also be a marker for an affective disorder or of a genetic predisposition to develop an affective disorder.38 Using in vivo hydrogen magnetic resonance spectroscopy, Charles et al (1994) observed an increase in central choline, the rate-limiting precursor to acetylcholine, in the brains of depressed patients relative to normal controls.39 In addition, a recent study using similar techniques found increased orbitofrontal cortex levels of choline in depressed adolescents in comparison with control subjects.40

The cholinergic-adrenergic theory of depression was postulated in the 1970s and 1980s when more was known about muscarinic than nicotinic ACh receptors. While much more is now known about nicotinic receptor neuropharmacology, few attempts have been made to adequately explain the role nicotinic receptors play in the context of the cholinergic-adrenergic theory of depression. However, it is now known that the neuroendocrine effects of physostigmine are mediated primarily through activation of nAChRs, not muscarinic receptors.41,42 In addition, studies characterizing the effects of smoking on mood throughout the day in normal smokers suggest that while mood improves immediately after smoking, mood impairments (ie irritability and depression) occur between cigarettes.43 This repetitive cycle of shifting mood suggests a role for nicotinic receptors in mood regulation and may partially explain the high prevalence of smoking in patients with affective disorders.44

Nicotine and depression

Nicotine dependence is the single most common psychiatric diagnosis in the United States, and major depression, anxiety disorders, and substance abuse are the most prevalent psychiatric comorbid conditions associated with nicotine dependence.45 The prevalence of nicotine dependence in patients with major depression ranges from 50–60%.44,46 Smokers with a history of major depression are also two to three times more likely to have failed smoking cessation attempts compared to dependent smokers without a history of major depression.47 Moreover, ex-smokers with a history of depression appear to be at substantial risk for the emergence of depressive symptom exacerbation, generally within one month of smoking cessation.44,48 In addition, clinically significant symptoms of mania and depression have been reported following smoking cessation in some individuals,49 and transdermal nicotine was reported to rapidly reduce depression in nonsmoking depressed patients.50 These findings, along with preclinical evidence that nicotine has antidepressant properties in animal models of depression51,52,53,54 and that ‘knock-out’ mice which lack the prominent β2-nAChR subunit are more prone to learned helplessness,55 emphasize the strong relationship between nicotinic receptor modulation and mood control.

An unresolved problem in the established association between depression and smoking is the issue of causality, since the potential for self-medication or precipitation of depression on cessation is inherent in the modulating effects of nicotine and non-nicotine constituents of tobacco smoke on neurotransmitter systems.45 While there is evidence to support the notion that depressed smokers self-medicate by smoking,56,57,58 other evidence suggests that smoking, particularly during adolescence, increases the risk of developing depression later in life.59,60,61 Still, other studies have suggested that common genetic factors may contribute to both smoking and major depression without one causing the other.62

Conflicting evidence regarding the relationship between nicotine and mood control might be explained by considering nicotine's complex neuropharmacology and the distribution of nicotinic receptors in neural circuits regulating responses to stress, the circadian rhythm, and behavioral reinforcement. There also is the possibility that nicotine exposure alters mood control circuitry in a state-dependent manner as has been reported for other pharmacological actions of nicotine.63 Thus, chronic nicotine exposure might enhance the risk of mood instability in those with a stable mood baseline or stabilize mood in individuals with pre-existing mood instability. Figure 1 illustrates plausible state-dependent effects of nicotine on mood.

Figure 1

State-dependent effects of nicotine. (a) Illustration of nicotine's state-dependent effects where the baseline mood state determines the affective response to nicotine. (b) Illustration of nicotine's state-dependent therapeutic effects where nicotine ultimately stabilizes mood in persons with affective disorders.

Nicotinic acetylcholine receptors and their distribution

Cholinergic neurons originate mainly in the basal forebrain and the diagonal band region of the reticular formation and are known to project and innervate widely into various regions of the brain.64,65 The cholinergic system arising from the basal forebrain makes broad projections mainly throughout the cortex and hippocampus. A second major cholinergic system arises in the pedunculopontine tegmentum and the laterodorsal pontine tegmentum, providing widespread innervation mainly to the thalamus and midbrain areas and also descending innervation to the brain stem. Overall, a relatively few cholinergic neurons make spare projections that cover broad areas. Therefore, the activity of a rather small number of cholinergic neurons can modulate relatively large neuronal systems.

