Muscarinic M1 and M2 receptors, fasting and seizure development in animals/M1 ve M2 muskarinik reseptorler, aclik ve hayvanlarda nobet gelisimi.
Subtypes, regional distribution and synaptic localization of muscarinic receptors
Five muscarinic receptor subtypes, [M.sub.1], [M.sub.2], [M.sub.3], [M.sub.4] and [M.sub.5] have been identified. Their regional distribution and function in the brain are shown in Table 1. Muscarinic receptors in brain are located in neurons and glia cells. The most prevalent subtypes in rat brain are [M.sub.1] and [M.sub.2] receptors (1).
[M.sub.1], [M.sub.3] and [M.sub.5] receptors preferentially couple to G[alpha]q subunit that activate phospholipase C and generate second messengers, inositol triphosphate (IP3) and diacyl glycerol (DAG) and so intracellular calcium levels increase (Figure 1). These receptors may also activate phospholipase [A.sub.2] and phospholipase D in certain cells (2). On the other hand muscarinic [M.sub.2] and [M.sub.4] receptors preferentially couple to G[alpha]i/o subunit that inhibits adenylate cyclase and reduce the production of second messenger cyclic adenosine monophosphate (cAMP).
In brain, [M.sub.1] receptors are most commonly located postsynaptically while [M.sub.2] receptors are most commonly located presynaptically (3) (Figure 1). Blockade of postsynaptic muscarinic receptors reduces the effects of acetylcholine, whereas blockade of presynaptic muscarinic autoreceptors causes an increase in acetylcholine release (4). [M.sub.2] receptor was shown to be the main presynaptic autoreceptor in hippocampus and cerebral cortex (4), while both [M.sub.1] and [M.sub.2] receptors are located presynaptically and postsynaptically in cerebral cortex and hippocampus (3, 4, 5). Blockade of the [M.sub.2] receptors increases acetylcholine release in rat cerebral cortex and hippocampus (5, 6), whereas does not change acetylcholine release in human cerebral cortex cell culture (7). Presynaptic muscarinic autoreceptors ([M.sub.1], [M.sub.2], [M.sub.3], [M.sub.4]) inhibit acetylcholine release and are also located on noncholinergic nerve terminals as heteroreceptors and contribute to the effects of acetylcholine (8, 9). Blockade of [M.sub.1] heteroreceptors leads to a decrease in dopamine release (10) and blockade of [M.sub.2] heteroreceptors leads to an increase in glutamate release (8).
Muscarinic agonists and antagonists
Muscarine, pilocarpine and arecoline are the naturally occurring muscarinic agonists. Methacholine, carbachol, bethanechol and oxotremorine are the most known synthetic muscarinic agonists. Oxotremorine-M is the most potent N-methyl quaternary derivative of oxotremorine and cannot pass through the blood brain barrier. Arecoline and pilocarpine are the partial agonists. Selectivity and affinity for the muscarinic receptor subtypes differ between the muscarinic agonists and antagonists. Pilocarpine demonstrated selectivity for [M.sub.1] and [M.sub.3] subtypes regarding the intrinsic relative activity ([RA.sub.i]) (11). In this study arecoline, carbachol and oxotremorine-M lacked marked selectivity among [M.sub.1] to [M.sub.4] receptors. Xanomeline, the synthetic muscarinic agonist demonstrated functional selectivity for the [M.sub.1] and [M.sub.4] (12) muscarinic receptor subtypes. However binding studies showed similar affinity of xanomeline at all five subtypes (13).
The affinities of atropine, scopolamine, biperiden and pirenzepine, the main muscarinic receptor antagonists are shown in Table 2. Atropine, the nonselective muscarinic receptor antagonist has equal affinity for all muscarinic receptor subtypes, however scopolamine has lower affinity for [M.sub.2] receptors than the other subtypes. Biperiden has highest affinity for [M.sub.1] receptors. And pirenzepine is the selective antagonist of [M.sub.1] subtype. According to the in vitro muscarinic receptor radio ligand binding assays, the affinities of pirenzepine, biperiden, scopolamine (14) and atropine (15) were 98, 46, 6 and 2 fold higher for [M.sub.1] subtype than [M.sub.2] subtype (Table 2). Additionally atropine and scopolamine had showed 10 times higher affinity for presynaptic receptors than postsynaptic receptors (16).
