Is the Antidepressant Activity of Selective Serotonin Reuptake Inhibitors Mediated by Nicotinic Acetylcholine Receptors?
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molecules Review Is the Antidepressant Activity of Selective Serotonin Reuptake Inhibitors Mediated by Nicotinic Acetylcholine Receptors? Hugo R. Arias 1,*,†, Katarzyna M. Targowska-Duda 2,†, Jesús García-Colunga 3,† and Marcelo O. Ortells 4 1 Department of Pharmacology and Physiology, Oklahoma State University College of Osteopathic Medicine, Tahlequah, OK 74464, USA 2 Department of Biopharmacy, Medical University of Lublin, 20-093 Lublin, Poland; [email protected] 3 Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Campus Juriquilla, Universidad Nacional Autónoma de México, Querétaro 76230, Mexico; [email protected] 4 Facultad de Medicina, Universidad de Morón, CONICET, Morón 1708, Argentina; [email protected] * Correspondence: [email protected]; Tel.: +1-918-525-6324; Fax: +1-918-280-2515 † These authors contributed equally to this work. Abstract: It is generally assumed that selective serotonin reuptake inhibitors (SSRIs) induce an- tidepressant activity by inhibiting serotonin (5-HT) reuptake transporters, thus elevating synaptic 5-HT levels and, finally, ameliorates depression symptoms. New evidence indicates that SSRIs may also modulate other neurotransmitter systems by inhibiting neuronal nicotinic acetylcholine receptors (nAChRs), which are recognized as important in mood regulation. There is a clear and strong association between major depression and smoking, where depressed patients smoke twice as much as the normal population. However, SSRIs are not efficient for smoking cessation therapy. In patients with major depressive disorder, there is a lower availability of functional nAChRs, although Citation: Arias, H.R.; their amount is not altered, which is possibly caused by higher endogenous ACh levels, which Targowska-Duda, K.M.; consequently induce nAChR desensitization. Other neurotransmitter systems have also emerged García-Colunga, J.; Ortells, M.O. Is as possible targets for SSRIs. Studies on dorsal raphe nucleus serotoninergic neurons support the the Antidepressant Activity of concept that SSRI-induced nAChR inhibition decreases the glutamatergic hyperstimulation observed Selective Serotonin Reuptake Inhibitors Mediated by Nicotinic in stress conditions, which compensates the excessive 5-HT overflow in these neurons and, conse- Acetylcholine Receptors? Molecules quently, ameliorates depression symptoms. At the molecular level, SSRIs inhibit different nAChR 2021, 26, 2149. https://doi.org/ subtypes by noncompetitive mechanisms, including ion channel blockade and induction of receptor 10.3390/molecules26082149 desensitization, whereas α9α10 nAChRs, which are peripherally expressed and not directly involved in depression, are inhibited by competitive mechanisms. According to the functional and structural Academic Editor: Dina Manetti results, SSRIs bind within the nAChR ion channel at high-affinity sites that are spread out between serine and valine rings. In conclusion, SSRI-induced inhibition of a variety of nAChRs expressed Received: 12 March 2021 in different neurotransmitter systems widens the complexity by which these antidepressants may Accepted: 5 April 2021 act clinically. Published: 8 April 2021 Keywords: selective serotonin reuptake inhibitors; antidepressants; nicotinic acetylcholine receptors; Publisher’s Note: MDPI stays neutral noncompetitive antagonists; neuronal pathways; molecular modeling with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Major depressive disorder (MDD), also known as clinical depression, is a neuropsychi- atric disorder characterized by depressed mood, sleep and cognitive disturbances, anxiety, Copyright: © 2021 by the authors. anhedonia or decreased interest in enjoyable activities, and suicidal thoughts, among other Licensee MDPI, Basel, Switzerland. This article is an open access article symptoms [1]. Although the etiology of MDD and related depression disorders is not fully distributed under the terms and understood, it is very complex and depends on neuronal, genetic, biological, cognitive, conditions of the Creative Commons sociocultural, and psychological aspects [2–4]. Attribution (CC BY) license (https:// Previous studies have determined that the malfunctioning of certain brain regions creativecommons.org/licenses/by/ could be one important aspect in the development of MDD [5]. The most important brain 4.0/). abnormalities associated with depression are located in the prefrontal neocortex, limbic Molecules 2021, 26, 2149. https://doi.org/10.3390/molecules26082149 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x 2 of 22 Molecules 2021, 26, 2149 2 of 21 could be one important aspect in the development of MDD [5]. The most important brain abnormalities associated with depression are located in the prefrontal neocortex, limbic system,system, basalbasal ganglia,ganglia, and brain stem stem regions. regions. In In animal animal models models of of depression depression,, as as well well as asin indepressed depressed patients, patients, the the size size and and number number of synapses of synapses are aresignificantly significantly reduced reduced in sev- in severaleral brain brain areas, areas, includin includingg the the nucleus nucleus accumbens accumbens (NAc), (NAc), amygdala, cingulate cortex,cortex, hippocampus,hippocampus, andand prefrontalprefrontal cortexcortex (PFC) (PFC) [ 2[2––44].]