Nicotinic acetylcholine receptors belong to a superfamily of ligand-gated ion channels that exist in many different subtypes constructed from a myriad of possible subunit combinations.64,65 These receptors are composed of five subunits that are assembled to form an ion channel, which opens when a ligand binds to a particular recognition site(s). While sodium and potassium ions compose most of the nAChR current, calcium can also make a significant contribution. The properties of a receptor can be modified depending on what subunits are included in the final receptor, a feature common to most families of ligand-gated ion channels. Eleven genes cloned from the nervous system code for nAChR subunits, which include eight proteins designated as alpha subunits (α2–α9) and three proteins designated as beta subunits (β2–β4).65,66,67,68 Most nicotinic receptors found in the nervous system require at least one type of alpha and one type of beta subunit to form functional nAChR channels. However, there are homomeric nicotinic receptors that contain five identical alpha subunits. This structural diversity coupled with the axonal, presynaptic, and postsynaptic locations of nAChRs contribute to the various roles these receptors play in both synaptic and volumetric neurotransmission throughout the central nervous system.64,69,70 Presynaptic nAChRs modulate the release of monoamines as well as GABA, glutamate, and various neuropeptides.65 These characteristics along with broad cholinergic innervation throughout the brain ensure that nAChRs are important modulators of neuronal excitability.

Nicotinic receptor activation appears to be short-lived, and time-dependent decreases in functional responsiveness to acute nicotinic agonist challenge develop with prolonged agonist exposure.64,71 A reversible (within minutes) loss of nAChR function induced after seconds-minutes of agonist exposure is termed ‘desensitization.’ More prolonged exposure to agonist can lead to more slowly reversible phases of loss of nAChR responsiveness termed ‘persistent inactivation,’ at least for some nAChR subtypes.65 These phases of desensitization and persistent inactivation add complexity to the understanding of the effects of nicotinic agonists on nAChR function and similarly complicate understanding the possible role of nicotinic receptors in the regulation of mood. Further complicating matters, degrees of nAChR activation, desensitization and persistent inactivation are subtype-, time-, and dose-dependent, reflecting both form and route of administration (bolus vs continuous), influences that make it difficult to extricate roles of nAChR in mood control.64,72 Long exposures to low concentrations of agonist will favor deeper levels of desensitization, and this situation is often the case for smokers, who maintain low concentrations of nicotine throughout the day.71,73,74,75 With this in mind, it has been proposed that nicotine's predominant effect on many nAChR subtypes over time (its time-averaged effect) is that of an antagonist.76 However, some nAChR subtypes are more resistant to desensitization than others, and there is some evidence that certain receptor subtypes become more sensitive to repeated agonist exposure.72

The most abundant forms of nAChR in the mammalian brain contain either α4 and β2 subunits or α7 subunits.77,78 However, less abundant nAChR subtypes may play disproportionate roles in some brain functions, and there are some brain regions that have non-α7 and -α4β2 agonist and antagonist profiles. For example, both medial habenula and locus coeruleus neurons express nAChRs with a pharmacologic profile that is consistent with expression of nAChR containing α3 and β4 subunits,79 but relatively few β2-subunits are contained in medial habenular nAChRs.80 Another example is that α7-containing nAChRs mediate the predominant nicotinic current in hippocampal neurons, but other nAChR responses may be attributable to α4β2 and α3β4-containing, and other nAChRs.81,82 Nicotinic receptor α3, α6 and β3 subunits are enriched in midbrain nuclei associated with behavioral reinforcement.71,73,74,75

Role of nicotinic receptors and the hypothalamic-pituitary axis (HPA)

One of the most replicated findings in biological psychiatry is that large numbers of unmedicated depressed patients exhibit HPA hyperactivity.29 The available evidence suggests that nAChR play important roles in mediating stress-related and possibly depression-inducing neuroendocrine effects of ACh. For example, the nAChR antagonist, mecamylamine, has been found to block the physostigmine-induced rise in plasma corticosterone levels in rats.41,42 In addition, ACh-induced CRF release from the hypothalamus is inhibited by nAChR blockade,83 which is consistent with findings that nAChR receptors have been identified presynaptically on CRF producing neuron terminals.84

Involvement of nAChR during stress is implicated by the observation that chronic stress causes a downregulation of nAChR in the brain.85 Direct involvement of nicotinic receptor activation in contributing to the neuroendocrine responses to stress is supported by the finding that mecamylamine abolishes the plasma corticosterone response to auditory stress in rats86 and has anxiolytic properties in animal models.87 Physiologically, nicotinic receptor blockade reduces the effects of stress on cardiovascular function88 and inhibits emotionally conditioned presser responses in rats.89 Overall, these findings suggest that nicotine directly and certain stressors indirectly, via ACh, stimulate the hypothalamic-pituitary axis (HPA) through activation of nAChRs. Thus, antidepressants may reduce symptoms of depression, in part, through blockade of nAChRs involved with stress-induced activation of the HPA.

