Nicotinic Acetylcholine Receptors As Targets for Antidepressants RD Shytle1–7, AA Silver2,3, RJ Lukas8, MB Newman1,6, DV Sheehan3,7 and PR Sanberg1–7

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Molecular Psychiatry (2002) 7, 525–535  2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp HYPOTHESIS Nicotinic acetylcholine receptors as targets for antidepressants RD Shytle1–7, AA Silver2,3, RJ Lukas8, MB Newman1,6, DV Sheehan3,7 and PR Sanberg1–7

1Center for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA; 2Center for Infant and Child Development, University of South Florida College of Medicine, Tampa, FL, USA; 3Departments of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, FL, USA; 4Neurosurgery, University of South Florida College of Medicine, Tampa, FL, USA; 5Pharmacology, University of South Florida College of Medicine, Tampa, FL, USA; 6Psychology, University of South Florida College of Medicine, Tampa, FL, USA; 7Neuroscience Program, University of South Florida College of Medicine, Tampa, FL, USA; 8Division of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA

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 contri- butions 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. Molecular Psychiatry (2002) 7, 525–535. doi:10.1038/sj.mp.4001035 Keywords: nicotinic; mechanism; antidepressant; cholinergic; depression

Introduction hypercholinergic neurotransmission, which is associated with depressed mood states, may be partially Currently accepted hypotheses regarding the etiology mediated through excessive activation of nAChR and of depression originated over 30 years ago following that the therapeutic actions of many antidepressants serendipitous clinical observations that monoamine- may be, in part, mediated through inhibition of these elevating medications improved mood in patients with receptors. depression. The pharmacological actions of these drugs formed the basis for the monoamine hypothesis of depression postulating a functional deficiency of Limitations of the monoamine deficiency monoaminergic neurotransmission in the affected hypothesis of depression brain. However, various anomalous findings and recent The hypothesis that depression is associated with a discoveries have led to consideration of alternative relative deficiency of the monoamines, norepinephrine hypotheses regarding the mechanism of action of anti- (NE) and serotonin (5-HT), which most antidepressants depressants. The purpose of the present article is to are known to elevate,1–3 continues to be widely held. highlight another apparently common pharmacological However, evidence is growing which increasingly characteristic of many antidepressant medications— exposes the limitations of this hypothesis.4 For the inhibition of nicotinic acetylcholine receptors example, cerebral spinal fluid levels of 5-HT in (nAChR). Evidence will be presented suggesting that unmedicated depressed patients have been reported to be elevated two-to-four times above levels in normal Correspondence: RD Shytle, PhD, Center for Aging and Brain controls.5 The tryptophan hydroxylase activation Repair, MDC-78, Departments of Neurosurgery, Psychiatry, and inhibitor, AGN2979, which would be expected to Neuroscience Program, University of South Florida College of reduce 5-HT levels, actually reduces depression clini- Medicine, 12901 Bruce B Downs Blvd, Tampa, FL 33613, USA. 6 E-mail: dshytleȰhsc.usf.edu cally. Moreover, the clinically effective and marketed Received 17 July 2001; revised 5 November 2001; accepted 13 antidepressant, tianeptine, enhances the reuptake of 5- November 2001 HT,7 the exact opposite effect of selective serotonin Antidepressants and nicotinic receptors RD Shytle et al 526 reuptake inhibitors (SSRIs). Finally, the potent cen- blocks the acute effects of nicotine in animals23 and is trally active monoamine reuptake inhibitor, EXP561, an effective smoking cessation drug (Zyban).27 which was predicted to be superior to imipramine pre- As shown in Table 1, the concentrations of antide- clinically, was completely devoid of clinical antidepressants that inhibit nAChRs are consistently in the pressant activity in humans.8 These findings do not low micromolar range as reported from different lab- support the hypothesis that depression is caused only oratories employing different methodological by a deficiency of monoamines, in particular serotonin. approaches. While the prominent monoaminergic In fact, some have even argued that enhanced NE and effects of these drugs occur at much lower concen- 5-HT levels induced by antidepressants may be respon- trations, it has been argued that concentrations sible for their delayed onset of action, sexual dysfunc- required to inhibit nAChRs are comparable to the anti- tion, and tendency to produce mania in patients pre- depressant concentrations