Social species form organizations that support individuals because the consequent social behaviors help these organisms survive. The isolation of these individuals may be a stressor. We reviewed the potential mechanisms of the effects of social isolation on cholinergic signaling and vice versa how changes in cholinergic signaling affect changes due to social isolation.There are two important problems regarding this topic. First, isolation schemes differ in their duration (1-165 days) and initiation (immediately after birth to adulthood). Second, there is an important problem that is generally not considered when studying the role of the cholinergic system in neurobehavioral correlates: muscarinic and nicotinic receptor subtypes do not differ sufficiently in their affinity for orthosteric site agonists and antagonists. Some potential cholinesterase inhibitors also affect other targets, such as receptors or other neurotransmitter systems. Therefore, the role of the cholinergic system in social isolation should be carefully considered, and multiple receptor systems may be involved in the central nervous system response, although some subtypes are involved in specific functions. To determine the role of a specific receptor subtype, the presence of a specific subtype in the central nervous system should be determined using search in knockout studies with the careful application of specific agonists/antagonists.

Institute of Physiology 1st Faculty of Medicine Charles University Prague Czechia

Zobrazit více v PubMed

Ago Y., Koda K., Ota Y., Kita Y., Fukada A., Takuma K., et al. (2011). Donepezil, but Not Galantamine, Blocks Muscarinic Receptor-Mediated In Vitro and In Vivo Responses. Synapse 65, 1373–1377. 10.1002/syn.20969 PubMed DOI

Ahlin G., Karlsson J., Pedersen J. M., Gustavsson L., Larsson R., Matsson P., et al. (2008). Structural Requirements for Drug Inhibition of the Liver Specific Human Organic Cation Transport Protein 1. J. Med. Chem. 51, 5932–5942. 10.1021/jm8003152 PubMed DOI

Albuquerque E. X., Pereira E. F., Alkondon M., Rogers S. W. (2009). Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function. Physiol. Rev. 89, 73–120. 10.1152/physrev.00015.2008 PubMed DOI PMC

Aleklett K., Boddy L. (2021). Fungal Behaviour: a New Frontier in Behavioural Ecology. Trends Ecol. Evol. 36, 787–796. 10.1016/j.tree.2021.05.006 PubMed DOI

Alexander S. P., Christopoulos A., Davenport A. P., Kelly E., Marrion N. V., Peters J. A., et al. (2017a). THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: G Protein-Coupled Receptors. Br. J. Pharmacol. 174 (1), S17–s129. 10.1111/bph.13878 PubMed DOI PMC

Alexander S. P., Peters J. A., Kelly E., Marrion N. V., Faccenda E., Harding S. D., et al. (2017b). THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Ligand-Gated Ion Channels. Br. J. Pharmacol. 174, S130–S159. 10.1111/bph.13879 PubMed DOI PMC

Becerra M. A., Herrera M. D., Marhuenda E. (2001). Action of Tacrine on Muscarinic Receptors in Rat Intestinal Smooth Muscle. J. Auton. Pharmacol. 21, 113–119. 10.1046/j.1365-2680.2001.00213.x PubMed DOI

Bell R., Warburton D. M., Brown K. (1985). Drugs as Research Tools in Psychology: Cholinergic Drugs and Aggression. Neuropsychobiology 14, 181–192. 10.1159/000118225 PubMed DOI

Bockman C. S., Zeng W., Hall J., Mittelstet B., Schwarzkopf L., Stairs D. J. (2018). Nicotine Drug Discrimination and Nicotinic Acetylcholine Receptors in Differentially Reared Rats. Psychopharmacology (Berl) 235, 1415–1426. 10.1007/s00213-018-4850-7 PubMed DOI

Branchi I., Campolongo P., Alleva E. (2004). Scopolamine Effects on Ultrasonic Vocalization Emission and Behavior in the Neonatal Mouse. Behav. Brain Res. 151, 9–16. 10.1016/S0166-4328(03)00277-8 PubMed DOI