CLINICAL AND RESEARCH CONSEQUENCES
Roles of musarinic receptors in physiological functions and pathological processes
As shown in Table 1, muscarinic receptors participate in many physiological functions including learning and memory formations, locomotor activity, sleep-wake cycle, regulation of heart rate, growth hormone, prolactin, gastric acid and salivary secretions and contraction of smooth muscles.
Muscarinic receptors contribute to the pathophysiology of various neurological disorders. It is known that cognitive function is impaired in Alzheimer's disease and schizophrenia. Selective [M.sub.1] agonism has been shown to retard the age, Alzheimer's disease or schizophrenia related dementia and cognitive deficits with few side effects (17). Additionally [M.sub.1] receptors have been demonstrated to control amyloid precursor protein (APP) processing and the generation of the neurotoxic APP fragment, amyloid [beta]-peptide (A[beta]) in Alzheimer's disease (18). Various researchers have suggested that cholinergic function may be improved by selective blockade of [M.sub.2] receptors alone or together with [M.sub.1] agonism in early stages of Alzheimer's disease. Post-mortem and brain-imaging studies have shown that [M.sub.1] muscarinic receptor protein and [M.sub.1] receptor mRNA were reduced in different brain regions of patients with schizophrenia (19). Benztropine, a selective [M.sub.1] receptor antagonist, reduces the adverse side effects of antipsychotic treatments in schizophrenic patients (20). However [M.sub.1] agonists are promising for reversing some of the cognitive impairments associated with schizophrenia (19). So the efficient way for the treatment of schizophrenia regarding the [M.sub.1] muscarinic receptor agonism vs antagonism remains unclear. In the caudate putamen, muscarinic [M.sub.2] receptors act as inhibitory heteroreceptors on dopaminergic terminals. Therefore, selective [M.sub.2] antagonism may provide beneficial effects in schizophrenia, where dopaminergic transmission is increased (21). Dopaminergic neurons in the striatum are lost in Parkinson's disease and this causes an imbalance between dopaminergic and cholinergic effects with an excess of cholinergic effects. This is associated with increased striatal acetylcholine levels, which contributes to the development of the motor signs typically associated to Parkinson's disease. Selective [M.sub.1] receptor antagonists are used for the prevention and the treatment of dyskinesia and the treatment of dystonia (20). Muscarinic [M.sub.4] receptor knockout mice displays enhanced locomotor activity and [D.sub.1] dopaminergic receptor related effects (21). [M.sub.4] muscarinic receptors seem to suppress [D.sub.1] receptor function. So, selective blockade of [M.sub.4] receptors are being investigated in the treatment of Parkinson's disease.
Convulsions induced by muscarinic agonists
Enhancement of cholinergic activity by [M.sub.1] and [M.sub.2] muscarinic receptor agonists carbachol (22) and pilocarpine (23) or the acetylcholinesterase inhibitor soman (24) produce convulsions in animals.
Pilocarpine, a nonspecific muscarinic receptor ago nist is commonly used to induce seizures in mice and rats with high systemic or intracerebral administrations. Pilocarpine-treated animals demonstrate structural dam ages (23) and tonic-clonic generalized seizures (25) like in humans with temporal lobe epilepsy. Animals display status epilepticus (SE) followed by a latent period. After this seizure-free period, spontaneous recurrent seizures (SRSs) are generated (25). [M.sub.1] muscarinic receptor knockout pilocarpine treated animals display no seizure activity. So [M.sub.1] receptors seem to be responsible for the seizure development (26). After binding to [M.sub.1] receptors, phospholipase C is activated. DAG and IP3 are produced, [Ca.sup.++] and [K.sup.+] currents are altered. Consequently, neuronal excitation is increased. The activity of ATPases in the hippocampus may be reduced. So, the plasma membrane could not be repolarized. As the [Ca.sup.++] ions could not be extruded, the increased [Ca.sup.++] levels elevates glutamate release and this leads to SE. The glutamate permits [Na.sup.+] and [Ca.sup.++] influx, thus the [Mg.sup.++] is moved out of the cell. [Mg.sup.++] acts as a blocker on the N-methyl-D-aspartate (NMDA) receptors. When [Mg.sup.++] is extruded, glutamate activates the NMDA receptors. This causes excessive [Ca.sup.++] entry and subsequent excitation and death of the cell. On the other hand, [M.sub.2] receptor activation by pilocarpine inhibits adenylate cyclase. This causes a reduction in the acetylcholine release and the excitability of the brain (27).