accumulated in the brain at disposed to bipolarity.4 about the time that these drugs begin to be therapeuti- The anomalous findings outlined above, and the long cally active.20,21 If antidepressants reduce depression, standing recognition of the discordance between the in part, through nAChR inhibition, the question rapid monoaminergic effects of antidepressants and remains as to how this might occur. their delayed therapeutic onset of action, have led to consideration of alternative hypotheses regarding the The cholinergic-adrenergic theory of depression mechanism of action of antidepressants. For example, recent reports suggest that chronic antidepressant treat- One of the most consistent findings in neuropsychiatry ment produces neurotropic-like effects such as is that patients with depression have dysfunctional enhanced regeneration of catecholamine axon ter- neuroendocrine systems possibly resulting from pro- minals in the cerebral cortex, enhanced hippocampal longed responses to stress.28,29 The available evidence synaptic plasticity, and the attenuation of stress- suggests that acetylcholine (ACh) plays a significant induced atrophy of the hippocampal CA3 pyramidal role in mediating neuroendocrine, emotional, and neurons. These downstream neurotropic effects of anti- physiological responses to stress. For example, central depressants are thought to explain their delayed onset acetylcholine turnover is increased following stress30 of action and ultimate therapeutic actions in the treat- and ACh facilitates the release of several stress-sensi- ment of depression.9,10 Another recently proposed tive neurohormones and peptides including corticos- hypothesis maintains that therapeutic properties of terone, ACTH, and CRF.31 antidepressants are primarily mediated through inhi- The cholinergic-adrenergic theory of depression bition of neuronal potassium (K+) channels and sub- hypothesizes a balance between cholinergic and adre- sequent interference with the stress-induced activation nergic systems, suggesting that overactivity of the chol- of tryptophan hydroxylase responsible for excessive inergic system over the adrenergic system could lead elevations of 5-HT.4 While not discounting these to depressive symptoms.32 Consistent with this potentially important effects of antidepressant drugs, hypothesis, strong evidence supports the presence of it is also worthwhile to consider how other common exaggerated responses (behavioral, neurochemical, pharmacological properties of antidepressants may sleep) to cholinergic agents in affective disorder contribute to their overall therapeutic mode of action. patients relative to controls.33 For example, the indirect One such property shared by many antidepressants is ACh agonist, physostigmine, when administered to the inhibition of nAChRs. normal subjects, causes an increase in heart rate and blood pressure and produces symptoms of dysphoria, depression, anxiety, irritability, aggressiveness and Antidepressants as nicotinic acetylcholine hostility. When physostigmine was administered to receptor antagonists patients with affective disorders, the symptoms of negative affect were more pronounced and longer last- Over the past 20 years, several independent groups ing.31,34 Depression-like symptoms have also been have reported on the nAChR inhibitory actions of observed in normal subjects receiving i.v. physostig- classic tricyclic antidepressants including imipram- mine or arecoline,35,36 and physostigmine was reported ine,11–13 nortriptyline, amitriptyline,14,15 and desipram- to induce depression in a majority of euthymic bipolar ine.13,16 More recent studies have characterized newer, patients maintained on lithium.37 more selective monoamine reuptake inhibitors includ- Cholinergic hyperactivity or hypersensitivity may ing fluoxetine,17–19 sertraline, paroxetine, nefazo- also be a marker for an affective disorder or of a genetic done,20 nisoxetine, citalopram, nomifensine,21 and predisposition to develop an affective disorder.38 Using GBR-1290922 as nAChR antagonists. Perhaps one of the in vivo hydrogen magnetic resonance spectroscopy, most interesting antidepressants demonstrated to have Charles et al (1994) observed an increase in central nAChR inhibitory activity is the atypical antidepress- choline, the rate-limiting precursor to acetylcholine, in ant, bupropion.20,23,24 Bupropion is unique because it the brains of depressed patients relative to normal con- is a relatively weak reuptake inhibitor of both NE and trols.39 In addition, a recent study using similar tech- DA, with little or no direct action on serotoninergic niques found increased orbitofrontal cortex levels of neurotransmission. Moreover, like the potent nicotinic choline in depressed adolescents in comparison with receptor antagonist, mecamylamine,25,26 bupropion control subjects.40