Brown D. A. (2010). Muscarinic Acetylcholine Receptors (mAChRs) in the Nervous System: Some Functions and Mechanisms. J. Mol. Neurosci. 41, 340–346. 10.1007/s12031-010-9377-2 PubMed DOI

Burnstock G. (2009). Autonomic Neurotransmission: 60 Years since Sir Henry Dale. Annu. Rev. Pharmacol. Toxicol. 49, 1–30. 10.1146/annurev.pharmtox.052808.102215 PubMed DOI

Cacioppo J. T., Hawkley L. C., Norman G. J., Berntson G. G. (2011). Social Isolation. Ann. N. Y Acad. Sci. 1231, 17–22. 10.1111/j.1749-6632.2011.06028.x PubMed DOI PMC

Cantí C., Bodas E., Marsal J., Solsona C. (1998). Tacrine and Physostigmine Block Nicotinic Receptors in Xenopus Oocytes Injected with Torpedo Electroplaque Membranes. Eur. J. Pharmacol. 363, 197–202. 10.1016/s0014-2999(98)00793-6 PubMed DOI

Carr B. J., Mihara K., Ramachandran R., Saifeddine M., Nathanson N. M., Stell W. K., et al. (2018). Myopia-Inhibiting Concentrations of Muscarinic Receptor Antagonists Block Activation of Alpha2A-Adrenoceptors In Vitro . Invest. Ophthalmol. Vis. Sci. 59, 2778–2791. 10.1167/iovs.17-22562 PubMed DOI

Caruso M. J., Reiss D. E., Caulfield J. I., Thomas J. L., Baker A. N., Cavigelli S. A., et al. (2018). Adolescent Chronic Variable Social Stress Influences Exploratory Behavior and Nicotine Responses in Male, but Not Female, BALB/cJ Mice. Brain Res. Bull. 138, 37–49. 10.1016/j.brainresbull.2017.08.001 PubMed DOI PMC

Champtiaux N., Changeux J. P. (2004). Knockout and Knockin Mice to Investigate the Role of Nicotinic Receptors in the central Nervous System. Prog. Brain Res. 145, 235–251. 10.1016/s0079-6123(03)45016-4 PubMed DOI

Cheeta S., Irvine E., File S. E. (2001). Social Isolation Modifies Nicotine's Effects in Animal Tests of Anxiety. Br. J. Pharmacol. 132, 1389–1395. 10.1038/sj.bjp.0703991 PubMed DOI PMC

Cilia J., Cluderay J. E., Robbins M. J., Reavill C., Southam E., Kew J. N., et al. (2005). Reversal of Isolation-Rearing-Induced PPI Deficits by an Alpha7 Nicotinic Receptor Agonist. Psychopharmacology (Berl) 182, 214–219. 10.1007/s00213-005-0069-5 PubMed DOI

Cilia J., Reavill C., Hagan J. J., Jones D. N. (2001). Long-term Evaluation of Isolation-Rearing Induced Prepulse Inhibition Deficits in Rats. Psychopharmacology (Berl) 156, 327–337. 10.1007/s002130100786 PubMed DOI

Cohen S., Syme S. L. (1985). in Social Support and Health/. Leonard Syme. Editor Sheldon Cohen S. (Orlando, Fla: Academic Press; ).

Da Vanzo J. P., Daugherty M., Ruckart R., Kang L. (1966). Pharmacological and Biochemical Studies in Isolation-Induced Fighting Mice. Psychopharmacologia 9, 210–219. 10.1007/BF02198481 PubMed DOI

Dani J. A. (2001). Overview of Nicotinic Receptors and Their Roles in the central Nervous System. Biol. Psychiatry 49, 166–174. 10.1016/s0006-3223(00)01011-8 PubMed DOI

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

Defeudis F. V. (1972). Binding of 3 H-Acetylcholine and 14 C- -aminobutyric Acid to Subcellular Fractions of the Brains of Differentially-Housed Mice. Neuropharmacology 11, 879–888. 10.1016/0028-3908(72)90047-0 PubMed DOI