Convulsions induced by muscarinic antagonists
Enginar et al. showed that mice deprived of food displayed seizures after food intake in a study exploring the effects of scopolamine on memory and learning processes (28). In a series of experiments, mice and rats fasted for [less than or equal to] 48 h and treated with antimuscarinics, scopolamine, atropine or biperiden developed convulsions soon after finding and eating the food pellet (29, 30). Antimuscarinic pretreatment and access to food are required in the generation of convulsions. Hypoglycaemia was prevented by glucose intake but convulsion development not. So, the contribution of a hypoglycaemic effect during fasting was ruled out (29). The binding characteristics of glutamatergic receptors were changed after fasting for 48 h. These changes were moderately blocked by scopolamine pretreatment and eating food (31). The convulsions seem similar with a form of reflex seizures called eating epilepsy regarding the triggering factors, exhibition of the seizure activity and response to antiepileptics (32). This new method/technique may provide insight into the seizures in patients.
It is very interesting that scopolamine has actually anticonvulsive effect. Scopolamine prevents seizures induced by anticholinesterase soman (24) and muscarinic agonist pilocarpine (22). The convulsive effects of scopolamine, atropine and biperiden have been suggested to be an anticholinergic effect arising from the antagonism of postsynaptic [M.sub.1] and/or [M.sub.2] muscarinic receptors. These receptors show different postsynaptic and presynaptic localizations and distributions in the brain and have different autoreceptor and heteroreceptor characteristics as mentioned above. Which of these receptors is responsible for the convulsions has not been fully understood yet. It has been reported that the topical administration of high concentrations of antimuscarinics to the brain produced seizures (33, 34). This effect has been suggested to imply an anticholinergic as well as cholinergic activity due to their efficacy in increasing the release of acetylcholine.
Prolonged fasting has been shown to alter the expression or binding characteristics of various receptors in brain. For instance; fasting for 48 h produced changes in glutamatergic receptors (31) and 120 h food deprivation decreased the gamma aminobutyric acid (GABA) receptors in the cerebellum (35). In the studies investigating the receptor binding and gene expression changes in rats with insulin-induced hypoglycaemia, [M.sub.1], [M.sub.2] and [M.sub.3] receptors in the cerebral cortex (36) and [M.sub.1] receptor expression in the hippocampus (37) were decreased. In a model of posttraumatic stress, the increase of [M.sub.2] expression in the frontal cortex and [M.sub.1] expression in the hippocampus show the effect of stress on receptor expression (38). Muscarinic receptor expression is also altered in various pathological conditions including schizophrenia (19), epilepsy (39) and cancer (40). There may such changes occur in the expression of muscarinic receptors leading to the convulsions. Thus, the relationship between receptor expression and fasting and the muscarinic receptor subtype which plays a role in the occurrence of convulsions need to be investigated.
Acetylcholine has prominent functions in the brain. Various physiological and pathological processes involve alterations in muscarinic receptor expression. Studies using [M.sub.1] and/or [M.sub.2] agonists and antagonists may clarify the underlying mechanisms of convulsions regarding the contribution of cholinergic/anticholinergic activities.
Author contributions: Concept; Literature Search; Writing; Merve Saygi Bacanak, Pharm. PhD.
Conflict of Interest: There is no conflict of interest.
Hakem Degerlendirmesi: Dis Bagimsiz.
