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David Janowsky: Cholinergic muscarinic mechanisms in depression and mania


         Dr. Thomas Ban recently published on a portion of his 1974 book in which he discussed the role of central cholinergic mechanisms in depression (Ban 1974). He has kindly invited me to comment on what has happened with respect to this topic in the 45 years since he published his comments. The following outlines, in condensed form and in approximate chronological order, a selective update of scientific progress in this area. The studies reviewed focus primarily on muscarinic effects, with nicotinic effects to be described at a later date. Much described here is taken from two recent articles (Van Enkhuizen, Janowsky, Olivier et al. 2015; Dulawa and Janowsky 2019) which discuss the above topic in greater depth.


1.      1889-1968: Early observations of acetylcholinesterase inhibitor and cholinergic agonist effects


         In 1889 E.F. Willoughby reported in the Lancet that the cholinergic agonist pilocarpine antagonized mania. Sixty-one years later Rowntree, Nevin and Wilson (1950) studied the acetylcholinesterase inhibitor diisoflurophosphonate (DFP) and observed antimanic and mood depressing effects in manics, as well as increases in depression in depressed patients and normals. Rowntree’s group also observed that some subjects exhibited psychotic symptoms. Subsequent studies of the effects of acetylcholinesterase inhibitor insecticides and nerve agents by Gershon and Shaw (1961) and Bowers, Goodman and Sim (1964) also demonstrated that these agents caused depression and anxiety. Consistent with these findings, preclinical studies by Domino and Olds (1968) demonstrated that cholinergic agents antagonized self-stimulation activity in rats. These findings are consistent with the observations of Helmut Selbach (1961), as described by Dr. Ban (1974), in which trophotropic (i.e., parasympathetic) predominance over ergotropic (i.e., sympathetic) influences were postulated to occur in depression and the anticholinergic effects of imipramine would shift mood to an ergotropic predominance thus alleviating depression.


2. 1972-1974: The adrenergic cholinergic balance hypothesis of mood disorders was proposed and explored


         The adrenergic-cholinergic balance hypothesis of mood disorders, in which an imbalance of too much acetylcholine activity relative to too little adrenergic (and/or dopaminergic) activity is thought to cause depression, and mania is caused by the converse was proposed by Janowsky, El-Yousef, Davis and Sekerke  (1972). This hypothesis was based largely on observations demonstrating that infusions of the short-acting and reversible acetylcholinesterase inhibitor, physostigmine, rapidly caused depression and anergia in patients with major depression and in depressed bipolar patients; it also dramatically reversed manic symptoms in patients who were in a manic state (Janowsky, El-Yousef, Davis and Sekerke 1973; Janowsky, El-Yousef and Davis 1974). Furthermore, a combination of marijuana and physostigmine caused profound depression in two normal volunteers (El Yousef, Janowsky, Davis et al. 1973); this was consistent with a rodent toxicity study demonstrating synergism between physostigmine and tetrahydrocannabinol (Rosenblatt, Janowsky, Davis et al. 1972). In addition, and consistent with the adrenergic cholinergic balance hypothesis, the dopamine/norepinephrine releasing psychostimulant methylphenidate antagonized physostigmine-induced lethargy and depression in patients. Conversely, physostigmine antagonized methylphenidate-induced psychostimulation, talkativeness and euphoria (Janowsky, El-Yousef and Davis 1973); these findings were augmented by experiments in rats in which physostigmine antagonized stereotyped gnawing behavior (Janowsky, El-Yousef and Davis 1979; Fibiger, Lynch and Cooper 1971).


3. 1973-1984: Follow-up studies of cholinergic agents causing depression and antagonizing mania


         Acetylcholine agonists, including pilocarpine, oxotremorine and arecoline (Carroll, Frazer, Schless and Mendels 1973; Davis, Berger, Hollister and Defraites 1978; Davis, Hollander, Davidson et al. 1987;) and acetylcholine precursors, including lecithin, deanol and choline (Tamminga, Smith, Change et al. 1976; Bajada 1982; Growden, Hirsch, Wurtman and Wiener 1977; Casey 1979), induced anxiety and depression in depressed and bipolar patients and antagonized mania in manics (Davis Berger, Hollister and Defraites 1978; Carroll, Frazer, Schless and Mendels 1973). In addition, exaggerated increases in depression were noted in patients suffering from depression or a history of depression (Janowsky, Risch, Parker et al. 1980) in contrast to more muted effects in subjects without a history of depression, findings suggesting cholinergic supersensitivity in patients with a history of a mood disorder.