Del-Bel E. A., Joca S. R., Padovan C. M., Guimarães F. S. (2002). Effects of Isolation-Rearing on serotonin-1A and M1-Muscarinic Receptor Messenger RNA Expression in the Hipocampal Formation of Rats. Neurosci. Lett. 332, 123–126. 10.1016/s0304-3940(02)00933-3 PubMed DOI

Dencker D., Thomsen M., Wörtwein G., Weikop P., Cui Y., Jeon J., et al. (2012). Muscarinic Acetylcholine Receptor Subtypes as Potential Drug Targets for the Treatment of Schizophrenia, Drug Abuse and Parkinson's Disease. ACS Chem. Neurosci. 3, 80–89. 10.1021/cn200110q PubMed DOI PMC

Deurveilher S., Ryan N., Burns J., Semba K. (2013). Social and Environmental Contexts Modulate Sleep Deprivation-Induced C-Fos Activation in Rats. Behav. Brain Res. 256, 238–249. 10.1016/j.bbr.2013.08.029 PubMed DOI

Dörner G., Bluth R., Tönjes R. (1982). Acetylcholine Concentrations in the Developing Brain Appear to Affect Emotionality and Mental Capacity in Later Life. Acta Biol. Med. Ger. 41, 721–723. PubMed

Egashira T. (2000). Effects of Breeding Conditions on Neurochemical Cholinergic and Monoaminergic Markers in Aged Rat Brain. Nihon Ronen Igakkai Zasshi 37, 233–238. 10.3143/geriatrics.37.233 PubMed DOI

Eiden L. E. (1998). The Cholinergic Gene Locus. J. Neurochem. 70, 2227–2240. 10.1046/j.1471-4159.1998.70062227.x PubMed DOI

Essman W. B. (1971). Changes in Cholinergic Activity and Avoidance Behavior by Nicotine in Differentially Housed Mice. Int. J. Neurosci. 2, 199–205. 10.3109/00207457109147002 PubMed DOI

Farar V., Mohr F., Legrand M., Lamotte d'Incamps B., Cendelin J., Leroy J., et al. (2012). Near-complete Adaptation of the PRiMA Knockout to the Lack of central Acetylcholinesterase. J. Neurochem. 122, 1065–1080. 10.1111/j.1471-4159.2012.07856.x PubMed DOI

Farar V., Myslivecek J. (2016). “Autoradiography Assessment of Muscarinic Receptors in the Central Nervous System,” in Muscarinic Receptor: From Structure to Animal Models. Editors Myslivecek J., Jakubik J. (New York: Springer; ), 159–180. 10.1007/978-1-4939-2858-3_9 DOI

Francès H., Lecrubier Y., Simon P. (1980). Isolation Increases the Responses to Beta-Adrenergic Stimulation in Mice. Biol. Psychiatry 15, 965–969. PubMed

Frances H., Maurin Y., Lecrubier Y., Puech A. J., Simon P. (1981). Effect of Chronic Lithium Treatment on Isolation-Induced Behavioral and Biochemical Effects in Mice. Eur. J. Pharmacol. 72, 337–341. 10.1016/0014-2999(81)90572-0 PubMed DOI

Garrido P., De Blas M., Ronzoni G., Cordero I., Antón M., Giné E., et al. (2013). Differential Effects of Environmental Enrichment and Isolation Housing on the Hormonal and Neurochemical Responses to Stress in the Prefrontal Cortex of the Adult Rat: Relationship to Working and Emotional Memories. J. Neural Transm. (Vienna) 120, 829–843. 10.1007/s00702-012-0935-3 PubMed DOI

Gaulton A., Hersey A., Nowotka M., Bento A. P., Chambers J., Mendez D., et al. (2016). The ChEMBL Database in 2017. Nucleic Acids Res. 45, D945–D954. 10.1093/nar/gkw1074 PubMed DOI PMC