Yazar Katkilari: Fikir; Literatur taramasi; Yaziyi Yazan; Dr. Ecz. Merve Saygi Bacanak
Cikar Catismasi: Yoktur.
 Levey AI, Kitt CA, Simonds WF, Price DL, Brann MR. Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. J Neurosci 1991; 11: 3218-26.
 Lemke TL, Williams DA. Foye's Principles of Medicinal Chemistry. 7th ed. Baltimore and Philadelphia: Lippincott Williams & Wilkins; 2012.
 Nathanson NM. Synthesis, trafficking, and localization of muscarinic acetylcholine receptors. Pharmacol Ther 2008; 119: 33-43. Doi:10.1016/j.pharmthera.2008.04.006
 Zhang W, Basile AS, Gomeza J, Volpicelli LA, Levey AI, Wess J. Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knock-out mice. J Neurosci 2002; 22: 1709-17.
 Vannucchi MG, Pepeu G. Muscarinic receptor modulation of acetylcholine release from rat cerebral cortex and hippocampus. Neurosci Lett 1995; 190: 53-56. Doi: 10.1016/0304-3940(95)11498-L
 Suzuki T, Fujimoto K, Oohata H, Kawashima K. Presynaptic [M.sub.1] muscarinic receptor modulates spontaneous release of acetylcholine from rat basal forebrain slices. Neurosci Lett 1988; 84: 209-12. Doi:10.1016/0304-3940(88)90409-0
 Marchi M, Ruelle A, Andrioli GC, Raiteri M. Pirenzepine-insensitive muscarinic autoreceptors regulate acetylcholine release in human neocortex. Brain Res 1990; 520: 347-50. Doi: 10.1016/0006-8993(90)91728-Y
 Rouse ST, Gilmor ML, Levey AI. Differential presynaptic and postsynaptic expression of m1-m4 muscarinic acetylcholine receptors at the perforant pathway/granule cell synapse. Neuroscience 1998; 86: 221-32. Doi: 10.1016/S0306-4522(97)00681-7
 Kamsler A, McHugh TJ, Gerber D, Huang SY, Tonegawa S. Presynaptic m1 muscarinic receptors are necessary for mGluR long term depression in the hippocampus. Proc Natl Acad Sci 2010; 107: 1618-23. Doi: 10.1073/pnas.0912540107
 Buckley NJ, Bonner TI, Brann MR. Localization of a family of muscarinic receptor mRNAs in rat brain. J Neurosci 1988; 12: 4646-52.
 Figueroa KW, Griffin MT, Ehlert FJ. Selectivity of agonists for the active state of [M.sub.1] to M4 muscarinic receptor subtypes. J Pharmacol Exp Ther 2009; 328: 331-42. Doi: 10.1124/jpet.108.145219
 Bymaster FP, Whitesitt CA, Shannon HE, DeLapp N, Ward JS, Calligaro DO, et al. Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer's disease. Drug Dev Res 1997; 40: 158-170.
 Wood MD, Murkitt KL, Ho M, Watson JM, Brown F, Hunter AJ, et al. Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry Br J Pharmacol 1999; 126: 1620-4.