4. 1973-1986: Mood depressant, cardiovascular and neuroendocrine effects of cholinomimetic drugs are due to increases in muscarinic activity and to central nervous system effects


         Depressant (anergy, sadness, negative thoughts), neuroendocrine (increases in beta endorphin, ACTH, epinephrine, cortisol), sleep (REM sleep changes) and cardiovascular changes (increased pulse rate and blood pressure) caused by cholinergic drugs appear to be centrally mediated. They occur when centrally acting physostigmine or arecoline were given, whereas neostigmine, a peripherally acting acetylcholinesterase inhibitor which does not enter the brain, did not cause these effects. The above effects also were antagonized by the centrally acting anti-muscarinic agent scopolamine but not by the non-centrally acting anticholinergic agent methscopolamine, again suggesting a muscarinic centrally mediated effect (Janowsky, El-Yousef and Davis 1974; Janowsky, Risch, Kennedy et al. 1986; Krieg and Berger 1986; Sitaram, Jones, Dube et al. 1983; Sitaram, Nurnberger, Gershon and Gillin 1983).


5. 1978—2004: Cholinomimetic Drugs mimic the effects of depression on sleep parameters


         Sleep parameters observed in depressed patients (i.e., shortened REM latency, increased REM density, increased REM activity, etc.) are mimicked by acetylcholinesterase inhibitors and acetylcholine receptor agonists in normals and these effects are exaggerated in mood disorder patients and their relatives, showing concordance in twin studies (Gillin, Sutton, Ruiz et al. 1991; Berger, Lund, Bronisch and von Zerssen 1983; Berger, Riemann, Hochli and Spiegel 1989; Berkowitz, Sutton, Janowsky et al. 1990; Lauriello, Kenny, Sutton et al. 1994; Sitaram, Dube, Keshavan et al. 1987; Rao, Lutchmansingh and Poland 1999; Sitaram et al 1982; Laurer, Modell, Schreiber et al. 2004; Sitaram, Nurnberger and Gershon1980).


6. 1981-2006: Cholinomimetic drugs mimic the endocrine changes occurring in depression


         Endocrine markers occurring in depression (increased ACTH, cortisol, beta endorphin, epinephrine and dexamethasone non-suppression) are mimicked by administration of cholinomimetic agents, including the acetylcholinesterase inhibitor, physostigmine and the acetylcholine agonist arecoline. Furthermore, beta-endorphin, growth hormone and ACTH increases are exaggerated in affective disorder patients (Rubin, Abbasi, Rhodes and Czambej 2003; Rubin, Rhodes, Miller et al. 2006; Risch, Janowsky and Gillin 1983; Risch, Janowsky, Mott et al.1985; Doerr and Berger 1983; O’Keane, O’Flinn, Lucey and Dinan 1992; Stoll, Sachs, Cohen et al. 1996; Davis and Davis1980).


7. 1996-2000: Cholinergic effects on pupillary constriction are exaggerated in depressives and muted in manics


         Pupillary reactivity to the muscarinic agonist pilocarpine is increased in depressed individuals and is sub-sensitive in manic patients (Sokolski and Dement 1996, 2000). These findings are consistent with the adrenergic-cholinergic balance hypothesis.


8. 1984-present: A number of studies suggest that the behavioral manifestations of stress are mediated by an increase in central acetylcholine


         In parallel with studies of the relationship of acetylcholine to depression are studies of the relationship of stress to cholinergic mechanisms as reviewed by Janowsky and Risch (1984) and Dagyte, Den Boer and Trentani (2011). These typical stress effects include the increase in blood pressure and pulse rate, the release of cortisol, ACTH, epinephrine and beta endorphin and the inducing of anxiety and dysphoria. In addition, as reviewed in depth elsewhere (Janowsky and Risch 1984; Dagyte, Den Boer and Trentani 2011; Janowsky, Overstreet and Nurnberger 1994)), stress increases central acetylcholine levels and this increase is probably due to central effects of corticotropin releasing factor. In addition, Fernandes, Koth, Parfitt et al. (2018) found in mice that increasing cholinergic tone with physostigmine shortly before an application of stress increases the impact of the stress. These authors also found that stress related increases in acetylcholine led to depressive symptoms in rodents. Similarly, Gollan, Hongxin, Bruno et al. (2017) reported that basal forebrain mediated increases in brain CRF are associated with increased cholinergic tone and depression. Furthermore, Chen, Rada, Butzler et al. (2010) reported that corticotropin releasing factor in the nucleus accumbens shell induces depression, anxiety and anhedonia. Finally, Day, Kohl, Le Moal and Maccari (1998) found that corticotropin-releasing factor, administered centrally but not peripherally, stimulates hippocampal acetylcholine release.