Molecular Psychiatry Antidepressants and nicotinic receptors RD Shytle et al 527 Table 1 Inhibition of nicotinic receptor function by various antidepressants and mecamylamine*

Antidepressant Nic→NE in rat Adrenal Cell lines Oocyte model hippocampus chromifﬁn SH-SY5Y Chick TE671/RD ␣3␤4 ␣3␤2 ␣4␤2 ␣7 ␣3␤4␣5 V274T␣7 muscle mecamylamine 0.19a 0.3b 0.1e 30h 0.6i 3.6i 2.5i 6.9i bupropion 1.4f 10.5f 1.4j 1j 10j 50j amitriptyline 2c imipramine ෂ3d desipramine 0.36a ෂ3d nisoxetine 0.59a ﬂuoxetine 0.57a 2.5g 11g 2.1g citalopram 0.93a nomifensine 1.84a sertraline 3.1g 21g 3.5g paroxetine 4.9g 23g 5.6g nefazodone 8.3g 33g 9.1g venlafaxine 12g NIg 24g

␮ = → *Values are IC50sin M (Note: NI No Inhibition). ‘Nic NE in rat hippocampus’ refers to an assay determining the functional inhibition of nAChR involved with nicotine-induced norepinephrine release from rat hippocampal neurons in culture. ‘Adrenal chromifﬁn’ refers to assays assessing functional inhibition of nAChR in adrenal chromifﬁn cells. Under ‘Cell Lines’, ‘SH-SY5Y’ refers to the human neuroblastoma cell line containing ␣3, ␤4, and ␣5 nAChR subunits, ‘TE671/RD’ refers to the human clonal cell line containing muscle-type nAChRs, and ‘Chick V274T’ refers to the epithelial cell line SH-EP1 transfected to stably express a chick nAChR ␣7 subunit mutated to contain a threonine rather than valine at amino acid 274 in the second transmem- brane domain. Under ‘Oocyte model’, receptor subunits listed refer to functional human (i) and rat (j) nAChRs expressed in oocytes. Letters in superscript refer to citation number in reference section (a = 18, b = 136, c = 15, d = 13, e = 138, f = 24, g = 20, h = 137, I = 134, j = 23).136–138