. SeveralSeveral hypotheses have been been described described and and proposed proposed in inorder order to toelucidate elucidate the theeti- etiologyology of ofMDD, MDD, but but each each one one includes includes various various neurotransmitter neurotransmitter systems systems [6,7].[ 6One,7]. of One the offirst the and first most and extensive most extensive depression depression hypothes hypotheseses is associated is associated with the with decrease the decrease in extra- incellular extracellular neurotransmitter neurotransmitter levels, levels,such as such serotonin as serotonin (5-HT), (5-HT), dopamine dopamine (DA), (DA),and nora- and noradrenalinedrenaline (NA) (NA) [8]. In [8 this]. In regard, this regard, substances substances that might that might elevate elevate monoamine monoamine levels levelswould wouldbe beneficial be beneficial for depression for depression treatment. treatment. Since the Since 1950s, the MDD 1950s, patients MDD patients have been have treated been treatedwith monoamine with monoamine oxidase oxidase inhibitors, inhibitors, which block which monoamine block monoamine reuptake reuptake and/or metabo- and/or metabolismlism (e.g., selegiline) (e.g., selegiline) [9,10]. Among [9,10]. monoamine Among monoamine reuptake reuptakeinhibitors inhibitors,, selective selectiveserotonin serotoninreuptake reuptakeinhibitors inhibitors (SSRIs; molecular (SSRIs; molecular structures structures are presented are presented in Figure in Figure 1) have1) have been beenclassified classified as some as some of the of most the most effective effective substances substances [7]. [7]. NH O H2N O NH F F Cl F F F F Cl Fluoxetine Nor-fluoxetine Sertraline H N F O O O O N N F Paroxetine Citalopram FigureFigure 1.1. MolecularMolecular structuresstructures ofof clinicallyclinically usedused selectiveselective serotoninserotonin reuptakereuptakeinhibitors inhibitors(SSRIs) (SSRIs)that that alsoalso inhibitinhibit variousvarious nicotinicnicotinic acetylcholineacetylcholine receptorreceptor (nAChR) (nAChR) subtypes. subtypes. The cholinergic–adrenergic hypothesis proposes that the underlying cause of depres- The cholinergic–adrenergic hypothesis proposes that the underlying cause of de- sion is an imbalance between the content of acetylcholine (ACh) and NA, producing an pression is an imbalance between the content of acetylcholine (ACh) and NA, producing overstimulation of the cholinergic system over the noradrenergic system [11]. Cholinergic an overstimulation of the cholinergic system over the noradrenergic system [11]. Cho- neurotransmission, which is mediated by muscarinic and nicotinic receptors, has been linergic neurotransmission, which is mediated by muscarinic and nicotinic receptors, has related to various neurophysiological processes, such as attention, learning and mem- been related to various neurophysiological processes, such as attention, learning and ory, mood, and appetite changes, as well as pathological conditions, including anxiety disordersmemory, mood, and MDD and appetite [12–14]. changes Higher, thanas well normal as pathological extracellular conditions, levels of including ACh and anx- its hydrolysisiety disorders metabolite, and MDD choline, [12–14]. have Higher been than observed normal in extracellular patients with levels depression of ACh [ 14and–16 its]. Moreover,hydrolysis treatmentmetabolite, with choline, physostigmine, have been anobserved acetylcholinesterase in patients with (AChE) depression inhibitor [14 that–16]. increasesMoreover, the treatment levels of synapticwith physostigmine, ACh, elicited an depression acetylcholinesterase symptoms in (AChE) humans inhibitor [17–19] andthat depression-likeincreases the levels effects of in synaptic rodents ACh, [20]. elicited depression symptoms in humans [17–19] and Mountingdepression evidence-like effects supports in rodents the view[20]. that other neurotransmitter circuits and path- waysMounting are involved evidence in the clinical supports activity the ofview SSRIs, that including other neurotransmitter those modulated bycircuits nicotinic and AChpathways receptors are (nAChRs).involved