 Witkin JM, Overshiner C, Li X, Catlow JT, Wishart GN, Schober DA, et al. M1 and M2 muscarinic receptor subtypes regulate antidepressant-like effects of the rapidly acting antidepressant scopolamine. J Pharmacol Exp Ther 2014; 351: 448-56. Doi: 10.1124/jpet.114.216804
 Buels KS, Fryer AD. Muscarinic receptor antagonists: effects on pulmonary function. Hofmann FB, editor. Handbook of Experimental Pharmacology. Berlin Heidelberg: Springer-Verlag; 2012.p.317-41. Doi: 10.1007/978-3-642-23274-9_14
 Szerb JC, Hadhazy P, Dudar JD. Release of [3H]acetylcholine from rat hippocampal slices: effect of septal lesion and of graded concentrations of muscarinic agonists and antagonists. Brain Res 1977; 128: 285-91. Doi: 10.1016/0006-8993(77)90995-7
 Langmead CJ, Watson J, Reavill C. Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol Ther 2008; 117: 232-43. Doi:10.1016/j.pharmthera.2007.09.009
 Fisher A. M1 muscarinic agonists target major hallmarks of Alzheimer's disease-the pivotal role of brain M1 receptors. Neurodegener Dis 2008; 5: 237-40. Doi: 10.1159/000113712
 Raedler TJ, Bymaster FP, Tandon R, Copolov D, Dean B. Towards a muscarinic hypothesis of schizophrenia. Mol Psychiatry 2007;12: 232-46. Doi: 10.1038/sj.mp.4001924
 Greig NH, Reale M, Tata AM. New pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors. Recent Pat CNS Drug Discov 2013; 8: 123-41. Doi: 10.2174/1574889811308020003
 Eglen RM. Overview of Muscarinic Receptor Subtypes. Hofmann FB, editor. Handbook of Experimental Pharmacology. Berlin Heidelberg: Springer-Verlag; 2012.p.3-28. Doi: 10.1007/978-3-642-23274-9_1
 Turski WA, Czuczwar SJ, Kleinrok Z, Turski L. Cholinomimetics produce seizures and brain damage in rats. Experientia 1983; 39: 1408-11. Doi: 10.1007/BF01990130
 Cavalheiro EA, Leite JP, Bortolotto ZA, Turski WA, Ikonomidou C, Turski L. Long-term effects of pilocarpine in rats: structural damage of the brain triggers kindling and spontaneous recurrent seizures. Epilepsia 1991; 32: 778-82. Doi: 10.1111/j.1528-1157.1991.tb05533.x
 Anderson DR, Harris LW, Bowersox SL, Lennox WJ, Anders JC. Efficacy of injectable anticholinergic drugs against soman-induced convulsive/subconvulsive activity. Drug Chem Toxicol 1994; 17: 139-48. Doi: 10.3109/01480549409014307
 Curia G, Longo D, Biagini G, Jones RS, Avoli M. The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods 2008; 172: 143-57. Doi: 10.1016/j.jneumeth.2008.04.019
 Hamilton SE, Loose MD, Qi M, Levey AI, Hille B, McKnight GS, et al. Disruption of the [M.sub.1] receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice. Proc Natl Acad Sci 1997; 94: 13311-6. Doi: 10.1073/pnas.94.24.13311
 Scorza FA, Arida RM, Naffah-Mazzacoratti Mda G, Scerni DA, Calderazzo L, Cavalheiro EA. The pilocarpine model of epilepsy: what have we learned? An Acad Bras Cienc 2009; 81: 345-65. Doi: 10.1590/S0001-37652009000300003
 Enginar N, Nurten A, Yamanturk P, Koyuncuoglu H. Scopolamine-induced convulsions in food given fasted mice: effects of physostigmine and MK-801. Epilepsy Res 1997; 28: 137-42. Doi: 10.1016/S0920-1211(97)00041-7
 Enginar N, Nurten A, Yamanturk-Celik P, Acikmese B. Scopolamine-induced convulsions in fasted mice after food intake: effects of glucose intake, antimuscarinic activity and anticonvulsant drugs. Neuropharmacology 2005; 49: 293-9. Doi: 10.1016/j. neuropharm.2005.01.032
 Enginar N, Nurten A, Ozunal ZG, Zengin A. Scopolamine-induced convulsions in fasted mice after food intake: the effect of duration of food deprivation. Epilepsia 2009; 50: 143-6. Doi: 10.1111/j.1528-1167.2008.01786.x
 Enginar N, Yamanturk P, Nurten A, Nurten R, Koyuncuoglu H. Scopolamine-induced convulsions in fasted mice after food intake: determination of blood glucose levels, [[.sup.3H]]glutamate binding kinetics and antidopaminergic drug effects. Neuropharmacology 2003; 44: 199-205. Doi: 10.1016/S0028-3908(02)00365-9
 Enginar N, Nurten A. Seizures triggered by food intake in antimuscarinic-treated fasted animals: evaluation of the experimental findings in terms of similarities to eating-triggered epilepsy. Epilepsia 2010; 51: 80-4. Doi: 10.1111/j.1528-1167.2010.02616.x
 Daniels JC, Spehlman R. The convulsant effect of topically applied atropine. Electroencephalogr Clin Neurophysiol 1973; 34: 83-7. Doi: 10.1016/0013-4694(73)90155-7
 Tan U, Senyuva F, Marangoz C. Electrocorticographic effects of topically applied scopolamine. Epilepsia 1978; 19: 223-32. Doi: 10.1111/j.1528-1157.1978.tb04484.x
 Weizman A, Bidder M, Fares F, Gavish M. Food deprivation modulates gamma-aminobutyric acid receptors and peripheral benzodiazepine binding sites in rats. Brain Res 1990; 535: 96-100.
