Muscarinic acetylcholine receptors expressed in the central nervous system mediate various functions, including cognition, memory, or reward. Therefore, muscarinic receptors represent potential pharmacological targets for various diseases and conditions, such as Alzheimer's disease, schizophrenia, addiction, epilepsy, or depression. Muscarinic receptors are allosterically modulated by neurosteroids and steroid hormones at physiologically relevant concentrations. In this review, we focus on the modulation of muscarinic receptors by neurosteroids and steroid hormones in the context of diseases and disorders of the central nervous system. Further, we propose the potential use of neuroactive steroids in the development of pharmacotherapeutics for these diseases and conditions.

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo Náměstí 2 Prague 6 166 10 Prague Czech Republic

Institute of Physiology Czech Academy of Sciences Vídeňská 1083 142 20 Prague Czech Republic

Zobrazit více v PubMed

Lambert J.J., Cooper M.A., Simmons R.D.J., Weir C.J., Belelli D. Neurosteroids: Endogenous Allosteric Modulators of GABA(A) Receptors. Psychoneuroendocrinology. 2009;34((Suppl. S1)):S48–S58. doi: 10.1016/j.psyneuen.2009.08.009. PubMed DOI

Sedlácek M., Korínek M., Petrovic M., Cais O., Adamusová E., Chodounská H., Vyklický L. Neurosteroid Modulation of Ionotropic Glutamate Receptors and Excitatory Synaptic Transmission. Physiol. Res. 2008;57((Suppl. S3)):S49–S57. doi: 10.33549/physiolres.931600. PubMed DOI

Thomsen M., Sørensen G., Dencker D. Physiological Roles of CNS Muscarinic Receptors Gained from Knockout Mice. Neuropharmacology. 2018;136:411–420. doi: 10.1016/j.neuropharm.2017.09.011. PubMed DOI PMC

Haga K., Kruse A.C., Asada H., Yurugi-Kobayashi T., Shiroishi M., Zhang C., Weis W.I., Okada T., Kobilka B.K., Haga T., et al. Structure of the Human M2 Muscarinic Acetylcholine Receptor Bound to an Antagonist. Nature. 2012;482:547–551. doi: 10.1038/nature10753. PubMed DOI PMC

Kruse A.C., Hu J., Pan A.C., Arlow D.H., Rosenbaum D.M., Rosemond E., Green H.F., Liu T., Chae P.S., Dror R.O., et al. Structure and Dynamics of the M3 Muscarinic Acetylcholine Receptor. Nature. 2012;482:552–556. doi: 10.1038/nature10867. PubMed DOI PMC

Thal D.M., Sun B., Feng D., Nawaratne V., Leach K., Felder C.C., Bures M.G., Evans D.A., Weis W.I., Bachhawat P., et al. Crystal Structures of the M1 and M4 Muscarinic Acetylcholine Receptors. Nature. 2016;531:335–340. doi: 10.1038/nature17188. PubMed DOI PMC

Vuckovic Z., Gentry P.R., Berizzi A.E., Hirata K., Varghese S., Thompson G., van der Westhuizen E.T., Burger W.A.C., Rahmani R., Valant C., et al. Crystal Structure of the M5 Muscarinic Acetylcholine Receptor. Proc. Natl. Acad. Sci. USA. 2019;116:26001–26007. doi: 10.1073/pnas.1914446116. PubMed DOI PMC

Jakubík J., Randáková A., Chetverikov N., El-Fakahany E.E., Doležal V. The Operational Model of Allosteric Modulation of Pharmacological Agonism. Sci. Rep. 2020;10:14421. doi: 10.1038/s41598-020-71228-y. PubMed DOI PMC

Wootten D., Christopoulos A., Sexton P.M. Emerging Paradigms in GPCR Allostery: Implications for Drug Discovery. Nat. Rev. Drug Discov. 2013;12:630–644. doi: 10.1038/nrd4052. PubMed DOI

Jakubik J., El-Fakahany E.E. Current Advances in Allosteric Modulation of Muscarinic Receptors. Biomolecules. 2020;10:325. doi: 10.3390/biom10020325. PubMed DOI PMC

Jakubík J., El-Fakahany E.E. Allosteric Modulation of GPCRs of Class A by Cholesterol. Int. J. Mol. Sci. 2021;22:1953. doi: 10.3390/ijms22041953. PubMed DOI PMC

Szczurowska E., Szánti-Pintér E., Randáková A., Jakubík J., Kudova E. Allosteric Modulation of Muscarinic Receptors by Cholesterol, Neurosteroids and Neuroactive Steroids. Int. J. Mol. Sci. 2022;23:13075. doi: 10.3390/ijms232113075. PubMed DOI PMC

Dolejší E., Szánti-Pintér E., Chetverikov N., Nelic D., Randáková A., Doležal V., Kudová E., Jakubík J. Neurosteroids and Steroid Hormones Are Allosteric Modulators of Muscarinic Receptors. Neuropharmacology. 2021;199:108798. doi: 10.1016/j.neuropharm.2021.108798. PubMed DOI

Dolejší E., Chetverikov N., Szánti-Pintér E., Nelic D., Randáková A., Doležal V., El-Fakahany E.E., Kudová E., Jakubík J. Neuroactive Steroids, WIN-Compounds and Cholesterol Share a Common Binding Site on Muscarinic Acetylcholine Receptors. Biochem. Pharmacol. 2021;192:114699. doi: 10.1016/j.bcp.2021.114699. PubMed DOI

Reddy D.S. Neurosteroids: Endogenous Role in the Human Brain and Therapeutic Potentials. Prog. Brain Res. 2010;186:113–137. doi: 10.1016/B978-0-444-53630-3.00008-7. PubMed DOI PMC

Baulieu E.E., Robel P. Neurosteroids: A New Brain Function? J. Steroid Biochem. Mol. Biol. 1990;37:395–403. doi: 10.1016/0960-0760(90)90490-C. PubMed DOI

Jo D.H., Abdallah M.A., Young J., Baulieu E.E., Robel P. Pregnenolone, Dehydroepiandrosterone, and Their Sulfate and Fatty Acid Esters in the Rat Brain. Steroids. 1989;54:287–297. doi: 10.1016/0039-128X(89)90003-2. PubMed DOI

Levey A.I., Kitt C.A., Simonds W.F., Price D.L., Brann M.R. Identification and Localization of Muscarinic Acetylcholine Receptor Proteins in Brain with Subtype-Specific Antibodies. J. Neurosci. 1991;11:3218–3226. doi: 10.1523/JNEUROSCI.11-10-03218.1991. PubMed DOI PMC

Abrams P., Andersson K.-E., Buccafusco J.J., Chapple C., de Groat W.C., Fryer A.D., Kay G., Laties A., Nathanson N.M., Pasricha P.J., et al. Muscarinic Receptors: Their Distribution and Function in Body Systems, and the Implications for Treating Overactive Bladder. Br. J. Pharmacol. 2006;148:565–578. doi: 10.1038/sj.bjp.0706780. PubMed DOI PMC

Bubser M., Byun N., Wood M.R., Jones C.K. Muscarinic Receptor Pharmacology and Circuitry for the Modulation of Cognition. Handb. Exp. Pharmacol. 2012;208:121–166. doi: 10.1007/978-3-642-23274-9_7. PubMed DOI

Crook J.M., Tomaskovic-Crook E., Copolov D.L., Dean B. Low Muscarinic Receptor Binding in Prefrontal Cortex from Subjects with Schizophrenia: A Study of Brodmann’s Areas 8, 9, 10, and 46 and the Effects of Neuroleptic Drug Treatment. Am. J. Psychiatry. 2001;158:918–925. doi: 10.1176/appi.ajp.158.6.918. PubMed DOI

Tsang S.W.Y., Lai M.K.P., Kirvell S., Francis P.T., Esiri M.M., Hope T., Chen C.P.L.-H., Wong P.T.-H. Impaired Coupling of Muscarinic M1 Receptors to G-Proteins in the Neocortex Is Associated with Severity of Dementia in Alzheimer’s Disease. Neurobiol Aging. 2006;27:1216–1223. doi: 10.1016/j.neurobiolaging.2005.07.010. PubMed DOI

