Mental Illness & the Cholinergic System (5)

To read the first article in this series, click here.

To read the previous article in this series, click here.

To watch my accompanying YouTube video to this blog post, click here.

With such widespread import, it is natural that cholinergic systems play pivotal roles in cognitive disease states. Most notably, Alzheimer’s disease (AD) is characterized by the loss of basal forebrain cholinergic neurons. Since the 1990’s, the primary treatment of Alzheimer’s disease is the use of inhibitors of the acetylcholinesterase enzyme that breaks down acetylcholine in the brain[1]. But the cholinergic system is involved in more than just Alzheimer’s disease.


Although it was later overshadowed by the ‘monoamine hypothesis of depression,’ a ‘cholinergic-adrenergic theory of depression’ was first proposed to explain the cognitive mechanisms behind clinical depression in 1972[2]. It was posited that emotional affect is dependent on a balance between cholinergic and noradrenergic systems (i.e. those dependent on the neurotransmitter norepinephrine), where an overstimulation of the cholinergic system leads to depression. Since then, as understanding of the cholinergic system has progressed, academic attention has returned to the role of the cholinergic system in depression.


The administration of some acetylcholinesterase inhibitors (e.g. physostigmine), the same class of drugs used to treat Alzheimer’s (AD) patients, have been shown to induce symptoms of depression[3]. All these drugs do is limit the reuptake of acetylcholine. This implies that higher levels of acetylcholine may be causal in some forms of depression, a finding in line with the cholinergic-adrenergic theory of depression. Apparently confirming this understanding, rodent studies have shown that nicotinic cholinergic receptor (nAChR) antagonists such as mecamylamine, which block the function of the class of cholinergic receptors that respond to nicotine, produce antidepressant effects[4].

Unfortunately, neuroscience is rarely so simple. Nicotine has also been shown to increase the antidepressant effects[5] of several antidepressants, including the selective serotonin reuptake inhibitor (SSRI) fluoxetine (brand name Prozac)[6]. This apparently contradictory result – that agonists and antagonists can both produce antidepressant effects, has been explained by the desensitizing nature of nAChR agonists, where chronic exposure to agonists leads to functional nAChR antagonism[7].


But this does not appear to be the case with cholinergic neurons. While it is commonly understood that receptors downregulate in response to agonists and upregulate in response to antagonists, the nicotinic cholinergic receptors have been shown to upregulate in response to the agonist nicotine in what has been described as a paradox[8] by neuroscientists[9][10]. Moreover, cholinergic antagonists have been shown to decrease the antidepressant effects of cholinergic agonists (e.g. mecamylamine blocks the antidepressant effect of nicotine[11]).

Further confirming the cholinergic receptors’ role in depression, in mice who have had their nicotinic cholinergic α7 receptor genetically removed (called knockout or KO mice), the inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) are overexpressed, as they are in depressed patients, and the mice exhibit a depression behavioral phenotype[12].


Interestingly, many drugs of the antidepressant class have cholinergic effects. Several SSRI’s antagonize nicotinic cholinergic receptors (nAChRs), including fluvoxamine[13] and fluoxetine, which inhibits all nAChR subtypes[14]. Aside from selective serotonin reuptake inhibitors, the reuptake inhibitors of norepinephrine (e.g. reboxetine), norepinephrine and dopamine (e.g. bupropion), and norepinephrine and serotonin (e.g. amitriptyline, imipramine, and nortriptyline) antagonize the nAChRs[15]. The uncommonly prescribed but fascinating norepinephrine and serotonin reuptake inhibitor mirtazapine (brand name Remeron) inhibits both nicotinic and muscarinic receptors in muscle and neurons, and its inhibition is increased in the presence of dietary zinc[16].


For the lay reader, this discussion may appear confusing. It is meant to. Neuroscientists and cognitive psychologists are still not sure how the cholinergic system affects depression, and this thorough review of their arguments is meant to illustrate just that. Still, I have a theory that explains the apparently contradictory findings.

While high levels of acetylcholine cause depression, nicotine does the opposite. Nicotine, however, does not agonize all the cholinergic neurons, unlike acetylcholine. Its selective modulation of the receptors may be the reason for its acute antidepressant effects. Moreover, antagonism of the cholinergic receptors causes them to upregulate, because they are starved for stimulation. Paradoxically, they also upregulate from the stimulation of nicotine. Since the receptors upregulate both from nicotine’s stimulatory effects and the inhibitory effects of antagonists, the upregulation of receptors is the key driver of the chronic antidepressant effect.