Nicotinic receptors and the mesolimbic dopamine system

Another role that nAChRs may play in regulating mood is through modulation of midbrain dopaminergic neurons. Nicotine is the primary component of tobacco that causes dependency, and like other addictive drugs, nicotine reinforces self-administration in animal studies.90,91 Considerable evidence suggests that midbrain dopamine neurons reinforce behavior leading to biologically rewarding events, but addictive drugs such as nicotine can inappropriately exert a reinforcing influence by activating the mesolimbic dopamine system.92 Recent studies suggest that the same concentration of nicotine achieved by smokers, activates and desensitizes multiple nicotinic receptors, thereby modulating the activity of mesolimbic dopamine neurons.93 Initial application of nicotine can increase the activity of the dopaminergic neurons, which could mediate the reinforcing and possibly acute antidepressant aspects of tobacco use. Prolonged exposure to even these low concentrations of nicotine, however, can cause desensitization of nAChRs, which helps to explain acute tolerance to nicotine's effects on mood. Thus, the mood altering effects of smoking may depend, in part, on the interplay between activation and desensitization of multiple nicotinic receptors modulating midbrain dopamine neurons. Likewise, antidepressants effective for smoking cessation may be efficacious, in part, through inhibiting the effects of nicotine on nAChRs localized on dopaminergic neurons. In this regard, it is noteworthy that bupropion (Zyban®) is relatively selective at inhibiting α3β2-nAChRs which have been implicated in nicotine-induced dopamine release from midbrain dopamine neurons.23

Nicotinic receptors and the circadian rhythm

Considerable evidence suggests a relationship between mood instability and disrupted circadian rhythm.94 While a role for cholinergic influences on the circadian system is clear, the extent to which these influences are mediated by nAChRs has been controversial, as have the specific actions of nicotine and acetylcholine in the suprachiasmatic nucleus (SCN) of the hypothalamus.95 However, new evidence suggests a regulatory role for nAChRs in both the developing and adult SCN.96 For example, a recent report of a significant increase in nAChR β2 subunit mRNA expression in the SCN during spontaneous waking and following sleep, deprivation relative to sleep, is the first demonstration of an activity-dependent regulation in the expression of this gene.97 Pharmacologically, nicotine is capable of causing phase shifts in the circadian rhythms of rats. Like light and carbachol, nicotine appears to cause phase delays in the early subjective night and phase advances in the late subjective night. Mecamylamine blocks these effects of nicotine, and mecamylamine alone blocks both the phase forward and phase delaying effects of light on the circadian rhythm.98,99 Nicotine's effect on nAChRs in the SCN might also contribute to the sleep problems which have been characterized in both adolescent and adult smoking populations.100,101

Preliminary clinical findings with mecamylamine

If antidepressants reduce depression, in part, through inhibition of nAChR, then one would expect antidepressant properties from a nAChR antagonist even in the absence of any effects on monoamine transporter function. Indeed, preliminary evidence suggests that the potent centrally acting nAChR antagonist, mecamylamine (Inversine®), which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder.102,103

