David Janowsky:Cholinergic muscarinic mechanisms in depression and mania


David Janowsky’s comment on Hector Warnes’ reply to Samuel Gershon’s comment on his response to Janowsky’s reply to his Comment


       I very much appreciate Dr. Hector Warnes continuing to address the complexity and plethora of neurochemical changes and interactions  that  can occur as these relate to a given antidepressant, in this case  Ketamine and/or   Scopolamine.  Dr. Warnes, in an earlier iteration of this  stream  (Warnes 2020a) lists, in addition to muscarinic mechanisms to explain scopolamine’s antidepressant effects, a variety of other neurochemicals relevant to antidepressant efficacy. He lists in part the influences of the following relevant neurotransmitters and neuromodulators including BDNF, norepinephrine, dopamine, serotonin, GABA interneurons, glutamate, SERT, glycine, voltage dependent calcium channels, protein kinase A, cyclic AMP, cyclic GMP, inositol  triphosphate and diacylglyceral.

       In his more recent post (Warnes 2020b), Dr. Warnes references the 2012 Duman and Voleti  paper and asks that I comment on it.  These authors present an excellent summary of the complex  signaling pathways which may underlie the  effectiveness of rapidly acting antidepressants, i.e., specifically Ketamine.  This work is later expanded by papers by Duman (2018) and Zanos, Thompson, Duman et al. (2018)   Their perspective is in contrast to the historic tendency to link   a specific disorder to a specific neuroactive compound. Thus, initially depression was considered to be a norepinephrine disorder.  At about the same time it was hypothesized to be a serotonergic disorder,  then a dopaminergic disorder,  more recently a glutaminergic disorder and, of course, a adrenergic-cholinergic balance disorder as described  by me.   These are valid perspectives and many  significant research findings have come from the unitary one neurotransmitter/one disorder focus. However, we may be blind metaphorically to the “elephant” we are touching, seeing only the part we focus on and not integrating the various perspectives or considering different interactive possibilities.  The beauty of the Duman and Voleti  article and many more recent such articles  lies in its comprehensiveness.  It illustrates the multiple ways that  a rapidly acting antidepressant might make a cascade of biochemical changes leading to an antidepressant effect.  For this cascade the  Duman and Voleti  mention GSK3, Wnt-Fz, mTOR, BDNF, GABA interneurones, glutamate, NMDA receptors and AMPA signaling  as parts of the  neurochemical cascade which appear to be necessary for Ketamine’s and probably Scopolamine’s  antidepressant effects to occur.  Although these authors  do emphasize glutaminergic  function and NMDA receptors as an end point, they do so  in the context of a multitude of neurochemical effects.

       In this context, Dr. Warnes thinks expansively when he mentions examples of how Ketamine might affect nicotinic function  and implies that such effects may regulate  Ketamine efficacy. He mentions that “alongside the action of ketamine (a non-monoaminergic antidepressant) is a N-methyl-D- -Aspartate (NMDA) receptor antagonist which also induces cholinergic neurmodulation  via hyper polarization of nicotine acetylcholine ion channels.”

       He further  wonders if it is reasonable to suggest “that there may be a muscarine mechanism in the chronic depressive  which might be alleviated with enhancing the nicotinic pathways.” This is a very interesting idea and looks at depression from a  surprisingly unique and unstudied point of view, i.e., muscarinic-nicotinic cholinergic interactions as such. 

       Significantly, I was unable to locate any studies in which depression-relevant effects of interactions between nicotinic and muscarinic function have been studied in animal models of depression or in humans. This contrasts with the multiple studies of acetylcholine-dopamine interactions studying  the pathophysiology and treatment of CNS disorders (Lester, Rogers and Blaha 2010) nor the multitude of  nicotinic and muscarinic interaction studies explored separately with serotonin, norepinephrine, dopamine and GABA, to mention a few of the neurochemicals  studied.   It would seem logical  to expect that muscarinic and nicotinic  system interactions, with  both  stimulated by acetylcholine  and consisting of separate acetylcholine receptors,  would be linked to each other behaviorally and thus  be an area worthy of exploration.



Duman RS, Voleti B.  Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-sting agents. Trends Neurosci, 2012;35(1):47–56. 

Duman RS. Ketamine and rapid acting antidepressants: a new era in the battle against depression and suicide.   F1000Res, 2018;7:F1000 Faculty Rev-659. 

Lester DB, Rogers TD, Blaha CD.  Acetylcholine-Dopamine interactions in the Pathophysiology and Treatment of CNS Disorders.  CNS Neurosci Ther, 2010;16(3):137-62. 

Warnes H. Hector Warnes’ response to David Janowsky’s reply. David Janowsky: Cholinergic muscarinic mechanisms in depression and mania. inhn.com.controversies, February 13, 2020a. 

Warnes H. Hector Warnes’ reply to Samuel Gershon’s comment on his response to David Janowsky’s reply to his (Warnes) comment. David Janowsky: Cholinergic muscarinic mechanisms in depression and mania. inhn.com.controversies, November 26, 2020b. 

Zanos P, Thompson SM, Duman RS, Karate CA, Gould TD.  Convergent mechanisms underlying rapid antidepressants action. CNS Drugs, 2018;32(3):197-227.


April 22, 2021