The cholinergic-adrenergic theory of depression was compared to dependent smokers without a history of postulated in the 1970s and 1980s when more was major depression.47 Moreover, ex-smokers with a his- known about muscarinic than nicotinic ACh receptors. tory of depression appear to be at substantial risk for While much more is now known about nicotinic recep- the emergence of depressive symptom exacerbation, tor neuropharmacology, few attempts have been made generally within one month of smoking cessation.44,48 to adequately explain the role nicotinic receptors play In addition, clinically signiﬁcant symptoms of mania in the context of the cholinergic-adrenergic theory of and depression have been reported following smoking depression. However, it is now known that the neuro- cessation in some individuals,49 and transdermal nic- endocrine effects of physostigmine are mediated prim- otine was reported to rapidly reduce depression in arily through activation of nAChRs, not muscarinic nonsmoking depressed patients.50 These ﬁndings, receptors.41,42 In addition, studies characterizing the along with preclinical evidence that nicotine has anti- effects of smoking on mood throughout the day in nor- depressant properties in animal models of mal smokers suggest that while mood improves depression51–54 and that ‘knock-out’ mice which lack immediately after smoking, mood impairments (ie irri- the prominent ␤2-nAChR subunit are more prone to tability and depression) occur between cigarettes.43 learned helplessness,55 emphasize the strong relation- This repetitive cycle of shifting mood suggests a role ship between nicotinic receptor modulation and for nicotinic receptors in mood regulation and may mood control. partially explain the high prevalence of smoking in An unresolved problem in the established associ- patients with affective disorders.44 ation between depression and smoking is the issue of causality, since the potential for self-medication or pre- cipitation of depression on cessation is inherent in the Nicotine and depression modulating effects of nicotine and non-nicotine con- Nicotine dependence is the single most common psy- stituents of tobacco smoke on neurotransmitter sys- chiatric diagnosis in the United States, and major tems.45 While there is evidence to support the notion depression, anxiety disorders, and substance abuse are that depressed smokers self-medicate by smoking,56–58 the most prevalent psychiatric comorbid conditions other evidence suggests that smoking, particularly dur- associated with nicotine dependence.45 The prevalence ing adolescence, increases the risk of developing of nicotine dependence in patients with major depression later in life.59–61 Still, other studies have depression ranges from 50–60%.44,46 Smokers with a suggested that common genetic factors may contribute history of major depression are also two to three times to both smoking and major depression without one more likely to have failed smoking cessation attempts causing the other.62

Molecular Psychiatry Antidepressants and nicotinic receptors RD Shytle et al 528 Conflicting evidence regarding the relationship descending innervation to the brain stem. Overall, a between nicotine and mood control might be explained relatively few cholinergic neurons make spare projec- by considering nicotine’s complex neuropharmacology tions that cover broad areas. Therefore, the activity of and the distribution of nicotinic receptors in neural cir- a rather small number of cholinergic neurons can cuits regulating responses to stress, the circadian modulate relatively large neuronal systems. rhythm, and behavioral reinforcement. There also is Nicotinic acetylcholine receptors belong to a super- the possibility that nicotine exposure alters mood con- family of ligand-gated ion channels that exist in many trol circuitry in a state-dependent manner as has been different subtypes constructed from a myriad of poss- reported for other pharmacological actions of nic- ible subunit combinations.64,65 These receptors are otine.63 Thus, chronic nicotine exposure might composed of five subunits that are assembled to form enhance the risk of mood instability in those with a an ion channel, which opens when a ligand binds to a stable mood baseline or stabilize mood in individuals particular recognition site(s). While sodium and pot- with pre-existing mood instability. Figure 1 illustrates assium ions compose most of the nAChR current, cal- plausible state-dependent effects of nicotine on mood. cium 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 fea- Nicotinic acetylcholine receptors and their ture common to most families of ligand-gated ion chan- distribution nels. Eleven genes cloned from the nervous system Cholinergic neurons originate mainly in the basal fore- code for nAChR subunits, which include eight proteins brain and the diagonal band region of the reticular for- designated as alpha subunits (␣2–␣9) and three pro- mation and are known to project and innervate widely teins designated as beta subunits (␤2–␤4).65–68 Most into various regions of the brain.64,65 The cholinergic nicotinic receptors found in the nervous system require system arising from the basal forebrain makes broad at least one type of alpha and one type of beta subunit projections mainly throughout the cortex and hippo- to form functional nAChR channels. However, there campus. A second major cholinergic system arises in are homomeric nicotinic receptors that contain five the pedunculopontine tegmentum and the laterodorsal identical alpha subunits. This structural diversity pontine tegmentum, providing widespread innervation coupled with the axonal, presynaptic, and postsynap- mainly to the thalamus and midbrain areas and also tic 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 complicat- ing 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 Figure 1 State-dependent effects of nicotine. (a) Illustration 64,72 of nicotine’s state-dependent effects where the baseline mood control. Long exposures to low concentrations of state determines the affective response to nicotine. (b) Illus- agonist will favor deeper levels of desensitization, and tration of nicotine’s state-dependent therapeutic effects where this situation is often the case for smokers, who main- nicotine ultimately stabilizes mood in persons with affect- tain low concentrations of nicotine throughout the ive disorders. day.71,73–75 With this in mind, it has been proposed that