We have previously proposed that the therapeutic effect of transdermal nicotine as an adjunct to neuroleptic treatment of Tourette's disorder104 may involve nAChR inactivation resulting from a prolonged continuous exposure to nicotine.105 In vitro studies with nicotine71 and preliminary positive clinical observations with mecamylamine in the clinical treatment of TD patients, further support the receptor inactivation hypothesis.106 Mecamylamine was originally used as a ganglionic blocker to treat hypertension with doses ranging from 25 to 90 mg day−1.107 However, more recent studies suggest that at lower doses (2.5–5 mg b.i.d.), mecamylamine functions as a potent centrally acting nAChR antagonist that may be useful for treating tobacco,26 cocaine108 and alcohol dependency.109 In addition, we reported an unexpected mood stabilizing response to mecamylamine in two Tourette's disorder (TD) patients who were subsequently found to have comorbid bipolar disorder as defined by DSM-IV criteria.102 To investigate the safety and efficacy of mecamylamine under more rigorous conditions, we recently conducted a multi-center double-blind placebo controlled study of mecamylamine monotherapy in children and adolescents diagnosed with TD who suffered predominately from behavioral and emotional symptoms.110 The results indicated that mecamylamine monotherapy was well tolerated, but no more effective than placebo for the treatment of tics. However, in patients with moderate to severe TD illness severity, mecamylamine treatment was associated with significant reductions in sudden mood changes and symptoms of depression. When treatment conditions were analyzed as a function of psychiatric comorbidity, patients with current major depression showed the greatest mecamylamine-related improvements.103 In summary, these preliminary findings with mecamylamine support the hypothesis that antidepressants may be efficacious, in part, through inhibition of nAChRs.


This paper reviews the evidence that many antidepressants function as nAChR antagonists at physiologically relevant concentrations. In addition, the authors provide a working hypothesis for how this pharmacological property contributes to the efficacy of antidepressants. Preliminary evidence that mecamylamine, a potent nicotinic receptor antagonist devoid of monoamine reuptake inhibition, may reduce depression lends some clinical support to this hypothesis. With this in mind, future preclinical and clinical research is warranted to investigate the therapeutic potential of selective nicotinic receptor antagonists for the treatment of mood disorders.


There are several limitations to the hypothesis that nAChR inhibition contributes to the efficacy of many antidepressants. First, while bupropion27 and nortriptyline,111 like mecamylamine,26 have been shown to be effective smoking cessation aids, clinical studies with other antidepressants have failed to show efficacy for smoking cessation.112,113 One explanation for this discrepancy is that different nAChR subtypes are involved with nicotine dependency and mood modulation, and most antidepressants affect those involved with mood modulation, but only a few also affect nAChR subtypes involved with nicotine dependency. Future studies should characterize the pharmacology of antidepressants across all known nAChR subtypes and compare these data with antidepressant efficacy as smoking cessation medications in order to deduce which subtypes might be involved with each therapeutic endpoint.

Second, the finding that β2 subunit knockout mice show enhanced learned helplessness55 is difficult to reconcile with the hypothesis that nAChR inhibition improves mood. One possibility is that normal mood states require an optimal amount of nAChR neurotransmission and that either too much or too little could result in dysfunctional mood states. Moreover, excessive rapid switching between nAChR activation and inactivation could lead to mood instability. At the concentrations of antidepressants that affect nAChRs, it is unlikely that complete receptor inhibition occurs, thus, allowing for a range of necessary neurotransmission, but with reduced potential for overstimulation during stressful situations. In this regard, it is noteworthy that in the controlled mecamylamine trial for TD, mecamylamine affected mood differently depending on the severity of illness.110 For example, while those treated with mecamylamine who had moderate to severe TD exhibited improvements in mood, those with mild TD severity actually showed a trend toward worsening of mood and enhanced mood instability. Patients treated with placebo, however, had no significant change in mood regardless of illness severity.110 Similar state-dependent effects of nicotinic receptor modulating drugs are common and have been recently reviewed.114

Third, while suggestive, the clinical data regarding the putative mood modulating effects of mecamylamine remain preliminary due to the small number of patients tested so far.102,103 Thus, further rigorous investigation in more diverse affective disorder populations is needed before definitive conclusions can be drawn. In addition, it will be important to determine if mecamylamine acts primarily as an antidepressant, mood stabilizer, or both. If mecamylamine has mood stabilizing properties, the question remains as to why established antidepressants with nAChR inhibitory properties fail to stabilize mood and in fact can precipitate mania and induce rapid cycling in some patients with affective disorders? One possibility is that the monoaminergic elevating properties of most antidepressants are responsible for the increased risk of switching to mania. With this in mind, it is interesting to note that bupropion, which is a fairly potent and selective nicotinic receptor antagonist,23 having relatively less monoaminergic elevating effects than other antidepressants, is often considered the least likely of all antidepressants to precipitate mania.115,116 While not addressed specifically in this paper, other established and putative mood stabilizers (without enhanced monoaminergic effects) such as carbamazepine, nimodipine, and diltiazem also inhibit certain nAChRs at clinically relevant concentrations.117,118 One potential way that nicotinic receptor antagonists could stabilize mood is by moderating the effects of light on the circadian rhythm, as has been found with mecamylamine.98,99