 Anju TR, Paulose CS. Cortical cholinergic dysregulation as a long-term consequence of neonatal hypoglycemia. Biochem Cell Biol 2015; 93: 47-53. Doi: 10.1139/bcb-2014-0035
 Sherin A, Anu J, Peeyush KT, Smijin S, Anitha M, Roshni BT, et al. Cholinergic and GABAergic receptor functional deficit in the hippocampus of insulin-induced hypoglycemic and streptozotocin-induced diabetic rats. Neuroscience 2012; 202: 69-76. Doi: 10.1016/j. neuroscience.2011.11.058
 Aykac A, Aydin B, Cabadak H, Guney Z. The change in muscarinic receptor subtypes in different brain regions of rats treated with fluoxetine or propranolol in a model of post-traumatic stress disorder. Behavioural Brain Res 2012; 232: 124-129. Doi: 10.1016/j.bbr.2012.04.002
 Graebenitz S, Kedo O, Speckmann EJ, Gorji A, Panneck H, Hans V, et al. Interictal-like network activity and receptor expression in the epileptic human lateral amygdala. Brain 2011; 134: 2929-47. Doi:10.1093/brain/awr202
 Spindel ER. Muscarinic Receptor Agonists and Antagonists: Effects on Cancer. Hofmann FB, editor. Handbook of Experimental Pharmacology. Berlin Heidelberg: Springer-Verlag; 2012.p.451-68. Doi: 10.1007/978-3-642-23274-9_19
 Levey AI. Immunological localization of m1-m5 muscarinic receptor subtypes in peripheral tissues and brain. Life Sci 1993; 52: 441-8.
 Nathaniel TI, Umesiri FE, Olajuyigbe F. Role of M1 receptor in the locomotion behavior of the African mole-rat (Cryptomys sp). J Integr Neurosci 2008; 7: 1-16.
 Ma L, Seager MA, Wittmann M, Jacobson M, Bickel D, Burno M, et al. Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation. Proc Natl Acad Sci 2009; 106: 15950-5. Doi: 10.1073/pnas.0900903106
 Coleman CG, Lydic R, Baghdoyan HA. M2 muscarinic receptors in pontine reticular formation of C57BL/6J mouse contribute to rapid eye movement sleep generation. Neuroscience 2004; 126: 821-30. Doi: 10.1016/j.neuroscience.2004.04.029
 Wess J, Duttaroy A, Gomeza J, Zhang W, Yamada M, Felder CC, et al. Muscarinic receptor subtypes mediating central and peripheral antinociception studied with muscarinic receptor knockout mice: a review. Life Sci 2003; 72: 2047-54. Doi: 10.1016/S0024-3205(03)00082-1
 Gautam D, Jeon J, Starost MF, Han SJ, Hamdan FF, Cui Y, et al. Neuronal M3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth. Proc Natl Acad Sci 2009; 106: 6398-403. Doi: 10.1073/pnas.0900977106
 Poulin B, Butcher A, McWilliams P, Bourgognon JM, Pawlak R, Kong KC, et al. The M3-muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner. Proc Natl Acad Sci 2010; 107: 9440-5. Doi: 10.1073/pnas.0914801107
 Yamada M, Lamping KG, Duttaroy A, Zhang W, Cui Y, Bymaster FP, et al. Cholinergic dilation of cerebral blood vessels is abolished in M(5) muscarinic acetylcholine receptor knockout mice. Proc Natl Acad Sci 2001; 98: 14096-101. Doi: 10.1073/pnas.251542998
 Foster DJ, Gentry PR, Lizardi-Ortiz JE, Bridges TM, Wood MR, Niswender CM, et al. M5 receptor activation produces opposing physiological outcomes in dopamine neurons depending on the receptor's location. J Neurosci 2014; 34: 3253-62. Doi: 10.1523/JNEUROSCI.4896-13.2014