Molecular Psychiatry Antidepressants and nicotinic receptors RD Shytle et al 529 nicotine’s predominant effect on many nAChR sub- Nicotinic receptors and the mesolimbic dopamine types over time (its time-averaged effect) is that of an system antagonist.76 However, some nAChR subtypes are more resistant to desensitization than others, and there is Another role that nAChRs may play in regulating mood some evidence that certain receptor subtypes become is through modulation of midbrain dopaminergic neu- more sensitive to repeated agonist exposure.72 rons. Nicotine is the primary component of tobacco The most abundant forms of nAChR in the mam- that causes dependency, and like other addictive ␣ ␤ ␣ drugs, nicotine reinforces self-administration in animal malian brain contain either 4 and 2 subunits or 7 90,91 subunits.77,78 However, less abundant nAChR subtypes studies. Considerable evidence suggests that mid- may play disproportionate roles in some brain func- brain dopamine neurons reinforce behavior leading to tions, and there are some brain regions that have non- biologically rewarding events, but addictive drugs such ␣7 and -␣4␤2 agonist and antagonist profiles. For as nicotine can inappropriately exert a reinforcing influence by activating the mesolimbic dopamine sys- example, both medial habenula and locus coeruleus 92 neurons express nAChRs with a pharmacologic profile tem. Recent studies suggest that the same concen- that is consistent with expression of nAChR containing tration of nicotine achieved by smokers, activates and ␣ ␤ 79 ␤ desensitizes multiple nicotinic receptors, thereby mod- 3 and 4 subunits, but relatively few 2-subunits 93 are contained in medial habenular nAChRs.80 Another ulating the activity of mesolimbic dopamine neurons. example is that ␣7-containing nAChRs mediate the pre- Initial application of nicotine can increase the activity dominant nicotinic current in hippocampal neurons, of the dopaminergic neurons, which could mediate the but other nAChR responses may be attributable to ␣4␤2 reinforcing and possibly acute antidepressant aspects and ␣3␤4-containing, and other nAChRs.81,82 Nicotinic of tobacco use. Prolonged exposure to even these low receptor ␣3, ␣6 and ␤3 subunits are enriched in mid- concentrations of nicotine, however, can cause desen- brain nuclei associated with behavioral reinforce- sitization of nAChRs, which helps to explain acute tol- ment.71,73–75 erance 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 Role of nicotinic receptors and the hypothalamic- dopamine neurons. Likewise, antidepressants effective pituitary axis (HPA) for smoking cessation may be efficacious, in part, One of the most replicated findings in biological psy- through inhibiting the effects of nicotine on nAChRs chiatry is that large numbers of unmedicated depressed localized on dopaminergic neurons. In this regard, it is 29 noteworthy that bupropion (Zyban) is relatively patients exhibit HPA hyperactivity. The available ␣ ␤ evidence suggests that nAChR play important roles in selective at inhibiting 3 2-nAChRs which have been implicated in nicotine-induced dopamine release from mediating stress-related and possibly depression- 23 inducing neuroendocrine effects of ACh. For example, midbrain dopamine neurons. the nAChR antagonist, mecamylamine, has been found to block the physostigmine-induced rise in plasma Nicotinic receptors and the circadian rhythm corticosterone levels in rats.41,42 In addition, ACh- induced CRF release from the hypothalamus is Considerable evidence suggests a relationship between inhibited by nAChR blockade,83 which is consistent mood instability and disrupted circadian rhythm.94 with findings that nAChR receptors have been ident- While a role for cholinergic influences on the circadian ified presynaptically on CRF producing neuron ter- system is clear, the extent to which these influences minals.84 are mediated by nAChRs has been controversial, as Involvement of nAChR during stress is implicated by have the specific actions of nicotine and acetylcholine the observation that chronic stress causes a downregul- in the suprachiasmatic nucleus (SCN) of the hypothala- ation of nAChR in the brain.85 Direct involvement of mus.95 However, new evidence suggests a regulatory nicotinic receptor activation in contributing to the neu- role for nAChRs in both the developing and adult roendocrine responses to stress is supported by the SCN.96 For example, a recent report of a significant finding that mecamylamine abolishes the plasma increase in nAChR ␤2 subunit mRNA expression in the corticosterone response to auditory stress in rats86 and SCN during spontaneous waking and following sleep, has anxiolytic properties in animal models.87 Physio- deprivation relative to sleep, is the first demonstration logically, nicotinic receptor blockade reduces the of an activity-dependent regulation in the expression effects of stress on cardiovascular function88 and of this gene.97 Pharmacologically, nicotine is capable inhibits emotionally conditioned presser responses in of causing phase shifts in the circadian rhythms of rats. rats.89 Overall, these findings suggest that nicotine Like light and carbachol, nicotine appears to cause directly and certain stressors indirectly, via ACh, phase delays in the early subjective night and phase stimulate the hypothalamic-pituitary axis (HPA) advances in the late subjective night. Mecamylamine through activation of nAChRs. Thus, antidepressants blocks these effects of nicotine, and mecamylamine may reduce symptoms of depression, in part, through alone blocks both the phase forward and phase delay- blockade of nAChRs involved with stress-induced acti- ing effects of light on the circadian rhythm.98,99 Nic- vation of the HPA. otine’s effect on nAChRs in the SCN might also contrib-