9. 1993-present: Imaging studies in humans show changes in muscarinic and nicotinic cholinergic receptors


         Sophisticated imaging techniques demonstrate that the acetylcholine precursor choline is elevated in brains of depressed patients and decreases when the depression is treated with antidepressants (Charles, Lazeyras, Krishnan et al. 1993; Renshaw, Lafer, Babb et al. 1997). Also, muscarinic-2 and muscarinic-4 receptor binding is decreased in depressed patients. Depressive disorder patients also show lower Beta-2 nicotinic acetylcholine receptor activity compared to controls. Similarly, lower nicotinic Beta-2 receptors in bipolar patients were found. This lowered receptor binding has been postulated to be due to increased acetylcholine levels causing decreased (down regulated) receptor binding (Zavitsanou, Katsifis, Attner and Huang 2004; Zavitsanou, Katsifis, Yu and Huang 2005; Jeon, Gibbons and Dean 2013; Gibbons, Scarr, McLean et al. 2009; Gibbons, Jeon, Scarr and Dean 2016; Comings, Wu, Rostamkhani et al. 2002; Wang, Hinrichs, Stock et al. 2004; MacMaster and Kusumakar 2006; Riley and Renshaw, 2018; Cannon, Klaver, Gandhi et al. 2011; Hannestad, Cosgraove, DellaGloia et al. 2013; Saricicek, Esterlis, Maloney et al. 2012; Renshaw, Lafer, Babb et al. 1997; Cannon, Carson, Nugent et al. 2006; Jeon, Dean, Scarr and Gibbons 2015).


10. 2006-present. The centrally acting antimuscarinic anticholinergic agent scopolamine alleviates depression


         In 2006 investigators at the intramural program at NIMH discovered, using a double-blind cross over design, that the pan-muscarinic acetylcholine blocking agent, scopolamine (4 micrograms/ kg. IV), was effective in rapidly alleviating bipolar and unipolar depression symptoms (Furey and Drevets 2006). These results were replicated in a subsequent study (Drevets and Furey 2010). A second replication study (Park, Furey, Nugent et al. 2019), also done at the NIMH by the same group, was negative but utilized a sicker patient group. In a study performed in Iran using oral medications, scopolamine (1.0 mg PO) was found to augment the effectiveness of oral citalopram in depressed outpatients (Khajavi, Farokhnia, Modabbernia  et al. 2012).

         The major breakthrough studies showing rapidly occurring antidepressant activity for scopolamine (Furey and Drevets 2006) and for ketamine were published within months of each other in 2006, with both studies originating in the intramural program at NIMH and with an overlap of investigators occurring. The effectiveness of both drugs was similar and the experimental design was also very similar. For a number of reasons, possibly in part based on decisions concerning marketing emphasis, drug company support of studies, patent issues and the role of fads in scientific exploration, ketamine has subsequently received much more media attention and many more clinical studies and preclinical studies have evaluated ketamine than have evaluated scopolamine as an antidepressant. However, preclinical studies of scopolamine alleviating depression-like behaviors in rodents have been continuing at a rapid pace and the results virtually all demonstrate that scopolamine is an effective antidepressant agent.


