The Muscarinic Cholinergic System (9)
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While some mushrooms exhibit acetylcholinesterase inhibitory qualities, the primary involvement of mushrooms in the study of the cholinergic system has come through the study of the toxic natural compound muscarine, derived of several mushroom species, including the notorious Amanita muscaria.
THE FIRST PARASYMPATHOMIMETIC
Muscarine, the first parasympathomimetic substance ever studied, was first identified by the Germans Oswald Schmiedeberg and Richard Kroppe from the University of Dorpat in the mid-19th century. Muscarine was discovered to stimulate a set of the cholinergic receptors that then took its name. Muscarine is a stronger agonist of the muscarinic cholinergic receptors (mAChR) than acetylcholine, likely because it does not get hydrolyzed by the acetylcholinesterase enzyme in the synaptic cleft.
THE MUSCARINIC RECEPTORS
There are five mAChRs, named M1-M5, encoded by the CHRM1-CHRM5 genes, respectively. The muscarinic cholinergic receptors have both cognitive and physical roles. In respect to cognition, the M1 and M4 receptors have been identified as critical. In mice who have had genes selectively removed, called knockout mice, it has been shown that knocking out either the M1 or M4 receptors leads to cognitive deficits, while knocking out the M1 receptor also leads to hyperactive behavior. Broadly, it appears that the M1 receptor is more important to cognition than the M4 receptor.
While the M5 receptor is the only muscarinic receptor found in VTA dopaminergic neurons, the M1 receptor is expressed extensively in the hippocampus and cortex. Its cognitive effects also extend to the prevention of neurodegeneration. It has been connected to the activation of the alpha-secretase enzyme that decreases amyloid-β levels. The aggregation of amyloid-β is the better understood of the two causal reasons for the development of Alzheimer’s (the less understood cause are the tau tangles). Beyond its cognitive effects, the M1 receptor has also been shown to play a key role in liver health, where its activation can attenuate acute liver injury.
MUSCARINIC RECEPTORS AND DOPAMINE
Unfortunately (or fortunately, depending on your opinion on dopamine), animal studies have shown that agonizing the M1 and M4 receptors attenuates dopamine-dependent addictive behavior. This happens when both receptors are agonized as well as when the M1 receptor is agonized alone, though the result is more profound when the M4 receptor is included. This indicates that agonizing the M1 receptor may diminish the functional role of dopamine in the brain, in the absence of addiction. This can have profound and potentially undesirable effects on human behavior, particularly in those not suffering from pathological addictions.
To return to an overview of the blog series on the cholinergic system, click here.
 Patocka, J. (2012). Natural cholinesterase inhibitors from mushrooms. Military Medical Science Letters, 81(1), 40-44.  Schmiedeberg, O. (1869). Das Muscarin: das giftige Alkaloid des Fliegenpilzes (Agaricus muscarius L.): seine Darstellung, chemischen Eigenschaften, physiologischen Wirkungen, toxicologische Bedeutung und sein Verhältniss zur Pilzvergiftung im allgemeinen. FCW Vogel.  Dale, H. H. (1914). The action of certain esters and ethers of choline, and their relation to muscarine. Journal of Pharmacology and Experimental Therapeutics, 6(2), 147-190.  Dennis, S. H., Pasqui, F., Colvin, E. M., Sanger, H., Mogg, A. J., Felder, C. C., ... & Mellor, J. R. (2016). Activation of muscarinic M1 acetylcholine receptors induces long-term potentiation in the hippocampus. Cerebral cortex, 26(1), 414-426.  Miyakawa, T., Yamada, M., Duttaroy, A., & Wess, J. (2001). Hyperactivity and intact hippocampus-dependent learning in mice lacking the M1 muscarinic acetylcholine receptor. Journal of Neuroscience, 21(14), 5239-5250.  Anagnostaras, S. G., Murphy, G. G., Hamilton, S. E., Mitchell, S. L., Rahnama, N. P., Nathanson, N. M., & Silva, A. J. (2003). Selective cognitive dysfunction in acetylcholine M 1 muscarinic receptor mutant mice. Nature neuroscience, 6(1), 51-58.  Bonsi P, Martella G, Cuomo D, Platania P, Sciamanna G, Bernardi G, Wess J, Pisani A. Loss of muscarinic autoreceptor function impairs long-term depression but not long-term potentiation in the striatum  Vilaró, M. T., Palacios, J., & Mengod, G. (1990). Localization of m5 muscarinic receptor mRNA in rat brain examined by in situ hybridization histochemistry. Neuroscience letters, 114(2), 154-159.  Davis, A. A., Fritz, J. J., Wess, J., Lah, J. J., & Levey, A. I. (2010). Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo. Journal of Neuroscience, 30(12), 4190-4196.  Binder, L. I., Guillozet-Bongaarts, A. L., Garcia-Sierra, F., & Berry, R. W. (2005). Tau, tangles, and Alzheimer's disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1739(2-3), 216-223.  Urrunaga, N. H., Jadeja, R. N., Rachakonda, V., Ahmad, D., McLean, L. P., Cheng, K., ... & Khurana, S. (2015). M1 muscarinic receptors modify oxidative stress response to acetaminophen-induced acute liver injury. Free Radical Biology and Medicine, 78, 66-81.