Molecular Psychiatry Antidepressants and nicotinic receptors RD Shytle et al 530 ute to the sleep problems which have been logical property contributes to the efficacy of antide- characterized in both adolescent and adult smoking pressants. Preliminary evidence that mecamylamine, a populations.100,101 potent nicotinic receptor antagonist devoid of monoamine reuptake inhibition, may reduce depression lends some clinical support to this hypoth- Preliminary clinical findings with mecamylamine esis. With this in mind, future preclinical and clinical If antidepressants reduce depression, in part, through research is warranted to investigate the therapeutic inhibition of nAChR, then one would expect antide- potential of selective nicotinic receptor antagonists for pressant properties from a nAChR antagonist even in the treatment of mood disorders. the absence of any effects on monoamine transporter function. Indeed, preliminary evidence suggests that Limitations the potent centrally acting nAChR antagonist, mecamylamine (Inversine), which is devoid of monoamine There are several limitations to the hypothesis that reuptake inhibition, may reduce symptoms of nAChR inhibition contributes to the efficacy of many depression and mood instability in patients with com- antidepressants. First, while bupropion27 and nortrip- orbid depression and bipolar disorder.102,103 tyline,111 like mecamylamine,26 have been shown to be We have previously proposed that the therapeutic effective smoking cessation aids, clinical studies with effect of transdermal nicotine as an adjunct to neuro- other antidepressants have failed to show efficacy for leptic treatment of Tourette’s disorder104 may involve smoking cessation.112,113 One explanation for this dis- nAChR inactivation resulting from a prolonged con- crepancy is that different nAChR subtypes are involved tinuous exposure to nicotine.105 In vitro studies with with nicotine dependency and mood modulation, and nicotine71 and preliminary positive clinical obser- most antidepressants affect those involved with mood vations with mecamylamine in the clinical treatment of modulation, but only a few also affect nAChR subtypes TD patients, further support the receptor inactivation involved with nicotine dependency. Future studies hypothesis.106 Mecamylamine was originally used as a should characterize the pharmacology of antidepress- ganglionic blocker to treat hypertension with doses ants across all known nAChR subtypes and compare ranging from 25 to 90 mg day−1.107 However, more these data with antidepressant efficacy as smoking recent studies suggest that at lower doses (2.5–5mg cessation medications in order to deduce which b.i.d.), mecamylamine functions as a potent centrally subtypes might be involved with each therapeutic acting nAChR antagonist that may be useful for treating endpoint. tobacco,26 cocaine108 and alcohol dependency.109 In Second, the finding that ␤2 subunit knockout mice addition, we reported an unexpected mood stabilizing show enhanced learned helplessness55 is difficult to response to mecamylamine in two Tourette’s disorder reconcile with the hypothesis that nAChR inhibition (TD) patients who were subsequently found to have improves mood. One possibility is that normal mood comorbid bipolar disorder as defined by DSM-IV cri- states require an optimal amount of nAChR neuro- teria.102 To investigate the safety and efficacy of meca- transmission and that either too much or too little mylamine under more rigorous conditions, we recently could result in dysfunctional mood states. Moreover, conducted a multi-center double-blind placebo con- excessive rapid switching between nAChR activation trolled study of mecamylamine monotherapy in chil- and inactivation could lead to mood instability. At the dren and adolescents diagnosed with TD who suffered concentrations of antidepressants that affect nAChRs, predominately from behavioral and emotional symp- it is unlikely that complete receptor inhibition occurs, toms.110 The results indicated that mecamylamine thus, allowing for a range of necessary neurotransmis- monotherapy was well tolerated, but no more effective sion, but with reduced potential for overstimulation than placebo for the treatment of tics. However, in during stressful situations. In this regard, it is note- patients with moderate to severe TD illness severity, worthy that in the controlled mecamylamine trial for mecamylamine treatment was associated with signifi- TD, mecamylamine affected mood differently cant reductions in sudden mood changes and symp- depending on the severity of illness.110 For example, toms of depression. When treatment conditions were while those treated with mecamylamine who had mod- analyzed as a function of psychiatric comorbidity, erate to severe TD exhibited improvements in mood, patients with current major depression showed the gre- those with mild TD severity actually showed a trend atest mecamylamine-related improvements.103 In sum- toward worsening of mood and enhanced mood insta- mary, these preliminary findings with mecamylamine bility. Patients treated with placebo, however, had no support the hypothesis that antidepressants may be significant change in mood regardless of illness sever- efficacious, in part, through inhibition of nAChRs. ity.110 Similar state-dependent effects of nicotinic receptor modulating drugs are common and have been recently reviewed.114 Discussion Third, while suggestive, the clinical data regarding This paper reviews the evidence that many antide- the putative mood modulating effects of mecamylam- pressants function as nAChR antagonists at physiologi- ine remain preliminary due to the small number of cally relevant concentrations. In addition, the authors patients tested so far.102,103 Thus, further rigorous provide a working hypothesis for how this pharmaco- investigation in more diverse affective disorder popu-