Fourth, as mentioned earlier, a growing body of preclinical evidence suggests that many antidepressants have important downstream neurotropic effects, such as enhanced neurogenesis in adult rat hippocampus.119 These findings raise the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic actions of antidepressant treatment.9,10 The question remains as to what role inhibition of nAChR by antidepressants may play in contributing to these therapeutic effects of chronic antidepressant exposure? Numerous studies have demonstrated that compounds interacting with nAChRs have, both in vivo and in vitro, the potential to be neuroprotective.120 Epidemiological and clinical studies suggest also a potential neuroprotective/ trophic role of nicotine in neurodegenerative disease, such as Alzheimer's and Parkinson's disease.121 Taken together experimental and clinical data largely indicate a neuroprotective/trophic role of nAChR modulation involving mainly α4, β2- and α7-nAChR subtypes.120,122,123,124,125,126,127,128 While it is clear that some level of nAChR activation is required for these neuroprotective/trophic effects to occur, it is also clear that overstimulation of certain nAChR subunits, such as α7 can lead to cytotoxicity.129,130 In fact, many of the neuroprotective nAChR ligands, including nicotine, have been characterized as partial agonists allowing for only a percentage of the current that would be achieved by full ACh-induced nAChR activation.130,131,132,133 Therefore, weak to moderate inhibitory actions of antidepressants at nAChRs under hypercholinergic conditions might result in significantly improved steady-state nAChR activation, while limiting the amount of receptor-mediated calcium flux which would prevent the sort of excessive cytotoxic activation seen, for example, when NMDA-type glutamate receptors are overstimulated.

Thus, there are several concepts to ponder when choosing therapies and avenues for discovery of new antidepressant medications. There are strengths to the monoamine hypothesis of depression in the clear and potent effects of antidepressant medications as inhibitors of monoamine uptake and in the clinical utility of antidepressants in therapy. Recent functional anatomic findings point to changes in neuronal circuitry in the etiology and in the treatment of depression, lending support to a neural plasticity model of anxiety, depression, and their treatment. The notion of mood normalization as a therapeutic goal and the established efficacy of antidepressants and mood stabilizers suggest the existence of mood set-points that are delicately affected by neurochemical balance and perhaps controlled and controllable via chemical inertial reels that allow gentle sways in mood but brace against radical swings in emotion. The cholinergic hypothesis of depression as elaborated here should be considered as an adjunct rather than an absolute alternative to these other ideas, in part because there are clear conjunctions between it and the other ideas. For example, nAChR activity modulates the release of monoamines, and nAChRs are plausible targets of at least some proven antidepressants at clinically effective concentrations. Nicotinic receptor activity is involved not only in direct excitatory neurotransmission, but also in the regulation of neurotransmission by modulating neurotransmitter release and by affecting neurite outgrowth and architecture of neuronal connections.65 At the same time, the balance between nAChR activation, desensitization, and persistent inactivation may be a substrate for circuit and signaling stabilization, which seems to be a critical feature in the control of mood. Therefore, whether or not nAChR are central to mood control, they seem to contribute to it (as shown in Figure 2), and consideration of their roles is likely to hasten an improved understanding of mood and its management.

Figure 2

Nicotinic receptor modulation of neural circuits regulating mood.

Future directions

Based on the evidence in support of the hypothesis that nAChR inhibition may reduce depression and stabilize mood, future research is clearly warranted to fully investigate the therapeutic potential of nicotinic receptor antagonists as a novel approach to treating affective disorders. This would include complete profiling of all antidepressants across all known nAChR subtypes, testing for both inhibition as well as the possibility of partial agonist effects or allosteric modulation at even lower concentrations than previously tested.

Several lead compounds are now under active development including an isomer of mecamylamine with prolonged inhibitory properties at human nAChRs and potentially fewer side-effects,134 as well as third generation compounds with very selective and potent inhibitory properties at various nAChR subunits.135,139 Development of these compounds as smoking cessation medications followed by post-approval investigation of their mood modulating potential may be a prudent research and development model to follow.


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Shytle, R., Silver, A., Lukas, R. et al. Nicotinic acetylcholine receptors as targets for antidepressants. Mol Psychiatry 7, 525–535 (2002).

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  • nicotinic
  • mechanism
  • antidepressant
  • cholinergic
  • depression

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