Gotti C., Clementi F. (2004). Neuronal Nicotinic Receptors: from Structure to Pathology. Prog. Neurobiol. 74, 363–396. 10.1016/j.pneurobio.2004.09.006 PubMed DOI

Grippo A. J., Scotti M. L., Wardwell J., Mcneal N., Bates S. L., Chandler D. L., et al. (2018). Cardiac and Behavioral Effects of Social Isolation and Experimental Manipulation of Autonomic Balance. Auton. Neurosci. 214, 1–8. 10.1016/j.autneu.2018.08.002 PubMed DOI PMC

Haddad E. B., Mak J. C., Hislop A., Haworth S. G., Barnes P. J. (1994). Characterization of Muscarinic Receptor Subtypes in Pig Airways: Radioligand Binding and Northern Blotting Studies. Am. J. Physiol. 266, L642–L648. 10.1152/ajplung.1994.266.6.L642 PubMed DOI

Hao S., Avraham Y., Bonne O., Berry E. M. (2001). Separation-induced Body Weight Loss, Impairment in Alternation Behavior, and Autonomic Tone: Effects of Tyrosine. Pharmacol. Biochem. Behav. 68, 273–281. 10.1016/s0091-3057(00)00448-2 PubMed DOI

Harada T., Fushimi K., Kato A., Ito Y., Nishijima S., Sugaya K., et al. (2010). Demonstration of Muscarinic and Nicotinic Receptor Binding Activities of Distigmine to Treat Detrusor Underactivity. Biol. Pharm. Bull. 33, 653–658. 10.1248/bpb.33.653 PubMed DOI

Herbut M., Roliński Z. (1985). The Cholinergic Influences on Aggression in Isolated Mice. Pol. J. Pharmacol. Pharm. 37, 1–10. PubMed

Heritch A. J., Henderson K., Westfall T. C. (1990). Effects of Social Isolation on Brain Catecholamines and Forced Swimming in Rats: Prevention by Antidepressant Treatment. J. Psychiatr. Res. 24, 251–258. 10.1016/0022-3956(90)90014-h PubMed DOI

Higashino K., Ago Y., Umeki T., Hasebe S., Onaka Y., Hashimoto H., et al. (2016). Rivastigmine Improves Isolation Rearing-Induced Prepulse Inhibition Deficits via Muscarinic Acetylcholine Receptors in Mice. Psychopharmacology (Berl) 233, 521–528. 10.1007/s00213-015-4123-7 PubMed DOI

Huang H. J., Liang K. C., Ke H. C., Chang Y. Y., Hsieh-Li H. M. (2011). Long-term Social Isolation Exacerbates the Impairment of Spatial Working Memory in APP/PS1 Transgenic Mice. Brain Res. 1371, 150–160. 10.1016/j.brainres.2010.11.043 PubMed DOI

Ito Y., Oyunzul L., Seki M., Fujino Oki T., Matsui M., Yamada S. (2009). Quantitative Analysis of the Loss of Muscarinic Receptors in Various Peripheral Tissues in M1-M5 Receptor Single Knockout Mice. Br. J. Pharmacol. 156, 1147–1153. 10.1111/j.1476-5381.2009.00113.x PubMed DOI PMC

Jones G. H., Marsden C. A., Robbins T. W. (1991). Behavioural Rigidity and Rule-Learning Deficits Following Isolation-Rearing in the Rat: Neurochemical Correlates. Behav. Brain Res. 43, 35–50. 10.1016/s0166-4328(05)80050-6 PubMed DOI

Kling A., Finer S., Gilmour J. (1969). Regional Development of Acetylcholinesterase Activity in the Maternally Reared and Maternally Deprived Cat. Int. J. Neuropharmacol 8, 25–31. 10.1016/0028-3908(69)90031-8 PubMed DOI