Potter P.E., Rauschkolb P.K., Pandya Y., Sue L.I., Sabbagh M.N., Walker D.G., Beach T.G. Pre- and Post-Synaptic Cortical Cholinergic Deficits Are Proportional to Amyloid Plaque Presence and Density at Preclinical Stages of Alzheimer’s Disease. Acta Neuropathol. 2011;122:49–60. doi: 10.1007/s00401-011-0831-1. PubMed DOI PMC

Scarr E. Muscarinic Receptors: Their Roles in Disorders of the Central Nervous System and Potential as Therapeutic Targets. CNS Neurosci. Ther. 2012;18:369–379. doi: 10.1111/j.1755-5949.2011.00249.x. PubMed DOI PMC

Moran S.P., Maksymetz J., Conn P.J. Targeting Muscarinic Acetylcholine Receptors for the Treatment of Psychiatric and Neurological Disorders. Trends Pharmacol. Sci. 2019;40:1006–1020. doi: 10.1016/j.tips.2019.10.007. PubMed DOI PMC

Westfall T.C. Cholinergic Neurotransmission in the Autonomic and Somatic Motor Nervous System. In: Squire L.R., editor. Encyclopedia of Neuroscience. Elsevier; Amsterdam, The Netherlands: 2009. pp. 827–834.

Saygı Bacanak M., Aydın B., Cabadak H., Nurten A., Gören M.Z., Enginar N. Contribution of M1 and M2 Muscarinic Receptor Subtypes to Convulsions in Fasted Mice Treated with Scopolamine and given Food. Behav. Brain Res. 2019;364:423–430. doi: 10.1016/j.bbr.2017.11.018. PubMed DOI

Reddy D.S. Role of Hormones and Neurosteroids in Epileptogenesis. Front. Cell Neurosci. 2013;7:115. doi: 10.3389/fncel.2013.00115. PubMed DOI PMC

Tata A.M. Muscarinic Acetylcholine Receptors: New Potential Therapeutic Targets in Antinociception and in Cancer Therapy. Recent Pat. CNS Drug. Discov. 2008;3:94–103. doi: 10.2174/157488908784534621. PubMed DOI

Comings D.E., Wu S., Rostamkhani M., McGue M., Iacono W.G., MacMurray J.P. Association of the Muscarinic Cholinergic 2 Receptor (CHRM2) Gene with Major Depression in Women. Am. J. Med. Genet. 2002;114:527–529. doi: 10.1002/ajmg.10406. PubMed DOI

Borroto-Escuela D.O., Agnati L.F., Fuxe K., Ciruela F. Muscarinic Acetylcholine Receptor-Interacting Proteins (MAChRIPs): Targeting the Receptorsome. Curr. Drug Targets. 2012;13:53–71. doi: 10.2174/138945012798868506. PubMed DOI

Pancani T., Bolarinwa C., Smith Y., Lindsley C.W., Conn P.J., Xiang Z. M4 MAChR-Mediated Modulation of Glutamatergic Transmission at Corticostriatal Synapses. ACS Chem. Neurosci. 2014;5:318–324. doi: 10.1021/cn500003z. PubMed DOI PMC

Fiorino D.F., Garcia-Guzman M. Muscarinic Pain Pharmacology: Realizing the Promise of Novel Analgesics by Overcoming Old Challenges. Handb. Exp. Pharmacol. 2012;208:191–221. doi: 10.1007/978-3-642-23274-9_9. PubMed DOI

Moehle M.S., Conn P.J. Roles of the M4 Acetylcholine Receptor in the Basal Ganglia and the Treatment of Movement Disorders. Mov. Disord. 2019;34:1089–1099. doi: 10.1002/mds.27740. PubMed DOI PMC

Riljak V., Janisova K., Myslivecek J. Lack of M4 Muscarinic Receptors in the Striatum, Thalamus and Intergeniculate Leaflet Alters the Biological Rhythm of Locomotor Activity in Mice. Brain Struct. Funct. 2020;225:1615–1629. doi: 10.1007/s00429-020-02082-x. PubMed DOI PMC

Dean B., Scarr E. Muscarinic M1 and M4 Receptors: Hypothesis Driven Drug Development for Schizophrenia. Psychiatry Res. 2020;288:112989. doi: 10.1016/j.psychres.2020.112989. PubMed DOI

Crook J.M., Tomaskovic-Crook E., Copolov D.L., Dean B. Decreased Muscarinic Receptor Binding in Subjects with Schizophrenia: A Study of the Human Hippocampal Formation. Biol. Psychiatry. 2000;48:381–388. doi: 10.1016/S0006-3223(00)00918-5. PubMed DOI

Raedler T.J., Bymaster F.P., Tandon R., Copolov D., Dean B. Towards a Muscarinic Hypothesis of Schizophrenia. Mol. Psychiatry. 2007;12:232–246. doi: 10.1038/sj.mp.4001924. PubMed DOI

Tozzi A., de Iure A., Tantucci M., Durante V., Quiroga-Varela A., Giampà C., Di Mauro M., Mazzocchetti P., Costa C., Di Filippo M., et al. Endogenous 17β-Estradiol Is Required for Activity-Dependent Long-Term Potentiation in the Striatum: Interaction with the Dopaminergic System. Front. Cell Neurosci. 2015;9:1–14. doi: 10.3389/fncel.2015.00192. PubMed DOI PMC

De Angelis F., Tata A.M. Analgesic Effects Mediated by Muscarinic Receptors: Mechanisms and Pharmacological Approaches. Cent. Nerv. Syst. Agents Med. Chem. 2016;16:218–226. doi: 10.2174/1871524916666160302103033. PubMed DOI

Piggott M., Owens J., O’Brien J., Paling S., Wyper D., Fenwick J., Johnson M., Perry R., Perry E. Comparative Distribution of Binding of the Muscarinic Receptor Ligands Pirenzepine, AF-DX 384, (R,R)-I-QNB and (R,S)-I-QNB to Human Brain. J. Chem. Neuroanat. 2002;24:211–223. doi: 10.1016/S0891-0618(02)00066-2. PubMed DOI

Yamada M., Lamping K.G., Duttaroy A., Zhang W., Cui Y., Bymaster F.P., McKinzie D.L., Felder C.C., Deng C.X., Faraci F.M., et al. Cholinergic Dilation of Cerebral Blood Vessels Is Abolished in M5 Muscarinic Acetylcholine Receptor Knockout Mice. Proc. Natl. Acad. Sci. USA. 2001;98:14096–14101. doi: 10.1073/pnas.251542998. PubMed DOI PMC

Bender A.M., Garrison A.T., Lindsley C.W. The Muscarinic Acetylcholine Receptor M5: Therapeutic Implications and Allosteric Modulation. ACS Chem. Neurosci. 2019;10:1025–1034. doi: 10.1021/acschemneuro.8b00481. PubMed DOI

Gould R.W., Gunter B.W., Bubser M., Matthews R.T., Teal L.B., Ragland M.G., Bridges T.M., Garrison A.T., Winder D.G., Lindsley C.W., et al. Acute Negative Allosteric Modulation of M5 Muscarinic Acetylcholine Receptors Inhibits Oxycodone Self-Administration and Cue-Induced Reactivity with No Effect on Antinociception. ACS Chem. Neurosci. 2019;10:3740–3750. doi: 10.1021/acschemneuro.9b00274. PubMed DOI PMC

Ballinger E.C., Ananth M., Talmage D.A., Role L.W. Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline. Neuron. 2016;91:1199–1218. doi: 10.1016/j.neuron.2016.09.006. PubMed DOI PMC

Bacanak M.S. Muscarinic M1 and M2 Receptors, Fasting and Seizure Development in Animals. Clin. Exp. Health Sci. 2018;8:308–313.