11. 2011-present: Specific areas of brain regulate central cholinergic depression like symptoms in rodents and scopolamine's antidepressant effects


         Increasing central acetylcholine in specific brain areas, including the ventral tegmental area, nucleus accumbens, hippocampus and medial prefrontal cortex in mice and rats, was found to cause depression-like behaviors. These behaviors were antagonized by scopolamine, by acetylcholine knockout techniques and by fluoxetine. Fluoxetine’s ability to increase acetylcholinesterase activity, i.e. to more effectively metabolize acetylcholine, was proposed as a reason for fluoxetine’s antidepressant effects (Small, Nunes, Hughley and Addy  2016; Addy, Nunes and Wickham 2015; Chau, Rada, Kim  et al. 2011; Navarria, Wohleb, Voleti et al. 2015; Mineur, Cahuzac, Mose et al. 2018; Chau, Rada, Kosloff et al. 2001; Padua-Reis, Aquino, Olierira et al. 2017; Witkin, Overshiner, Li et al. 2014).


12. 2015-present: Scopolamine combined with certain other drugs showed increased antidepressant efficacy/synergy in animal models of depression


         Venlafaxin plus scopolamine and reboxetine plus scopolamine showed synergistic increased antidepressant effects, as did ketamine plus scopolamine and citalopram plus scopolamine. Similarly, scopolamine plus the II mGlu receptor antagonist LY341495 exerted synergistic antidepressant effects in rats and mice, thus suggesting therapeutic potential (Singh and Singh, 2015; Palucha-Poniewiera, Podkowa, Lenda and Pilc 2017; Petryshen, Lewis, Denney et al. 2016; Podkowa, Podkowa, Salat et al. 2016; Martin, Schober, Nikolayey et al. 2017).


13. 2011-present: A number of neurotransmitters and neuromodulators are necessary for scopolamine to exert antidepressant effects


         There is evidence from rat and mouse studies that other neurotransmitters and neuromodulators are necessary for scopolamine to exert its antidepressant effects. These include protein Kinase A (Dong, Zhou, Wei  et al. 2018), mTOR activation (Voleti, Navarria, Liu et al. 2013; Martin, Schober, Nikolayey et al. 2017; Liu, Banasr, Li N et al.  Terwilliger 2013), brain derived neurotrophic factor (Yu, Li, Zhou et al. 2018; Ghosal, Bange, Yue et al. 2018), monoaminergic neurotransmitters including norepinephrine (Palucha-Poniewiera, Podkowa, Lenda and Pilc 2017) and dopamine), GABA interneurons (Wohleb, Wu, Gerhard et al. 2016; Wohleb, Gerhard, Thomas and Duman 2017), mGlu7 receptor ligands (Podkowa, Podkowa, Salat et al. 2016; Podkowa, Pilc, Podkowa et al. 2018), Vesicular glutamate transporter 1, AMPAR (Yu, Li, Zhou et al. 2018; Yu, Li, Shen et al. 2018; Martin, Schober, Nikolayey et al. 2017) and voltage dependent calcium channels (Yu, Li, Zhou et al. 2018; Yu, Li, Shen et al. 2018; Yu, Lv, Shen et al. 2019). Thus, how muscarinic effects occur as they relate to downstream phenomena remains an area open for much further exploration, the results of which may give important clues as to the pathophysiology of mood disorders.


14. The cholinergic-nicotinic nervous system and affective disorders


         The role of nicotinic activity as it relates to affective disorders is not a major focus of this communication. Very few experiments have studied whether nicotine has antidepressant effects in non-smoking depressed patients (Salin-Pascual, Rosas, Jimenez-Genchi et al. 1996). Those that have done so have generally shown antidepressant effects. Stimulation of nicotinic receptors also leads to antidepressant and antianxiety effects in animal models of depression (Andreasen, Henningsen, Bate et al. 2011; Andreasen, Redrobe and Nielsen 2012; Picciotto, Lewis, van Schalkwyk and Mineur 2015; Mineur and Picciotto 2010; Mineur, Fote, Blakeman et al. 2016; Mineur, Mose, Blakeman et al. 2018; Biala, Pekala, Boguszewska-Czbara et al. 2017). For example, stimulation of alpha 7 nicotinic receptors causes antidepressant effects in animal models (Zhao, Julian, Pan et al. 2017) and when these receptors are blocked or knocked out, depression-like behaviors occur (Zhang, Liu and Zhou 2018). In addition, surprisingly few studies have explored potential interactions between muscarinic and nicotinic activity. As an exception He, Zhang, Wang et al. (2015) reported that muscarinic activation inhibits nicotinic activity in sympathetic neurons and in chromaffin cells. Given that both systems are cholinergic, studies of their interactions could yield important insights regarding pathophysiology and treatment possibilities.



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September 12, 2019