Koda K., Ago Y., Kawasaki T., Hashimoto H., Baba A., Matsuda T. (2008). Galantamine and Donepezil Differently Affect Isolation Rearing-Induced Deficits of Prepulse Inhibition in Mice. Psychopharmacology (Berl) 196, 293–301. 10.1007/s00213-007-0962-1 PubMed DOI

Koda K., Ago Y., Yano K., Nishimura M., Kobayashi H., Fukada A., et al. (2011). Involvement of Decreased Muscarinic Receptor Function in Prepulse Inhibition Deficits in Mice Reared in Social Isolation. Br. J. Pharmacol. 162, 763–772. 10.1111/j.1476-5381.2010.01080.x PubMed DOI PMC

Koukouli F., Changeux J. P. (2020). Do Nicotinic Receptors Modulate High-Order Cognitive Processing? Trends Neurosci. 43, 550–564. 10.1016/j.tins.2020.06.001 PubMed DOI

Kruse A. C., Kobilka B. K., Gautam D., Sexton P. M., Christopoulos A., Wess J. (2014). Muscarinic Acetylcholine Receptors: Novel Opportunities for Drug Development. Nat. Rev. Drug Discov. 13, 549–560. 10.1038/nrd4295 PubMed DOI PMC

Lapiz M. D., Fulford A., Muchimapura S., Mason R., Parker T., Marsden C. A. (2003). Influence of Postweaning Social Isolation in the Rat on Brain Development, Conditioned Behavior, and Neurotransmission. Neurosci. Behav. Physiol. 33, 13–29. 10.1023/a:1021171129766 PubMed DOI

Lehmann K., Hundsdörfer B., Hartmann T., Teuchert-Noodt G. (2004). The Acetylcholine Fiber Density of the Neocortex Is Altered by Isolated Rearing and Early Methamphetamine Intoxication in Rodents. Exp. Neurol. 189, 131–140. 10.1016/j.expneurol.2004.05.017 PubMed DOI

Leng A., Feldon J., Ferger B. (2004). Long-term Social Isolation and Medial Prefrontal Cortex: Dopaminergic and Cholinergic Neurotransmission. Pharmacol. Biochem. Behav. 77, 371–379. 10.1016/j.pbb.2003.11.011 PubMed DOI

Li H. Q., Pratelli M., Godavarthi S., Zambetti S., Spitzer N. C. (2020). Decoding Neurotransmitter Switching: The Road Forward. J. Neurosci. 40, 4078–4089. 10.1523/JNEUROSCI.0005-20.2020 PubMed DOI PMC

Lockhart B., Closier M., Howard K., Steward C., Lestage P. (2001). Differential Inhibition of [3H]-Oxotremorine-M and [3H]-Quinuclinidyl Benzilate Binding to Muscarinic Receptors in Rat Brain Membranes with Acetylcholinesterase Inhibitors. Naunyn Schmiedebergs Arch. Pharmacol. 363, 429–438. 10.1007/s002100000382 PubMed DOI

Maelicke A., Albuquerque E. X. (2000). Allosteric Modulation of Nicotinic Acetylcholine Receptors as a Treatment Strategy for Alzheimer's Disease. Eur. J. Pharmacol. 393, 165–170. 10.1016/s0014-2999(00)00093-5 PubMed DOI

Maksay G., Laube B., Betz H. (1999). Selective Blocking Effects of Tropisetron and Atropine on Recombinant glycine Receptors. J. Neurochem. 73, 802–806. 10.1046/j.1471-4159.1999.0730802.x PubMed DOI

Mallet J., Houhou L., Pajak F., Oda Y., Cervini R., Bejanin S., et al. (1998). The Cholinergic Locus: ChAT and VAChT Genes. J. Physiol. Paris 92, 145–147. 10.1016/S0928-4257(98)80153-8 PubMed DOI