Zhang W., Yamada M., Gomeza J., Basile A.S., Wess J. Multiple Muscarinic Acetylcholine Receptor Subtypes Modulate Striatal Dopamine Release, as Studied with M1-M5 Muscarinic Receptor Knock-out Mice. J. Neurosci. 2002;22:6347–6352. doi: 10.1523/JNEUROSCI.22-15-06347.2002. PubMed DOI PMC

Lösel R., Wehling M. Nongenomic Actions of Steroid Hormones. Nat. Rev. Mol. Cell Biol. 2003;4:46–56. doi: 10.1038/nrm1009. PubMed DOI

Bixo M., Andersson A., Winblad B., Purdy R.H., Bäckström T. Progesterone, 5α-Pregnane-3,20-Dione and 3α-Hydroxy-5α-Pregnane-20-One in Specific Regions of the Human Female Brain in Different Endocrine States. Brain Res. 1997;764:173–178. doi: 10.1016/S0006-8993(97)00455-1. PubMed DOI

Janowsky J.S. The Role of Ovarian Hormones in Preserving Cognition in Aging. Curr. Psychiatry Rep. 2002;4:467–473. doi: 10.1007/s11920-002-0075-9. PubMed DOI

Gibbs R.B. Estrogen Therapy and Cognition: A Review of the Cholinergic Hypothesis. Endocr. Rev. 2010;31:224–253. doi: 10.1210/er.2009-0036. PubMed DOI PMC

Guennoun R. Progesterone in the Brain: Hormone, Neurosteroid and Neuroprotectant. Int. J. Mol. Sci. 2020;21:5271. doi: 10.3390/ijms21155271. PubMed DOI PMC

Caruso D., Pesaresi M., Abbiati F., Calabrese D., Giatti S., Garcia-Segura L.M., Melcangi R.C. Comparison of Plasma and Cerebrospinal Fluid Levels of Neuroactive Steroids with Their Brain, Spinal Cord and Peripheral Nerve Levels in Male and Female Rats. Psychoneuroendocrinology. 2013;38:2278–2290. doi: 10.1016/j.psyneuen.2013.04.016. PubMed DOI

Nordberg A., Alafuzoff I., Winblad B. Nicotinic and Muscarinic Subtypes in the Human Brain: Changes with Aging and Dementia. J. Neurosci. Res. 1992;31:103–111. doi: 10.1002/jnr.490310115. PubMed DOI

Davies P., Verth A.H. Regional Distribution of Muscarinic Acetylcholine Receptor in Normal and Alzheimer’s-Type Dementia Brains. Brain Res. 1977;138:385–392. doi: 10.1016/0006-8993(77)90758-2. PubMed DOI

Lee K.S., Frey K.A., Koeppe R.A., Buck A., Mulholland G.K., Kuhl D.E. In Vivo Quantification of Cerebral Muscarinic Receptors in Normal Human Aging Using Positron Emission Tomography and [11C]Tropanyl Benzilate. J. Cereb. Blood Flow Metab. 1996;16:303–310. doi: 10.1097/00004647-199603000-00016. PubMed DOI

Zubieta J.K., Koeppe R.A., Frey K.A., Kilbourn M.R., Mangner T.J., Foster N.L., Kuhl D.E. Assessment of Muscarinic Receptor Concentrations in Aging and Alzheimer Disease with [11C]NMPB and PET. Synapse. 2001;39:275–287. doi: 10.1002/1098-2396(20010315)39:4<275::AID-SYN1010>3.0.CO;2-3. PubMed DOI

Dewey S.L., Volkow N.D., Logan J., MacGregor R.R., Fowler J.S., Schlyer D.J., Bendriem B. Age-Related Decreases in Muscarinic Cholinergic Receptor Binding in the Human Brain Measured with Positron Emission Tomography (PET) J. Neurosci. Res. 1990;27:569–575. doi: 10.1002/jnr.490270418. PubMed DOI

Suhara T., Inoue O., Kobayashi K., Suzuki K., Tateno Y. Age-Related Changes in Human Muscarinic Acetylcholine Receptors Measured by Positron Emission Tomography. Neurosci. Lett. 1993;149:225–228. doi: 10.1016/0304-3940(93)90777-I. PubMed DOI

Podruchny T.A., Connolly C., Bokde A., Herscovitch P., Eckelman W.C., Kiesewetter D.O., Sunderland T., Carson R.E., Cohen R.M. In Vivo Muscarinic 2 Receptor Imaging in Cognitively Normal Young and Older Volunteers. Synapse. 2003;48:39–44. doi: 10.1002/syn.10165. PubMed DOI

Norbury R., Travis M.J., Erlandsson K., Waddington W., Owens J., Pimlott S., Ell P.J., Murphy D.G.M. In Vivo Imaging of Muscarinic Receptors in the Aging Female Brain with (R,R)[123I]-I-QNB and Single Photon Emission Tomography. Exp. Gerontol. 2005;40:137–145. doi: 10.1016/j.exger.2004.10.002. PubMed DOI

Gibbs R.B. Estrogen Replacement Enhances Acquisition of a Spatial Memory Task and Reduces Deficits Associated with Hippocampal Muscarinic Receptor Inhibition. Horm. Behav. 1999;36:222–233. doi: 10.1006/hbeh.1999.1541. PubMed DOI

El-Bakri N.K., Adem A., Suliman I.A., Mulugeta E., Karlsson E., Lindgren J.U., Winblad B., Islam A. Estrogen and Progesterone Treatment: Effects on Muscarinic M(4) Receptor Subtype in the Rat Brain. Brain Res. 2002;948:131–137. doi: 10.1016/S0006-8993(02)02962-1. PubMed DOI

van Huizen F., March D., Cynader M.S., Shaw C. Muscarinic Receptor Characteristics and Regulation in Rat Cerebral Cortex: Changes during Development, Aging and the Oestrous Cycle. Eur. J. Neurosci. 1994;6:237–243. doi: 10.1111/j.1460-9568.1994.tb00266.x. PubMed DOI

Vaucher E., Reymond I., Najaffe R., Kar S., Quirion R., Miller M.M., Franklin K.B.J. Estrogen Effects on Object Memory and Cholinergic Receptors in Young and Old Female Mice. Neurobiol. Aging. 2002;23:87–95. doi: 10.1016/S0197-4580(01)00250-0. PubMed DOI

Bartholomeusz C.F., Wesnes K.A., Kulkarni J., Vitetta L., Croft R.J., Nathan P.J. Estradiol Treatment and Its Interaction with the Cholinergic System: Effects on Cognitive Function in Healthy Young Women. Horm. Behav. 2008;54:684–693. doi: 10.1016/j.yhbeh.2008.07.007. PubMed DOI

Rainbow T.C., Degroff V., Luine V.N., McEwen B.S. Estradiol 17β Increases the Number of Muscarinic Receptors in Hypothalamic Nuclei. Brain Res. 1980;198:239–243. doi: 10.1016/0006-8993(80)90362-5. PubMed DOI

Dohanich G.P., Witcher J.A., Weaver D.R., Clemens L.G. Alteration of Muscarinic Binding in Specific Brain Areas Following Estrogen Treatment. Brain Res. 1982;241:347–350. doi: 10.1016/0006-8993(82)91075-7. PubMed DOI

Cardoso C.C., Pereira R.T.S., Koyama C.A., Porto C.S., Abdalla F.M.F. Effects of Estrogen on Muscarinic Acetylcholine Receptors in the Rat Hippocampus. Neuroendocrinology. 2004;80:379–386. doi: 10.1159/000084202. PubMed DOI

Cardoso C.C., Ricardo V.P., Frussa-Filho R., Porto C.S., Abdalla F.M.F. Effects of 17ß-Estradiol on Expression of Muscarinic Acetylcholine Receptor Subtypes and Estrogen Receptor Alpha in Rat Hippocampus. Eur. J. Pharmacol. 2010;634:192–200. doi: 10.1016/j.ejphar.2010.02.032. PubMed DOI

dos Santos Pereira R.T., Porto C.S., Godinho R.O., Abdalla F.M.F. Effects of Estrogen on Intracellular Signaling Pathways Linked to Activation of Muscarinic Acetylcholine Receptors and on Acetylcholinesterase Activity in Rat Hippocampus. Biochem. Pharmacol. 2008;75:1827–1834. doi: 10.1016/j.bcp.2008.01.016. PubMed DOI