From personal experience, I can tell you almost certainty that while nicotine upregulates the cholinergic receptors, acetylcholine does not. An overabundance of acetylcholine causes quick receptor downregulation. This is why having more acetylcholine in the brain (i.e. through the action of acetylcholinesterase inhibitors) can produce depressive symptoms while having more nicotine in the brain does just the opposite. Nicotine is selective in its stimulation and produces upregulation of receptors, while acetylcholine is not selective and produces downregulation of receptors. Puzzle solved.

To continue to the next blog post in this series, click here.

To return to an overview of the blog series on the cholinergic system, click here.

[1] Baxter, M. G., & Crimins, J. L. (2018). Acetylcholine Receptor Stimulation for Cognitive Enhancement: Better the Devil You Know?. Neuron, 98(6), 1064-1066. [2] Janowsky, D., Davis, J., El-Yousef, M. K., & Sekerke, H. J. (1972). A cholinergic-adrenergic hypothesis of mania and depression. The Lancet, 300(7778), 632-635. [3] Janowsky, D. S., El-Yousef, M. K., & Davis, J. M. (1974). Acetylcholine and depression. Psychosomatic medicine. [4] Andreasen, J. T., & Redrobe, J. P. (2009). Nicotine, but not mecamylamine, enhances antidepressant-like effects of citalopram and reboxetine in the mouse forced swim and tail suspension tests. Behavioural brain research, 197(1), 150-156. [5] Popik, P., Kozela, E., & Krawczyk, M. (2003). Nicotine and nicotinic receptor antagonists potentiate the antidepressant‐like effects of imipramine and citalopram. British journal of pharmacology, 139(6), 1196-1202. [6] Vazquez-Palacios, G., Bonilla-Jaime, H., & Velazquez-Moctezuma, J. (2004). Antidepressant-like effects of the acute and chronic administration of nicotine in the rat forced swimming test and its interaction with flouxetine. Pharmacology Biochemistry and Behavior, 78(1), 165-169. [7] Gentry, C. L., & Lukas, R. J. (2002). Regulation of nicotinic acetylcholine receptor numbers and function by chronic nicotine exposure. Current Drug Targets-CNS & Neurological Disorders, 1(4), 359-385. [8] Wonnacott, S. (1990). The paradox of nicotinic acetylcholine receptor upregulation by nicotine. Trends in pharmacological sciences, 11(6), 216-219. [9] Fenster, C. P., Rains, M. F., Noerager, B., Quick, M. W., & Lester, R. A. (1997). Influence of subunit composition on desensitization of neuronal acetylcholine receptors at low concentrations of nicotine. Journal of Neuroscience, 17(15), 5747-5759. [10] Picciotto, M. R., Lewis, A. S., van Schalkwyk, G. I., & Mineur, Y. S. (2015). Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states. Neuropharmacology, 96, 235-243. [11] Tizabi, Y., Overstreet, D. H., Rezvani, A. H., Louis, V. A., Clark Jr, E., Janowsky, D. S., & Kling, M. A. (1999). Antidepressant effects of nicotine in an animal model of depression. Psychopharmacology, 142(2), 193-199. [12] Zhang, J. C., Yao, W., Ren, Q., Yang, C., Dong, C., Ma, M., ... & Hashimoto, K. (2016). Depression-like phenotype by deletion of α7 nicotinic acetylcholine receptor: Role of BDNF-TrkB in nucleus accumbens. Scientific reports, 6, 36705. [13] Brindley, R. L., Bauer, M. B., Hartley, N. D., Horning, K. J., & Currie, K. P. (2017). Sigma‐1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors. Journal of neurochemistry, 143(2), 171-182. [14] García-Colunga, J., Targowska-Duda, K. M., & Arias, H. R. (2016). Functional and structural interactions between selective serotonin reuptake inhibitors and nicotinic acetylcholine receptors. Neurotransmitter, 3, e1293. [15] Laikowski, M. M., Reisdorfer, F., & Moura, S. (2019). NAChR α4β2 Subtype and their Relation with Nicotine Addiction, Cognition, Depression and Hyperactivity Disorder. Current medicinal chemistry, 26(20), 3792-3811. [16] Hernández-Abrego, A., Vázquez-Gómez, E., & García-Colunga, J. (2018). Effects of the antidepressant mirtazapine and zinc on nicotinic acetylcholine receptors. Neuroscience letters, 665, 246-251.