Muscarinic Antagonists and Muscarinic Genes (11)

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

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As many antidepressants antagonize the nicotinic receptors, several antipsychotics antagonize the muscarinic receptors, including haloperidol (brand name Haldol) and chlorpromazine (brand name Thorazine), widely prescribed in in mental health asylums across the US [1]. As one would expect, several natural toxins also antagonize the receptors, including the toxin produces by the African black mamba snake, which antagonize the M1 and M4 receptors[2], performing roughly the opposite biochemical function of xanomeline.


The muscarinic genes are much less studied than the nicotinic genes, which we shall get to shortly. Nonetheless, we know a little about them. In genome wide association studies, the CHRM1 gene (corresponding to the M1 receptor) has mostly been associated with nicotine dependence[3]. The CHRM2 gene has been associated with alcohol dependence[4][5], intelligence[6][7] (e.g. fascinatingly, rs324650’s T allele is associated with increases of 4.6 IQ points), and depression[8]. CHRM3 has mostly been associated with lung and cardiovascular issues, as well as with schizophrenia[9]. CHRM4 has also been tied to schizophrenia[10]. Finally, CHRM5 has been associated with severity of cigarette smoking[11], which is interesting, since nicotine does not agonize the M5 receptor.

Now that the reader has been introduced to the muscarinic receptors, we can move on to the far more interesting nicotinic cholinergic receptors.

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[1] Zeng, X. P., Le, F., & Richelson, E. (1997). Muscarinic m4 receptor activation by some atypical antipsychotic drugs. European journal of pharmacology, 321(3), 349-354. [2] Jolkkonen, M., Oras, A., Toomela, T., Karlsson, E., Järv, J., & Åkerman, K. E. (2001). Kinetic evidence for different mechanisms of interaction of black mamba toxins MTα and MTβ with muscarinic receptors. Toxicon, 39(2-3), 377-382. [3] Lou, X. Y., Ma, J. Z., Payne, T. J., Beuten, J., Crew, K. M., & Li, M. D. (2006). Gene-based analysis suggests association of the nicotinic acetylcholine receptor β1 subunit (CHRNB1) and M1 muscarinic acetylcholine receptor (CHRM1) with vulnerability for nicotine dependence. Human genetics, 120(3), 381-389. [4] Wang, J. C., Hinrichs, A. L., Stock, H., Budde, J., Allen, R., Bertelsen, S., ... & Jones, K. (2004). Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome. Human molecular genetics, 13(17), 1903-1911. [5] Luo, X., Kranzler, H. R., Zuo, L., Wang, S., Blumberg, H. P., & Gelernter, J. (2005). CHRM2 gene predisposes to alcohol dependence, drug dependence and affective disorders: results from an extended case–control structured association study. Human Molecular Genetics, 14(16), 2421-2434. [6] Dick, D. M., Aliev, F., Kramer, J., Wang, J. C., Hinrichs, A., Bertelsen, S., ... & Porjesz, B. (2007). Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence. Behavior genetics, 37(2), 265-272. [7] Gosso, M. F., Van Belzen, M., De Geus, E. J. C., Polderman, J. C., Heutink, P., Boomsma, D. I., & Posthuma, D. (2006). Association between the CHRM2 gene and intelligence in a sample of 304 Dutch families. Genes, Brain and Behavior, 5(8), 577-584. [8] Comings, D. E., Wu, S., Rostamkhani, M., McGue, M., Iacono, W. G., & MacMurray, J. P. (2002). Association of the muscarinic cholinergic 2 receptor (CHRM2) gene with major depression in women. American journal of medical genetics, 114(5), 527-529. [9] Wang, Q., Cheng, W., Li, M., Ren, H., Hu, X., Deng, W., ... & Wu, H. M. (2016). The CHRM3 gene is implicated in abnormal thalamo-orbital frontal cortex functional connectivity in first-episode treatment-naive patients with schizophrenia. Psychological medicine, 46(7), 1523-1534. [10] Scarr, E., Um, J. Y., Cowie, T. F., & Dean, B. (2013). Cholinergic muscarinic M4 receptor gene polymorphisms: a potential risk factor and pharmacogenomic marker for schizophrenia. Schizophrenia research, 146(1-3), 279-284. [11] Anney, R. J., Lotfi-Miri, M., Olsson, C. A., Reid, S. C., Hemphill, S. A., & Patton, G. C. (2007). Variation in the gene coding for the M5 muscarinic receptor (CHRM5) influences cigarette dose but is not associated with dependence to drugs of addiction: evidence from a prospective population based cohort study of young adults. BMC genetics, 8(1), 46.