Ch’ng S.S., Walker A.J., McCarthy M., Le T.-K., Thomas N., Gibbons A., Udawela M., Kusljic S., Dean B., Gogos A. The Impact of Removal of Ovarian Hormones on Cholinergic Muscarinic Receptors: Examining Prepulse Inhibition and Receptor Binding. Brain Sci. 2020;10:106. doi: 10.3390/brainsci10020106. PubMed DOI PMC

Aguirre C., Jayaraman A., Pike C., Baudry M. Progesterone Inhibits Estrogen-Mediated Neuroprotection against Excitotoxicity by down-Regulating Estrogen Receptor-β. J. Neurochem. 2010;115:1277–1287. doi: 10.1111/j.1471-4159.2010.07038.x. PubMed DOI PMC

Norbury R., Travis M.J., Erlandsson K., Waddington W., Ell P.J., Murphy D.G.M. Estrogen Therapy and Brain Muscarinic Receptor Density in Healthy Females: A SPET Study. Horm. Behav. 2007;51:249–257. doi: 10.1016/j.yhbeh.2006.10.007. PubMed DOI

Hösli E., Hösli L. Cellular Localization of Estrogen Receptors on Neurones in Various Regions of Cultured Rat CNS: Coexistence with Cholinergic and Galanin Receptors. Int. J. Dev. Neurosci. 1999;17:317–330. doi: 10.1016/S0736-5748(99)00038-6. PubMed DOI

Hammond R., Nelson D., Gibbs R.B. GPR30 Co-Localizes with Cholinergic Neurons in the Basal Forebrain and Enhances Potassium-Stimulated Acetylcholine Release in the Hippocampus. Psychoneuroendocrinology. 2011;36:182–192. doi: 10.1016/j.psyneuen.2010.07.007. PubMed DOI PMC

Toran-Allerand C.D., Miranda R.C., Bentham W.D., Sohrabji F., Brown T.J., Hochberg R.B., MacLusky N.J. Estrogen Receptors Colocalize with Low-Affinity Nerve Growth Factor Receptors in Cholinergic Neurons of the Basal Forebrain. Proc. Natl. Acad. Sci. USA. 1992;89:4668–4672. doi: 10.1073/pnas.89.10.4668. PubMed DOI PMC

Russell J.K., Jones C.K., Newhouse P.A. The Role of Estrogen in Brain and Cognitive Aging. Neurotherapeutics. 2019;16:649–665. doi: 10.1007/s13311-019-00766-9. PubMed DOI PMC

Bredfeldt T.G., Greathouse K.L., Safe S.H., Hung M.-C., Bedford M.T., Walker C.L. Xenoestrogen-Induced Regulation of EZH2 and Histone Methylation via Estrogen Receptor Signaling to PI3K/AKT. Mol. Endocrinol. 2010;24:993–1006. doi: 10.1210/me.2009-0438. PubMed DOI PMC

Wilkenfeld S.R., Lin C., Frigo D.E. Communication between Genomic and Non-Genomic Signaling Events Coordinate Steroid Hormone Actions. Steroids. 2018;133:2–7. doi: 10.1016/j.steroids.2017.11.005. PubMed DOI PMC

Finkelstein Y., Koffler B., Rabey J.M., Gilad G.M. Dynamics of Cholinergic Synaptic Mechanisms in Rat Hippocampus after Stress. Brain Res. 1985;343:314–319. doi: 10.1016/0006-8993(85)90749-8. PubMed DOI

Myslivecek J., Kvetnanský R. The Effects of Stress on Muscarinic Receptors. Heterologous Receptor Regulation: Yes or No? Auton. Autacoid Pharmacol. 2006;26:235–251. doi: 10.1111/j.1474-8673.2006.00359.x. PubMed DOI

Sarter M., Hasselmo M.E., Bruno J.P., Givens B. Unraveling the Attentional Functions of Cortical Cholinergic Inputs: Interactions between Signal-Driven and Cognitive Modulation of Signal Detection. Brain Res. Rev. 2005;48:98–111. doi: 10.1016/j.brainresrev.2004.08.006. PubMed DOI

Solari N., Hangya B. Cholinergic Modulation of Spatial Learning, Memory and Navigation. Eur. J. Neurosci. 2018;48:2199–2230. doi: 10.1111/ejn.14089. PubMed DOI PMC

Blokland A., Sambeth A., Prickaerts J., Riedel W.J. Why an M1 Antagonist Could Be a More Selective Model for Memory Impairment than Scopolamine. Front. Neurol. 2016;7:167. doi: 10.3389/fneur.2016.00167. PubMed DOI PMC

Chintoh A., Fulton J., Koziel N., Aziz M., Sud M., Yeomans J.S. Role of Cholinergic Receptors in Locomotion Induced by Scopolamine and Oxotremorine-M. Pharmacol. Biochem. Behav. 2003;76:53–61. doi: 10.1016/S0091-3057(03)00196-5. PubMed DOI

Bartolomeo A.C., Morris H., Buccafusco J.J., Kille N., Rosenzweig-Lipson S., Husbands M.G., Sabb A.L., Abou-Gharbia M., Moyer J.A., Boast C.A. The Preclinical Pharmacological Profile of WAY-132983, a Potent M1 Preferring Agonist. J. Pharmacol. Exp. Ther. 2000;292:584–596. PubMed

Bakker C., Tasker T., Liptrot J., Hart E.P., Klaassen E.S., Doll R.J., Brown G.A., Brown A., Congreve M., Weir M., et al. Safety, Pharmacokinetics and Exploratory pro-Cognitive Effects of HTL0018318, a Selective M1 Receptor Agonist, in Healthy Younger Adult and Elderly Subjects: A Multiple Ascending Dose Study. Alzheimers. Res. Ther. 2021;13:87. doi: 10.1186/s13195-021-00816-5. PubMed DOI PMC

Long N.M., Kuhl B.A., Chun M.M. Stevens’ Handbook of Experimental Psychology and Cognitive Neuroscience. Wiley; New York, NY, USA: 2018. Memory and Attention; pp. 1–37.

Chun M.M., Johnson M.K. Memory: Enduring Traces of Perceptual and Reflective Attention. Neuron. 2011;72:520–535. doi: 10.1016/j.neuron.2011.10.026. PubMed DOI PMC

Bichot N.P., Heard M.T., DeGennaro E.M., Desimone R. A Source for Feature-Based Attention in the Prefrontal Cortex. Neuron. 2015;88:832–844. doi: 10.1016/j.neuron.2015.10.001. PubMed DOI PMC

Thiele A., Bellgrove M.A. Neuromodulation of Attention. Neuron. 2018;97:769–785. doi: 10.1016/j.neuron.2018.01.008. PubMed DOI PMC

Levey A.I. Muscarinic Acetylcholine Receptor Expression in Memory Circuits: Implications for Treatment of Alzheimer Disease. Proc. Natl. Acad. Sci. USA. 1996;93:13541–13546. doi: 10.1073/pnas.93.24.13541. PubMed DOI PMC

Volpicelli L.A., Levey A.I. Muscarinic Acetylcholine Receptor Subtypes in Cerebral Cortex and Hippocampus. Prog. Brain Res. 2004;145:59–66. doi: 10.1016/S0079-6123(03)45003-6. PubMed DOI

Eglen R.M. Overview of Muscarinic Receptor Subtypes. In: Fryer A.D., Arthur C., Nathanson N.M., editors. Handb Exp Pharmacol. Springer; Berlin/Heidelberg, Germany: 2012. pp. 3–28. PubMed