Manouze H., Ghestem A., Poillerat V., Bennis M., Ba-M’hamed S., Benoliel J. J., et al. (2019). Effects of Single Cage Housing on Stress, Cognitive, and Seizure Parameters in the Rat and Mouse Pilocarpine Models of Epilepsy. eneuro 6, ENEURO 0179-0118 2019. 10.1523/eneuro.0179-18.2019 PubMed DOI PMC

Matsumoto K., Fujiwara H., Araki R., Yabe T. (2019). Post-weaning Social Isolation of Mice: A Putative Animal Model of Developmental Disorders. J. Pharmacol. Sci. 141, 111–118. 10.1016/j.jphs.2019.10.002 PubMed DOI

Mccormick C. M., Robarts D., Kopeikina K., Kelsey J. E. (2005). Long-lasting, Sex- and Age-specific Effects of Social Stressors on Corticosterone Responses to Restraint and on Locomotor Responses to Psychostimulants in Rats. Horm. Behav. 48, 64–74. 10.1016/j.yhbeh.2005.01.008 PubMed DOI

Mighiu A. S., Heximer S. P. (2012). Controlling Parasympathetic Regulation of Heart Rate: a Gatekeeper Role for RGS Proteins in the Sinoatrial Node. Front. Physiol. 3, 204. 10.3389/fphys.2012.00204 PubMed DOI PMC

Millan M. J., Gobert A., Panayi F., Rivet J. M., Dekeyne A., Brocco M., et al. (2008). The Melanin-Concentrating Hormone1 Receptor Antagonists, SNAP-7941 and GW3430, Enhance Social Recognition and Dialysate Levels of Acetylcholine in the Frontal Cortex of Rats. Int. J. Neuropsychopharmacol. 11, 1105–1122. 10.1017/S1461145708008894 PubMed DOI

Muchimapura S., Mason R., Marsden C. A. (2003). Effect of Isolation Rearing on Pre- and post-synaptic Serotonergic Function in the Rat Dorsal hippocampus. Synapse 47, 209–217. 10.1002/syn.10167 PubMed DOI

Murphy G. P., Dudley S. A. (2009). Kin Recognition: Competition and Cooperation in Impatiens (Balsaminaceae). Am. J. Bot. 96, 1990–1996. 10.3732/ajb.0900006 PubMed DOI

Myslivecek J., Farar V., Valuskova P. (2017). M(4) Muscarinic Receptors and Locomotor Activity Regulation. Physiol. Res. 66, S443–s455. 10.33549/physiolres.933796 PubMed DOI

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

Myslivecek J. (2019). “M4 Muscarinic Receptors – Structure, Ligands, Detection and Function,” in Acetylcholine Receptors in Health and Disease. Editor Gupta A. E. (New York: Nova Science Publishers; ), 41–68.

Myslivecek J. (2015). The Basis of the Stress Reaction. Curr. Sci. 109, 716–726.

Noschang C., Lampert C., Krolow R., De Almeida R. M. M. (2021). Social Isolation at Adolescence: a Systematic Review on Behaviour Related to Cocaine, Amphetamine and Nicotine Use in Rats and Mice. Psychopharmacology (Berl) 238, 927–947. 10.1007/s00213-021-05777-z PubMed DOI

O'neill H. C., Rieger K., Kem W. R., Stevens K. E. (2003). DMXB, an Alpha7 Nicotinic Agonist, Normalizes Auditory Gating in Isolation-Reared Rats. Psychopharmacology (Berl) 169, 332–339. 10.1007/s00213-003-1482-2 PubMed DOI

Oehler J., Jähkel M., Schmidt J. (1980). Effect of Social Isolation on the Transmitter Sensitivity of Striatal and Hippocampal Neurons of the Rat. Acta Biol. Med. Ger. 39, 1089–1093. PubMed

Okada R., Fujiwara H., Mizuki D., Araki R., Yabe T., Matsumoto K. (2015). Involvement of Dopaminergic and Cholinergic Systems in Social Isolation-Induced Deficits in Social Affiliation and Conditional Fear Memory in Mice. Neuroscience 299, 134–145. 10.1016/j.neuroscience.2015.04.064 PubMed DOI