Molecular Psychiatry Antidepressants and nicotinic receptors RD Shytle et al 531 lations is needed before definitive conclusions can be receptor-mediated calcium flux which would prevent drawn. In addition, it will be important to determine the sort of excessive cytotoxic activation seen, for if mecamylamine acts primarily as an antidepressant, example, when NMDA-type glutamate receptors are mood stabilizer, or both. If mecamylamine has mood overstimulated. stabilizing properties, the question remains as to why Thus, there are several concepts to ponder when established antidepressants with nAChR inhibitory choosing therapies and avenues for discovery of new properties fail to stabilize mood and in fact can precipi- antidepressant medications. There are strengths to the tate mania and induce rapid cycling in some patients monoamine hypothesis of depression in the clear and with affective disorders? One possibility is that the potent effects of antidepressant medications as inhibi- monoaminergic elevating properties of most antide- tors of monoamine uptake and in the clinical utility of pressants are responsible for the increased risk of antidepressants in therapy. Recent functional anatomic switching to mania. With this in mind, it is interesting findings point to changes in neuronal circuitry in the to note that bupropion, which is a fairly potent and etiology and in the treatment of depression, lending selective nicotinic receptor antagonist,23 having rela- support to a neural plasticity model of anxiety, tively less monoaminergic elevating effects than other depression, and their treatment. The notion of mood antidepressants, is often considered the least likely of normalization as a therapeutic goal and the established all antidepressants to precipitate mania.115,116 While efficacy of antidepressants and mood stabilizers sug- not addressed specifically in this paper, other estab- gest the existence of mood set-points that are delicately lished and putative mood stabilizers (without affected by neurochemical balance and perhaps con- enhanced monoaminergic effects) such as carbamazep- trolled and controllable via chemical inertial reels that ine, nimodipine, and diltiazem also inhibit certain allow gentle sways in mood but brace against radical nAChRs at clinically relevant concentrations.117,118 swings in emotion. The cholinergic hypothesis of One potential way that nicotinic receptor antagonists depression as elaborated here should be considered as could stabilize mood is by moderating the effects of an adjunct rather than an absolute alternative to these light on the circadian rhythm, as has been found with other ideas, in part because there are clear conjunctions mecamylamine.98,99 between it and the other ideas. For example, nAChR Fourth, as mentioned earlier, a growing body of pre- activity modulates the release of monoamines, and clinical evidence suggests that many antidepressants nAChRs are plausible targets of at least some proven have important downstream neurotropic effects, such antidepressants at clinically effective concentrations. as enhanced neurogenesis in adult rat hippocampus.119 Nicotinic receptor activity is involved not only in These findings raise the possibility that increased cell direct