Jiang S., Li Y., Zhang C., Zhao Y., Bu G., Xu H., Zhang Y.-W. M1 Muscarinic Acetylcholine Receptor in Alzheimer’s Disease. Neurosci. Bull. 2014;30:295–307. doi: 10.1007/s12264-013-1406-z. PubMed DOI PMC

Buchanan K.A., Petrovic M.M., Chamberlain S.E.L., Marrion N.V., Mellor J.R. Facilitation of Long-Term Potentiation by Muscarinic M(1) Receptors Is Mediated by Inhibition of SK Channels. Neuron. 2010;68:948–963. doi: 10.1016/j.neuron.2010.11.018. PubMed DOI PMC

Kim W.B., Cho J.-H. Encoding of Contextual Fear Memory in Hippocampal-Amygdala Circuit. Nat. Commun. 2020;11:1382. doi: 10.1038/s41467-020-15121-2. PubMed DOI PMC

Poulin B., Butcher A., McWilliams P., Bourgognon J.-M., Pawlak R., Kong K.C., Bottrill A., Mistry S., Wess J., Rosethorne E.M., et al. The M3-Muscarinic Receptor Regulates Learning and Memory in a Receptor Phosphorylation/Arrestin-Dependent Manner. Proc. Natl. Acad. Sci. USA. 2010;107:9440–9445. doi: 10.1073/pnas.0914801107. PubMed DOI PMC

Ratner M.H., Kumaresan V., Farb D.H. Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders. Front. Endocrinol. (Lausanne) 2019;10:169. doi: 10.3389/fendo.2019.00169. PubMed DOI PMC

Daniel J.M., Hulst J.L., Berbling J.L. Estradiol Replacement Enhances Working Memory in Middle-Aged Rats When Initiated Immediately after Ovariectomy But Not after a Long-Term Period of Ovarian Hormone Deprivation. Endocrinology. 2006;147:607–614. doi: 10.1210/en.2005-0998. PubMed DOI

Pallarés M., Darnaudéry M., Day J., Le Moal M., Mayo W. The Neurosteroid Pregnenolone Sulfate Infused into the Nucleus Basalis Increases Both Acetylcholine Release in the Frontal Cortex or Amygdala and Spatial Memory. Neuroscience. 1998;87:551–558. doi: 10.1016/S0306-4522(98)00174-2. PubMed DOI

Darnaudéry M., Koehl M., Piazza P.V., Le Moal M., Mayo W. Pregnenolone Sulfate Increases Hippocampal Acetylcholine Release and Spatial Recognition. Brain Res. 2000;852:173–179. doi: 10.1016/S0006-8993(99)01964-2. PubMed DOI

Luine V.N., Khylchevskaya R.I., McEwen B.S. Effect of Gonadal Steroids on Activities of Monoamine Oxidase and Choline Acetylase in Rat Brain. Brain Res. 1975;86:293–306. doi: 10.1016/0006-8993(75)90704-0. PubMed DOI

Singh M., Meyer E.M., Millard W.J., Simpkins J.W. Ovarian Steroid Deprivation Results in a Reversible Learning Impairment and Compromised Cholinergic Function in Female Sprague-Dawley Rats. Brain Res. 1994;644:305–312. doi: 10.1016/0006-8993(94)91694-2. PubMed DOI

Fader A.J., Johnson P.E., Dohanich G.P. Estrogen Improves Working but Not Reference Memory and Prevents Amnestic Effects of Scopolamine of a Radial-Arm Maze. Pharmacol. Biochem. Behav. 1999;62:711–717. doi: 10.1016/S0091-3057(98)00219-6. PubMed DOI

Tanabe F., Miyasaka N., Kubota T., Aso T. Estrogen and Progesterone Improve Scopolamine-Induced Impairment of Spatial Memory. J. Med. Dent. Sci. 2004;51:89–98. PubMed

Daniel J.M., Dohanich G.P. Acetylcholine Mediates the Estrogen-Induced Increase in NMDA Receptor Binding in CA1 of the Hippocampus and the Associated Improvement in Working Memory. J. Neurosci. 2001;21:6949–6956. doi: 10.1523/JNEUROSCI.21-17-06949.2001. PubMed DOI PMC

Steffensen S.C., Jones M.D., Hales K., Allison D.W. Dehydroepiandrosterone Sulfate and Estrone Sulfate Reduce GABA-Recurrent Inhibition in the Hippocampus via Muscarinic Acetylcholine Receptors. Hippocampus. 2006;16:1080–1090. doi: 10.1002/hipo.20232. PubMed DOI

Frick K.M., Kim J. Mechanisms Underlying the Rapid Effects of Estradiol and Progesterone on Hippocampal Memory Consolidation in Female Rodents. Horm. Behav. 2018;104:100–110. doi: 10.1016/j.yhbeh.2018.04.013. PubMed DOI PMC

Barros L.A., Tufik S., Andersen M.L. The Role of Progesterone in Memory: An Overview of Three Decades. Neurosci. Biobehav. Rev. 2015;49:193–204. doi: 10.1016/j.neubiorev.2014.11.015. PubMed DOI

Ouanes S., Popp J. High Cortisol and the Risk of Dementia and Alzheimer’s Disease: A Review of the Literature. Front. Aging Neurosci. 2019;11:43. doi: 10.3389/fnagi.2019.00043. PubMed DOI PMC

de Quervain D., Schwabe L., Roozendaal B. Stress, Glucocorticoids and Memory: Implications for Treating Fear-Related Disorders. Nat. Rev. Neurosci. 2017;18:7–19. doi: 10.1038/nrn.2016.155. PubMed DOI

Schwabe L., Joëls M., Roozendaal B., Wolf O.T., Oitzl M.S. Stress Effects on Memory: An Update and Integration. Neurosci. Biobehav. Rev. 2012;36:1740–1749. doi: 10.1016/j.neubiorev.2011.07.002. PubMed DOI

Sánchez-Resendis O., Medina A.C., Serafín N., Prado-Alcalá R.A., Roozendaal B., Quirarte G.L. Glucocorticoid-Cholinergic Interactions in the Dorsal Striatum in Memory Consolidation of Inhibitory Avoidance Training. Front. Behav. Neurosci. 2012;6:33. doi: 10.3389/fnbeh.2012.00033. PubMed DOI PMC

Power A.E., Roozendaal B., McGaugh J.L. Glucocorticoid Enhancement of Memory Consolidation in the Rat Is Blocked by Muscarinic Receptor Antagonism in the Basolateral Amygdala. Eur. J. Neurosci. 2000;12:3481–3487. doi: 10.1046/j.1460-9568.2000.00224.x. PubMed DOI

Kelemen E., Bahrendt M., Born J., Inostroza M. Hippocampal Corticosterone Impairs Memory Consolidation during Sleep but Improves Consolidation in the Wake State. Hippocampus. 2014;24:510–515. doi: 10.1002/hipo.22266. PubMed DOI PMC

Aguilera G. HPA Axis Responsiveness to Stress: Implications for Healthy Aging. Exp. Gerontol. 2011;46:90–95. doi: 10.1016/j.exger.2010.08.023. PubMed DOI PMC

Mizoguchi K., Shoji H., Ikeda R., Tanaka Y., Maruyama W., Tabira T. Suppression of Glucocorticoid Secretion Enhances Cholinergic Transmission in Rat Hippocampus. Brain Res. Bull. 2008;76:612–615. doi: 10.1016/j.brainresbull.2008.03.003. PubMed DOI

Hemrick-Luecke S.K., Bymaster F.P., Evans D.C., Wess J., Felder C.C. Muscarinic Agonist-Mediated Increases in Serum Corticosterone Levels Are Abolished in m(2) Muscarinic Acetylcholine Receptor Knockout Mice. J. Pharmacol. Exp. Ther. 2002;303:99–103. doi: 10.1124/jpet.102.036020. PubMed DOI

Meziane H., Mathis C., Ungerer A., Paul S.M. The Neurosteroid Pregnenolone Sulfate Reduces Learning Deficits Induced by Scopolamine and Has Promnestic Effects in Mice Performing an Appetitive Learning Task. Psychopharmacology. 1996;126:323–330. doi: 10.1007/BF02247383. PubMed DOI