Oki T., Takagi Y., Inagaki S., Taketo M. M., Manabe T., Matsui M., et al. (2005). Quantitative Analysis of Binding Parameters of [3H]N-Methylscopolamine in central Nervous System of Muscarinic Acetylcholine Receptor Knockout Mice. Brain Res. Mol. Brain Res. 133, 6–11. 10.1016/j.molbrainres.2004.09.012 PubMed DOI

Okuda T., Haga T. (2003). High-affinity Choline Transporter. Neurochem. Res. 28, 483–488. 10.1023/a:1022809003997 PubMed DOI

Ouchi H., Ono K., Murakami Y., Matsumoto K. (2013). Social Isolation Induces Deficit of Latent Learning Performance in Mice: a Putative Animal Model of Attention Deficit/hyperactivity Disorder. Behav. Brain Res. 238, 146–153. 10.1016/j.bbr.2012.10.029 PubMed DOI

Pascuzzo G. J., Akaike A., Maleque M. A., Shaw K. P., Aronstam R. S., Rickett D. L., et al. (1984). The Nature of the Interactions of Pyridostigmine with the Nicotinic Acetylcholine Receptor-Ionic Channel Complex. I. Agonist, Desensitizing, and Binding Properties. Mol. Pharmacol. 25, 92–101. PubMed

Perrier A. L., Massoulié J., Krejci E. (2002). PRiMA: the Membrane Anchor of Acetylcholinesterase in the Brain. Neuron 33, 275–285. 10.1016/s0896-6273(01)00584-0 PubMed DOI

Petkov V. V., Rousseva S. (1984). Effects of Caffeine on Aggressive Behavior and Avoidance Learning of Rats with Isolation Syndrome. Methods Find Exp. Clin. Pharmacol. 6, 433–436. PubMed

Plaschke M., Dörner G., Krause E., Krause M., Kuhlmey H. M., Schuster T., et al. (1987). Vesicle Population of Synapses in the hippocampus of the Rat Following Early Postnatal Deprivation and Administration of Pyridostigmine. J. Hirnforsch 28, 1–11. PubMed

Plaschke M., Wenzel J., Dörner G., Tönjes R. (1986). Effect of Early Postnatal Social and Nutritional Deprivation and Simultaneous Treatment with Pyridostigmine on Synaptogenesis in the hippocampus of the Rat. Electron Microscopy, Morphometric and Stereologic Studies. J. Hirnforsch 27, 145–158. PubMed

Sahley T. L., Panksepp J., Zolovick A. J. (1981). Cholinergic Modulation of Separation Distress in the Domestic Chick. Eur. J. Pharmacol. 72, 261–264. 10.1016/0014-2999(81)90283-1 PubMed DOI

Samochocki M., Höffle A., Fehrenbacher A., Jostock R., Ludwig J., Christner C., et al. (2003). Galantamine Is an Allosterically Potentiating Ligand of Neuronal Nicotinic but Not of Muscarinic Acetylcholine Receptors. J. Pharmacol. Exp. Ther. 305, 1024–1036. 10.1124/jpet.102.045773 PubMed DOI

Shao S., Li M., Du W., Shao F., Wang W. (2014). Galanthamine, an Acetylcholine Inhibitor, Prevents Prepulse Inhibition Deficits Induced by Adolescent Social Isolation or MK-801 Treatment. Brain Res. 1589, 105–111. 10.1016/j.brainres.2014.09.032 PubMed DOI

Silverman R. B. (2004). “Receptors,” in The Organic Chemistry of Drug Design and Drug Action. Editor Silverman R. B.. Second Edition (San Diego: Academic Press; ), 121–172l. 10.1016/b978-0-08-051337-9.50008-0 DOI

Skok V. I. (2002). Nicotinic Acetylcholine Receptors in Autonomic Ganglia. Auton. Neurosci. 97, 1–11. 10.1016/s1566-0702(01)00386-1 PubMed DOI