excitatory neurotransmission, but also in the proliferation and increased neuronal number may be a regulation of neurotransmission by modulating neuro- mechanism by which antidepressant treatment over- transmitter release and by affecting neurite outgrowth comes the stress-induced atrophy and loss of hippo- and architecture of neuronal connections.65 At the campal neurons and may contribute to the therapeutic same time, the balance between nAChR activation, actions of antidepressant treatment.9,10 The question desensitization, and persistent inactivation may be a remains as to what role inhibition of nAChR by antide- substrate for circuit and signaling stabilization, which pressants may play in contributing to these therapeutic seems to be a critical feature in the control of mood. effects of chronic antidepressant exposure? Numerous Therefore, whether or not nAChR are central to mood studies have demonstrated that compounds interacting control, they seem to contribute to it (as shown in with nAChRs have, both in vivo and in vitro, the poten- Figure 2), and consideration of their roles is likely to tial to be neuroprotective.120 Epidemiological and clini- hasten an improved understanding of mood and its cal studies suggest also a potential neuroprotective/ management. trophic role of nicotine in neurodegenerative disease, such as Alzheimer’s and Parkinson’s disease.121 Taken Future directions together experimental and clinical data largely indicate a neuroprotective/trophic role of nAChR modulation Based on the evidence in support of the hypothesis that involving mainly ␣4, ␤2- and ␣7-nAChR sub- nAChR inhibition may reduce depression and stabilize types.120,122–128 While it is clear that some level of mood, future research is clearly warranted to fully nAChR activation is required for these investigate the therapeutic potential of nicotinic recep- neuroprotective/trophic effects to occur, it is also clear tor antagonists as a novel approach to treating affective that overstimulation of certain nAChR subunits, such disorders. This would include complete profiling of all as ␣7 can lead to cytotoxicity.129,130 In fact, many of the antidepressants across all known nAChR subtypes, neuroprotective nAChR ligands, including nicotine, testing for both inhibition as well as the possibility of have been characterized as partial agonists allowing for partial agonist effects or allosteric modulation at even only a percentage of the current that would be achieved lower concentrations than previously tested. by full ACh-induced nAChR activation.130–133 There- Several lead compounds are now under active devel- fore, weak to moderate inhibitory actions of antide- opment including an isomer of mecamylamine with pressants at nAChRs under hypercholinergic con- prolonged inhibitory properties at human nAChRs and ditions might result in significantly improved steady- potentially fewer side-effects,134 as well as third gener- state nAChR activation, while limiting the amount of ation compounds with very selective and potent

Molecular Psychiatry Antidepressants and nicotinic receptors RD Shytle et al 532

Figure 2 Nicotinic receptor modulation of neural circuits regulating mood.

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