Urani A., Privat A., Maurice T. The Modulation by Neurosteroids of the Scopolamine-Induced Learning Impairment in Mice Involves an Interaction with Sigma1 (Σ1) Receptors. Brain Res. 1998;799:64–77. doi: 10.1016/S0006-8993(98)00469-7. PubMed DOI

Johnson D.A., Wu T.H., Li P.K., Maher T.J. The Effect of Steroid Sulfatase Inhibition on Learning and Spatial Memory. Brain Res. 2000;865:286–290. doi: 10.1016/S0006-8993(00)02372-6. PubMed DOI

Rhodes M.E., Li P.K., Burke A.M., Johnson D.A. Enhanced Plasma DHEAS, Brain Acetylcholine and Memory Mediated by Steroid Sulfatase Inhibition. Brain Res. 1997;773:28–32. doi: 10.1016/S0006-8993(97)00867-6. PubMed DOI

Hardy J.A., Higgins G.A. Alzheimer’s Disease: The Amyloid Cascade Hypothesis. Science. 1992;256:184–185. doi: 10.1126/science.1566067. PubMed DOI

Chen G.-F., Xu T.-H., Yan Y., Zhou Y.-R., Jiang Y., Melcher K., Xu H.E. Amyloid Beta: Structure, Biology and Structure-Based Therapeutic Development. Acta Pharmacol. Sin. 2017;38:1205–1235. doi: 10.1038/aps.2017.28. PubMed DOI PMC

Rudajev V., Novotny J. Cholesterol as a Key Player in Amyloid β-Mediated Toxicity in Alzheimer’s Disease. Front. Mol. Neurosci. 2022;15:937056. doi: 10.3389/fnmol.2022.937056. PubMed DOI PMC

Nitsch R.M., Slack B.E., Wurtman R.J., Growdon J.H. Release of Alzheimer Amyloid Precursor Derivatives Stimulated by Activation of Muscarinic Acetylcholine Receptors. Science. 1992;258:304–307. doi: 10.1126/science.1411529. PubMed DOI

Hock C., Maddalena A., Raschig A., Müller-Spahn F., Eschweiler G., Hager K., Heuser I., Hampel H., Müller-Thomsen T., Oertel W., et al. Treatment with the Selective Muscarinic M1 Agonist Talsaclidine Decreases Cerebrospinal Fluid Levels of A Beta 42 in Patients with Alzheimer’s Disease. Amyloid. 2003;10:1–6. doi: 10.3109/13506120308995249. PubMed DOI

Cisse M., Braun U., Leitges M., Fisher A., Pages G., Checler F., Vincent B. ERK1-Independent α-Secretase Cut of β-Amyloid Precursor Protein via M1 Muscarinic Receptors and PKCα/ε. Mol. Cell Neurosci. 2011;47:223–232. doi: 10.1016/j.mcn.2011.04.008. PubMed DOI

Giacobini E., Cuello A.C., Fisher A. Reimagining Cholinergic Therapy for Alzheimer’s Disease. Brain. 2022;145:2250–2275. doi: 10.1093/brain/awac096. PubMed DOI

Caccamo A., Oddo S., Billings L.M., Green K.N., Martinez-Coria H., Fisher A., LaFerla F.M. M1 Receptors Play a Central Role in Modulating AD-like Pathology in Transgenic Mice. Neuron. 2006;49:671–682. doi: 10.1016/j.neuron.2006.01.020. PubMed DOI

Fisher A., Bezprozvanny I., Wu L., Ryskamp D.A., Bar-Ner N., Natan N., Brandeis R., Elkon H., Nahum V., Gershonov E., et al. AF710B, a Novel M1/Σ1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer’s Disease. Neurodegener. Dis. 2016;16:95–110. doi: 10.1159/000440864. PubMed DOI PMC

Dwomoh L., Tejeda G.S., Tobin A.B. Targeting the M1 Muscarinic Acetylcholine Receptor in Alzheimer’s Disease. Neuronal Signal. 2022;6:NS20210004. doi: 10.1042/NS20210004. PubMed DOI PMC

Hampel H., Mesulam M.-M., Cuello A.C., Farlow M.R., Giacobini E., Grossberg G.T., Khachaturian A.S., Vergallo A., Cavedo E., Snyder P.J., et al. The Cholinergic System in the Pathophysiology and Treatment of Alzheimer’s Disease. Brain. 2018;141:1917–1933. doi: 10.1093/brain/awy132. PubMed DOI PMC

Newhouse P., Dumas J. Estrogen-Cholinergic Interactions: Implications for Cognitive Aging. Horm. Behav. 2015;74:173–185. doi: 10.1016/j.yhbeh.2015.06.022. PubMed DOI PMC

Fernandez J.W., Grizzell J.A., Wecker L. The Role of Estrogen Receptor β and Nicotinic Cholinergic Receptors in Postpartum Depression. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2013;40:199–206. doi: 10.1016/j.pnpbp.2012.10.002. PubMed DOI

Bettio L.E.B., Rajendran L., Gil-Mohapel J. The Effects of Aging in the Hippocampus and Cognitive Decline. Neurosci. Biobehav. Rev. 2017;79:66–86. doi: 10.1016/j.neubiorev.2017.04.030. PubMed DOI

Breijyeh Z., Karaman R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules. 2020;25:5789. doi: 10.3390/molecules25245789. PubMed DOI PMC

Kahn R.S., Sommer I.E., Murray R.M., Meyer-Lindenberg A., Weinberger D.R., Cannon T.D., O’Donovan M., Correll C.U., Kane J.M., van Os J., et al. Schizophrenia. Nat. Rev. Dis. Prim. 2015;1:15067. doi: 10.1038/nrdp.2015.67. PubMed DOI

Shen L.-H., Liao M.-H., Tseng Y.-C. Recent Advances in Imaging of Dopaminergic Neurons for Evaluation of Neuropsychiatric Disorders. J. Biomed. Biotechnol. 2012;2012:259349. doi: 10.1155/2012/259349. PubMed DOI PMC

O’Donnell P., Grace A.A. Dysfunctions in Multiple Interrelated Systems as the Neurobiological Bases of Schizophrenic Symptom Clusters. Schizophr. Bull. 1998;24:267–283. doi: 10.1093/oxfordjournals.schbul.a033325. PubMed DOI

Sur C., Mallorga P.J., Wittmann M., Jacobson M.A., Pascarella D., Williams J.B., Brandish P.E., Pettibone D.J., Scolnick E.M., Conn P.J. N-Desmethylclozapine, an Allosteric Agonist at Muscarinic 1 Receptor, Potentiates N-Methyl-D-Aspartate Receptor Activity. Proc. Natl. Acad. Sci. USA. 2003;100:13674–13679. doi: 10.1073/pnas.1835612100. PubMed DOI PMC

Miller A.D., Blaha C.D. Midbrain Muscarinic Receptor Mechanisms Underlying Regulation of Mesoaccumbens and Nigrostriatal Dopaminergic Transmission in the Rat. Eur. J. Neurosci. 2005;21:1837–1846. doi: 10.1111/j.1460-9568.2005.04017.x. PubMed DOI

Scarr E., Dean B. Muscarinic Receptors: Do They Have a Role in the Pathology and Treatment of Schizophrenia? J. Neurochem. 2008;107:1188–1195. doi: 10.1111/j.1471-4159.2008.05711.x. PubMed DOI

Mancama D., Arranz M.J., Landau S., Kerwin R. Reduced Expression of the Muscarinic 1 Receptor Cortical Subtype in Schizophrenia. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2003;119B:2–6. doi: 10.1002/ajmg.b.20020. PubMed DOI

Shannon H.E., Rasmussen K., Bymaster F.P., Hart J.C., Peters S.C., Swedberg M.D., Jeppesen L., Sheardown M.J., Sauerberg P., Fink-Jensen A. Xanomeline, an M(1)/M(4) Preferring Muscarinic Cholinergic Receptor Agonist, Produces Antipsychotic-like Activity in Rats and Mice. Schizophr. Res. 2000;42:249–259. doi: 10.1016/S0920-9964(99)00138-3. PubMed DOI