Sowell J. W., Tang Y., Valli M. J., Chapman J. M., Usher L. A., Vaughan C. M., et al. (1992). Synthesis and Cholinergic Properties of Bis[[(dimethylamino)methyl]furanyl] Analogues of Ranitidine. J. Med. Chem. 35, 1102–1108. 10.1021/jm00084a015 PubMed DOI

Thal D. M., Sun B., Feng D., Nawaratne V., Leach K., Felder C. C., et al. (2016). Crystal Structures of the M1 and M4 Muscarinic Acetylcholine Receptors. Nature 531, 335–340. 10.1038/nature17188 PubMed DOI PMC

Tobin G., Giglio D., Lundgren O. (2009). Muscarinic Receptor Subtypes in the Alimentary Tract. J. Physiol. Pharmacol. 60, 3–21. PubMed

Tomizawa M., Yamamoto I. (1992). Binding of Nicotinoids and the Related Compounds to the Insect Nicotinic Acetyicholine Receptor. J. Pestic. Sci. 17, 231–236. 10.1584/jpestics.17.4_231 DOI

Valuskova P., Farar V., Forczek S., Krizova I., Myslivecek J. (2018). Autoradiography of 3H-Pirenzepine and 3H-AFDX-384 in Mouse Brain Regions: Possible Insights into M1, M2, and M4 Muscarinic Receptors Distribution. Front. Pharmacol. 9, 124. 10.3389/fphar.2018.00124 PubMed DOI PMC

Vass M., Kooistra A. J., Yang D., Stevens R. C., Wang M. W., De Graaf C. (2018). Chemical Diversity in the G Protein-Coupled Receptor Superfamily. Trends Pharmacol. Sci. 39, 494–512. 10.1016/j.tips.2018.02.004 PubMed DOI

Wang H., Liang S., Burgdorf J., Wess J., Yeomans J. (2008). Ultrasonic Vocalizations Induced by Sex and Amphetamine in M2, M4, M5 Muscarinic and D2 Dopamine Receptor Knockout Mice. PLoS ONE 3, e1893. 10.1371/journal.pone.0001893 PubMed DOI PMC

Wess J. (2005). Allosteric Binding Sites on Muscarinic Acetylcholine Receptors. Mol. Pharmacol. 68, 1506–1509. 10.1124/mol.105.019141 PubMed DOI

Wongwitdecha N., Marsden C. A. (1996). Effects of Social Isolation Rearing on Learning in the morris Water Maze. Brain Res. 715, 119–124. 10.1016/0006-8993(95)01578-7 PubMed DOI

Yang Z., Ney A., Cromer B. A., Ng H. L., Parker M. W., Lynch J. W. (2007). Tropisetron Modulation of the glycine Receptor: Femtomolar Potentiation and a Molecular Determinant of Inhibition. J. Neurochem. 100, 758–769. 10.1111/j.1471-4159.2006.04242.x PubMed DOI

Yoshimura H. (1980). Cholinergic Mechanisms in Scent Marking Behavior by Mongolian Gerbils (Meriones unguiculatus). Pharmacol. Biochem. Behav. 13, 519–523. 10.1016/0091-3057(80)90274-9 PubMed DOI

Yoshimura H., Ueki S. (1977). Biochemical Correlates in Mouse-Killing Behavior of the Rat: Prolonged Isolation and Brain Cholinergic Function. Pharmacol. Biochem. Behav. 6, 193–196. 10.1016/0091-3057(77)90073-9 PubMed DOI

Zhuang Z. P., Kung M. P., Kung H. F. (1993). Synthesis of (R,S)-trans-8-hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)amino]tetral in (trans-8-OH-PIPAT): a New 5-HT1A Receptor Ligand. J. Med. Chem. 36, 3161–3165. 10.1021/jm00073a016 PubMed DOI

Multitargeting nature of muscarinic orthosteric agonists and antagonists