 Jones CK, Byun N, Bubser M. Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia. Neuropsychopharmacology 2012; 37: 16-42. Doi: 10.1038/npp.2011.199
Merve Saygi Bacanak (1,2)
(1) Department of Medical Pharmacology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
(2) First and Emergency Aid Program, Department of Medical Services and Techniques, Vocational School of Health Services, Marmara University, Istanbul, Turkey
ORCID IDw of the authors: M.S.B. 0000-0001-9774-2657
Correspondence Author/Sorumlu Yazar: Merve Saygi Bacanak E-mail/E-posta: firstname.lastname@example.org
Table 1: Distribution and function of muscarinic receptor subtypes Muscarinic receptor subtype Widely distributed region in the brain [M.sub.1] Cerebral cortex, hippocampus, striatum (41) Forebrain, thalamus, motor neurons [M.sub.2] (1) Hypothalamus, hippocampus (21) [M.sub.3] Corpus striatum (21) (*) [M.sub.4] Substantia nigra pars compacta, ventral tegmental area (21) (**) [M.sub.5] Muscarinic receptor subtype Associated physiological functions [M.sub.1] Receptor stimulation [right arrow] Regulation of learning and memory like cognitive functions (18), regulation of locomotor activity (42), increases wakefulness while reducing delta sleep (43) Receptor blockade a Increased cognitive performance including memory (21), decreased REM sleep-like state (44) [M.sub.2] Receptor stimulation [right arrow] antinociceptive effect (45) Receptor knockout [right arrow] Reduced food intake and increased locomotor activity, decreased pituitary and serum growth hormone (GH) and prolactin (46) Receptor stimulation [right arrow] [M.sub.3] regulation of metabolic functions and longitudinal growth (46), regulation of learning and memory like cognitive functions (47) Receptor knockout [right arrow] Increased locomotor activity and dopaminergic activity so contribution to antiparkinsonian effect (21) Receptor stimulation [right arrow] [M.sub.4] Contribution to antipsychotic effect (21), antinociceptive effect (45) Receptor knockout [right arrow] Abolished cholinergically induced cerebral vasodilation (48) Receptor stimulation [right arrow] [M.sub.5] Increased dopamine release in substantia nigra pars compacta, inhibition of dopamine release in striatum (49) (*) [M.sub.4] receptors are distributed in the corpus striatum being co-localized with dopamine receptors (21). (**) [M.sub.5] is the only muscarinic subtype expressed by the dopamine-containing neurons of the substantia nigra pars compacta (21). Table 2: Comparison of binding affinities for atropine, scopolamine, biperiden and pirenzepine at human muscarinic receptors as Ki values [M.sub.1] [M.sub.2] [M.sub.3] [M.sub.4] Atropine 0,17 0,339 0,209 0,107 Scopolamine 0,83 (0,05) 5,3 (1,4) 0,34 (0,06) 0,38 (0,07) Biperiden 2,2 (0,23) 102 (24) 5,3 (1,3) 3,1 (0,8) Pirenzepine 43 (14) 4200 (1370) 468 (172) 148 (53) [M.sub.5] Atropine 0,316 Scopolamine 0,34 (0,11) Biperiden 4,4 (1,4) Pirenzepine 237 (122) Human cloned receptors were expressed in Chinese hamster ovary cell membranes. Binding was measured as competition with [3H]N-methyl-scopolamine. Data represent as Ki (mean [+ or -] S.E.M.) in nanomolar (14, 15).