Bymaster F.P., Felder C., Ahmed S., McKinzie D. Muscarinic Receptors as a Target for Drugs Treating Schizophrenia. Curr Drug Targets CNS Neurol Disord. 2002;1:163–181. doi: 10.2174/1568007024606249. PubMed DOI

Bodick N.C., Offen W.W., Levey A.I., Cutler N.R., Gauthier S.G., Satlin A., Shannon H.E., Tollefson G.D., Rasmussen K., Bymaster F.P., et al. Effects of Xanomeline, a Selective Muscarinic Receptor Agonist, on Cognitive Function and Behavioral Symptoms in Alzheimer Disease. Arch. Neurol. 1997;54:465–473. doi: 10.1001/archneur.1997.00550160091022. PubMed DOI

Shekhar A., Potter W.Z., Lightfoot J., Lienemann J., Dubé S., Mallinckrodt C., Bymaster F.P., McKinzie D.L., Felder C.C. Selective Muscarinic Receptor Agonist Xanomeline as a Novel Treatment Approach for Schizophrenia. Am. J. Psychiatry. 2008;165:1033–1039. doi: 10.1176/appi.ajp.2008.06091591. PubMed DOI

Sako Y., Kurimoto E., Mandai T., Suzuki A., Tanaka M., Suzuki M., Shimizu Y., Yamada M., Kimura H. TAK-071, a Novel M1 Positive Allosteric Modulator with Low Cooperativity, Improves Cognitive Function in Rodents with Few Cholinergic Side Effects. Neuropsychopharmacology. 2019;44:950–960. doi: 10.1038/s41386-018-0168-8. PubMed DOI PMC

Gogos A., Sbisa A.M., Sun J., Gibbons A., Udawela M., Dean B. A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings. Int. J. Endocrinol. 2015;2015:1–16. doi: 10.1155/2015/615356. PubMed DOI PMC

Marx C.E., Bradford D.W., Hamer R.M., Naylor J.C., Allen T.B., Lieberman J.A., Strauss J.L., Kilts J.D. Pregnenolone as a Novel Therapeutic Candidate in Schizophrenia: Emerging Preclinical and Clinical Evidence. Neuroscience. 2011;191:78–90. doi: 10.1016/j.neuroscience.2011.06.076. PubMed DOI

Ahmed Juvale I.I., Che Has A.T. The Evolution of the Pilocarpine Animal Model of Status Epilepticus. Heliyon. 2020;6:e04557. doi: 10.1016/j.heliyon.2020.e04557. PubMed DOI PMC

Williamson J., Singh T., Kapur J. Neurobiology of Organophosphate-Induced Seizures. Epilepsy Behav. 2019;101:106426. doi: 10.1016/j.yebeh.2019.07.027. PubMed DOI

Duysen E.G., Stribley J.A., Fry D.L., Hinrichs S.H., Lockridge O. Rescue of the Acetylcholinesterase Knockout Mouse by Feeding a Liquid Diet; Phenotype of the Adult Acetylcholinesterase Deficient Mouse. Brain Res. Dev. Brain Res. 2002;137:43–54. doi: 10.1016/S0165-3806(02)00367-X. PubMed DOI

Farar V., Mohr F., Legrand M., Lamotte d’Incamps B., Cendelin J., Leroy J., Abitbol M., Bernard V., Baud F., Fournet V., et al. Near-Complete Adaptation of the PRiMA Knockout to the Lack of Central Acetylcholinesterase. J. Neurochem. 2012;122:1065–1080. doi: 10.1111/j.1471-4159.2012.07856.x. PubMed DOI

Miller S.L., Aroniadou-Anderjaska V., Pidoplichko V.I., Figueiredo T.H., Apland J.P., Krishnan J.K.S., Braga M.F.M. The M1 Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala. J. Pharmacol. Exp. Ther. 2017;360:23–32. doi: 10.1124/jpet.116.236125. PubMed DOI PMC

Palomero-Gallagher N., Schleicher A., Bidmon H.-J., Pannek H.-W., Hans V., Gorji A., Speckmann E.-J., Zilles K. Multireceptor Analysis in Human Neocortex Reveals Complex Alterations of Receptor Ligand Binding in Focal Epilepsies. Epilepsia. 2012;53:1987–1997. doi: 10.1111/j.1528-1167.2012.03634.x. PubMed DOI

Akyüz E., Doğanyiğit Z., Paudel Y.N., Kaymak E., Yilmaz S., Uner A., Shaikh M.F. Increased ACh-Associated Immunoreactivity in Autonomic Centers in PTZ Kindling Model of Epilepsy. Biomedicines. 2020;8:113. doi: 10.3390/biomedicines8050113. PubMed DOI PMC

Wang Y., Tan B., Wang Y., Chen Z. Cholinergic Signaling, Neural Excitability, and Epilepsy. Molecules. 2021;26:2258. doi: 10.3390/molecules26082258. PubMed DOI PMC

Reddy D.S., Estes W.A. Clinical Potential of Neurosteroids for CNS Disorders. Trends Pharmacol. Sci. 2016;37:543–561. doi: 10.1016/j.tips.2016.04.003. PubMed DOI PMC

Rhodes M.E., Li P.K., Flood J.F., Johnson D.A. Enhancement of Hippocampal Acetylcholine Release by the Neurosteroid Dehydroepiandrosterone Sulfate: An in Vivo Microdialysis Study. Brain Res. 1996;733:284–286. doi: 10.1016/0006-8993(96)00751-2. PubMed DOI

Osborne D.M., Frye C.A. Estrogen Increases Latencies to Seizures and Levels of 5alpha-Pregnan-3alpha-Ol-20-One in Hippocampus of Wild-Type, but Not 5alpha-Reductase Knockout, Mice. Epilepsy Behav. 2009;16:411–414. doi: 10.1016/j.yebeh.2009.08.016. PubMed DOI PMC

Reddy D.S. Neuroendocrine Aspects of Catamenial Epilepsy. Horm. Behav. 2013;63:254–266. doi: 10.1016/j.yhbeh.2012.04.016. PubMed DOI PMC

Thorn C.A., Popiolek M., Stark E., Edgerton J.R. Effects of M1 and M4 Activation on Excitatory Synaptic Transmission in CA1. Hippocampus. 2017;27:794–810. doi: 10.1002/hipo.22732. PubMed DOI PMC

Dasari S., Gulledge A.T. M1 and M4 Receptors Modulate Hippocampal Pyramidal Neurons. J. Neurophysiol. 2011;105:779–792. doi: 10.1152/jn.00686.2010. PubMed DOI PMC

Righes Marafiga J., Vendramin Pasquetti M., Calcagnotto M.E. GABAergic Interneurons in Epilepsy: More than a Simple Change in Inhibition. Epilepsy Behav. 2021;121:106935. doi: 10.1016/j.yebeh.2020.106935. PubMed DOI

Jones N.C., Lee H.E., Yang M., Rees S.M., Morris M.J., O’Brien T.J., Salzberg M.R. Repeatedly Stressed Rats Have Enhanced Vulnerability to Amygdala Kindling Epileptogenesis. Psychoneuroendocrinology. 2013;38:263–270. doi: 10.1016/j.psyneuen.2012.06.005. PubMed DOI

Poewe W., Seppi K., Tanner C.M., Halliday G.M., Brundin P., Volkmann J., Schrag A.-E., Lang A.E. Parkinson Disease. Nat. Rev. Dis. Prim. 2017;3:17013. doi: 10.1038/nrdp.2017.13. PubMed DOI

McGregor M.M., Nelson A.B. Circuit Mechanisms of Parkinson’s Disease. Neuron. 2019;101:1042–1056. doi: 10.1016/j.neuron.2019.03.004. PubMed DOI

Acharya S., Kim K.-M. Roles of the Functional Interaction between Brain Cholinergic and Dopaminergic Systems in the Pathogenesis and Treatment of Schizophrenia and Parkinson’s Disease. Int. J. Mol. Sci. 2021;22:4299. doi: 10.3390/ijms22094299. PubMed DOI PMC

Moehle M.S., Pancani T., Byun N., Yohn S.E., Wilson G.H., Dickerson J.W., Remke D.H., Xiang Z., Niswender C.M., Wess J., et al. Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M4 Muscarinic Receptor. Neuron. 2017;96:1358–1372.e4. doi: 10.1016/j.neuron.2017.12.008. PubMed DOI PMC

Foster D.J., Wilson J.M., Remke D.H., Mahmood M.S., Uddin M.J., Wess J., Patel S., Marnett L.J., Niswender C.M., Jones C.K., et al. Antipsychotic-like Effects of M 4 Positive Allosteric Modulators Are Mediated by CB 2 Receptor-Dependent Inhibition of Dopamine Release. Neuron. 2016;91:1244–1252. doi: 10.1016/j.neuron.2016.08.017. PubMed DOI PMC

Eskow Jaunarajs K.L., Bonsi P., Chesselet M.F., Standaert D.G., Pisani A. Striatal Cholinergic Dysfunction as a Unifying Theme in the Pathophysiology of Dystonia. Prog. Neurobiol. 2015;127–128:91–107. doi: 10.1016/j.pneurobio.2015.02.002. PubMed DOI PMC

Sawada H., Ibi M., Kihara T., Honda K., Nakamizo T., Kanki R., Nakanishi M., Sakka N., Akaike A., Shimohama S. Estradiol Protects Dopaminergic Neurons in a MPP+Parkinson’s Disease Model. Neuropharmacology. 2002;42:1056–1064. doi: 10.1016/S0028-3908(02)00049-7. PubMed DOI

Borowicz-Reutt K. Neurosteroids and Their Neuroprotective Actions; Proceedings of the Health Science International Conference (HSIC 2017); 4–5 October 2017. Malang, Indonesia; Paris, France: Atlantis Press; 2017.

Nestler E.J. International Review of Neurobiology. Volume 124. Academic Press Inc.; Cambridge, MA, USA: 2015. Role of the Brain’s Reward Circuitry in Depression; pp. 151–170. PubMed PMC

Cooper S., Robison A.J., Mazei-Robison M.S. Reward Circuitry in Addiction. Neurotherapeutics. 2017;14:687–697. doi: 10.1007/s13311-017-0525-z. PubMed DOI PMC

Moran-Santa Maria M.M., Flanagan J., Brady K. Ovarian Hormones and Drug Abuse. Curr. Psychiatry Rep. 2014;16:511. doi: 10.1007/s11920-014-0511-7. PubMed DOI PMC

Fox H.C., Sofuoglu M., Morgan P.T., Tuit K.L., Sinha R. The Effects of Exogenous Progesterone on Drug Craving and Stress Arousal in Cocaine Dependence: Impact of Gender and Cue Type. Psychoneuroendocrinology. 2013;38:1532–1544. doi: 10.1016/j.psyneuen.2012.12.022. PubMed DOI PMC

Lynch W.J., Roth M.E., Mickelberg J.L., Carroll M.E. Role of Estrogen in the Acquisition of Intravenously Self-Administered Cocaine in Female Rats. Pharmacol. Biochem. Behav. 2001;68:641–646. doi: 10.1016/S0091-3057(01)00455-5. PubMed DOI

Everitt B.J., Robbins T.W. Neural Systems of Reinforcement for Drug Addiction: From Actions to Habits to Compulsion. Nat. Neurosci. 2005;8:1481–1489. doi: 10.1038/nn1579. PubMed DOI

Gunter B.W., Gould R.W., Bubser M., McGowan K.M., Lindsley C.W., Jones C.K. Selective Inhibition of M5 Muscarinic Acetylcholine Receptors Attenuates Cocaine Self-Administration in Rats. Addict. Biol. 2018;23:1106–1116. doi: 10.1111/adb.12567. PubMed DOI PMC

Gentry P.R., Kokubo M., Bridges T.M., Kett N.R., Harp J.M., Cho H.P., Smith E., Chase P., Hodder P.S., Niswender C.M., et al. Discovery of the First M5-Selective and CNS Penetrant Negative Allosteric Modulator (NAM) of a Muscarinic Acetylcholine Receptor: (S)-9b-(4-Chlorophenyl)-1-(3,4-Difluorobenzoyl)-2,3-Dihydro-1H-Imidazo[2,1-a]Isoindol-5(9bH)-One (ML375) J. Med. Chem. 2013;56:9351–9355. doi: 10.1021/jm4013246. PubMed DOI PMC

Wohleb E.S., Wu M., Gerhard D.M., Taylor S.R., Picciotto M.R., Alreja M., Duman R.S. GABA Interneurons Mediate the Rapid Antidepressant-like Effects of Scopolamine. J. Clin. Investig. 2016;126:2482–2494. doi: 10.1172/JCI85033. PubMed DOI PMC

Dagytė G., Den Boer J.A., Trentani A. The Cholinergic System and Depression. Behav. Brain Res. 2011;221:574–582. doi: 10.1016/j.bbr.2010.02.023. PubMed DOI

Gibbons A.S., Scarr E., McLean C., Sundram S., Dean B. Decreased Muscarinic Receptor Binding in the Frontal Cortex of Bipolar Disorder and Major Depressive Disorder Subjects. J. Affect. Disord. 2009;116:184–191. doi: 10.1016/j.jad.2008.11.015. PubMed DOI PMC

Gillin J.C., Sutton L., Ruiz C., Darko D., Golshan S., Risch S.C., Janowsky D. The Effects of Scopolamine on Sleep and Mood in Depressed Patients with a History of Alcoholism and a Normal Comparison Group. Biol. Psychiatry. 1991;30:157–169. doi: 10.1016/0006-3223(91)90170-Q. PubMed DOI

Witkin J.M., Overshiner C., Li X., Catlow J.T., Wishart G.N., Schober D.A., Heinz B.A., Nikolayev A., Tolstikov V.V., Anderson W.H., et al. M1 and M2 Muscarinic Receptor Subtypes Regulate Antidepressant-like Effects of the Rapidly Acting Antidepressant Scopolamine. J. Pharmacol. Exp. Ther. 2014;351:448–456. doi: 10.1124/jpet.114.216804. PubMed DOI

Navarria A., Wohleb E.S., Voleti B., Ota K.T., Dutheil S., Lepack A.E., Dwyer J.M., Fuchikami M., Becker A., Drago F., et al. Rapid Antidepressant Actions of Scopolamine: Role of Medial Prefrontal Cortex and M1-Subtype Muscarinic Acetylcholine Receptors. Neurobiol. Dis. 2015;82:254–261. doi: 10.1016/j.nbd.2015.06.012. PubMed DOI PMC

Standeven L.R., McEvoy K.O., Osborne L.M. Progesterone, Reproduction, and Psychiatric Illness. Best Pract. Res. Clin. Obstet. Gynaecol. 2020;69:108–126. doi: 10.1016/j.bpobgyn.2020.06.001. PubMed DOI PMC

Furey M.L., Khanna A., Hoffman E.M., Drevets W.C. Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women than in Men. Neuropsychopharmacology. 2010;35:2479–2488. doi: 10.1038/npp.2010.131. PubMed DOI PMC

Andréen L., Sundström-Poromaa I., Bixo M., Nyberg S., Bäckström T. Allopregnanolone Concentration and Mood--a Bimodal Association in Postmenopausal Women Treated with Oral Progesterone. Psychopharmacology. 2006;187:209–221. doi: 10.1007/s00213-006-0417-0. PubMed DOI

Wharton W., Gleason C.E., Olson S.R.M.S., Carlsson C.M., Asthana S. Neurobiological Underpinnings of the Estrogen—Mood Relationship. Curr. Psychiatry Rev. 2012;8:247–256. doi: 10.2174/157340012800792957. PubMed DOI PMC