Although the neurotransmitter dopamine plays a prominent role in the treatment of schizophrenia, the dopamine hypothesis fails to explain several aspects of the disorder. It is evident that the pathophysiology of schizophrenia involves other neurotransmitter systems as well. In this review, we discuss the increasing data implicating the cholinergic system in its pathogenesis. Cholinergic neurotransmission plays a crucial role in various central nervous system functions. The cholinergic system consists of two families of receptors, the muscarinic cholinergic and the nicotinic cholinergic, that use acetylcholine as a neurotransmitter. Data from clinical pharmacology, neuroimaging, and postmortem studies suggest an alteration of the muscarinic cholinergic system in schizophrenia. Muscarinic agonists are being evaluated as new treatment options with putative antipsychotic and cognition enhancing properties. Smoking is highly prevalent among schizophrenic subjects. Nicotine improves attention in schizophrenia. Nicotinic receptors, in particular the α7 nicotinic receptor, are candidates for the development of new medications to treat cognitive and perceptual deficits in schizophrenia. This review summarizes the evidence in support of a role for the muscarinic cholinergic system and the nicotinic cholinergic system in the pathophysiology of schizophrenia. As current treatments fail to sufficiently address all aspects of schizophrenia, promising new pharmacologic approaches that focus on the cholinergic system are currently under development.
This is a preview of subscription content,to check access.
Access this article
Similar content being viewed by others
References and Recommended Reading
Carlsson A:The current status of the dopamine hypothesis of schizophrenia.Neuropsychopharmacology 1988,1:179–186.
Kapur S, Remington G:Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient.Biol Psychiatry 2001,50:873–83.
Laruelle M, Abi-Dargham A, van Dyck CH, et al.:Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects.Proc Natl Acad Sci U S A. 1996,93:9235–40.
Abi-Dargham A, Gil R, Krystal J, et al.:Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort.Am J Psychiatry 1998,155:761–767.
Cooper JR, Bloom FE, Roth RH:The Biochemical Basis of Neuropharmacology. New York: Oxford University Press; 1996.
Cummings JL, Cole G:Alzheimer disease.JAMA 2002,287:2335–2338.
Dale HH:The action of certain esters and ethers of choline, and their relation to muscarine.J Pharmacol Exp Ther 1914,6:147–190.
Picciotto M, Caldarone BJ, King SL, Zachariou V:Nicotinic receptors in the brain: links between molecular biology and behavior.Neuropsychopharmacology 2000,22:451–465.
Levey AI, Kitt CA, Simonds WF, et al.:Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies.J Neurosci 1991,11:3218–3226.
Flynn DD, Ferrari-DiLeo G, Mash DC, Levey AI:Differential regulation of molecular subtypes of muscarinic receptors in Alzheimer’s disease.J Neurochem 1995,64:1888–1891.
Wu M, Shanabrough M, Leranth C, Alreja M:Cholinergic excitation of septohippocampal GABA but not cholinergic neurons: Implications for learning and memory.J Neurosci 2000,20:3900–3908.
Zhang W, Yamada M, Gomeza J, et al.: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.
Tandon R, Greden JF:Cholinergic activity and negative schizophrenic symptoms.Arch Gen Psychiatry 1989,46:745–753.
Tandon R, Taylor SF, DeQuardo JR, et al.:The cholinergic system in schizophrenia reconsidered: anticholinergic modulation of sleep and symptom profiles.Neuropsychopharmacology 1999,22:S189-S202.
Perry EK, Perry RH:Acetylcholine and hallucinations: disease-related compared to drug-induced alterations in human consciousness.Brain Cogn 1995,28:240–258.
Tandon R, Shipley JE, Greden JF, et al.:Muscarinic cholinergic hyperactivity in schizophrenia. Relationship to positive and negative symptoms.Schizophr Res 1991,4:23–30.
Tandon R, DeQuardo JR, Goodson J, et al.:Effect of anticholinergics on positive and negative symptoms in schizophrenia.Psychopharmacol Bull 1992,28:297–302.
Minzenberg MJ, Poole JH, Benton C, Vinogradov S:Association of anticholinergic load with impairment of complex attention and memory in schizophrenia.Am J Psychiatry 2004,161:116–124.
Friedman JI:Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists.Psychopharmacology (Berl) 2004,174:45–53.
Buchanan RW, Summerfelt A, Tek C, Gold J:An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia.Schizophr Res 2003,59:29–33.
Stryjer R, Strous RD, Bar F, et al.:Beneficial effect of donepezil augmentation for the management of comorbid schizophrenia and dementia.Clin Neuropharmacol 2003,26:12–17.
Friedman JI, Adler DN, Howanitz E, et al.:A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia.Biol Psychiatry 2002,51:349–357.
Tugal O, Yazici KM, Yagcioglu AE, Gogus A:A double-blind, placebo controlled, cross-over trial of adjunctive donepezil for cognitive impairment in schizophrenia.Int J Neuropsychopharmacol 2004,7:117–123.
Raedler TJ, Knable MB, Jones DW, et al.:In vivo olanzapine occupancy of muscarinic acetylcholine receptors in patients with schizophrenia.Neuropsychopharmacology 2000,23:56–68.
Raedler TJ, Knable MB, Jones DW, et al.:Central muscarinic acetylcholine receptor availability in patients treated with clozapine.Neuropsychopharmacology 2003,28:1531–1537.
Raedler TJ, Knable MB, Jones DW, et al.:In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia.Am J Psychiatry 2003,160:118–127.
Davies MA, Compton-Toth BA, Hufeisen SJ, et al.:The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine’s actions? Psychopharmacology (Berl) 2005,178:451–460.
Burstein ES, Ma JN, Wong S, et al.:Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist.J Pharmacol Exp Ther 2005,315:1278–1287.
Tandon R:Effects of atypical antipsychotics on polysomnographic measures in schizophrenia.Bibl Psychiatr 1997,167:219–222.
Tandon R, Kane JM:Neuropharmacological basis of clozapine’s mechanism of action.Arch Gen Psychiatry 1993,50:157–159.
Bodick NC, Offen WW, Levey AI, 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.
Shekhar A, Potter WZ, Lienemann J, et al.:Efficacy of xanomeline, a selective muscarinic agonist, in treating schizophrenia: a double-blind, placebo controlled study [abstract]. Presented at the 40th Annual Meeting ACNP. Waikoloa, HI; December 9–13, 2001.
Bymaster FP, Shannon HE, Rasmussen K, et al.:Unexpected antipsychotic-like activity with the muscarinic receptor ligand (5R,6R)6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo [3.2.1] octane.Eur J Pharmacol 1998,356:109–119.
Rasmussen T, Fink-Jensen A, Sauerberg P, et al.:The muscarinic receptor agonist BuTAC, a novel potential antipsychotic, does not impair learning and memory in mouse passive avoidance.Schizophr Res 2001,49:193–201.
Dean B, Crook JM, Opeskin K, et al.:The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia.Mol Psychiatry 1996,1:54–58.
Crook JM, Dean B, Pavey G, Copolov D:The binding of [3H]AF-DX 384 is reduced in the caudate-putamen of subjects with schizophrenia.Life Sci 1999,64:1761–1771.
Deng C, Huang XF:Decreased density of muscarinic receptors in the superior temporal gyrus in schizophrenia.J Neurosci Res 2005,81:883–890.
Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B:Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation.Biol Psychiatry 2000,48:381–388.
Crook JM, Tomaskovic-Crook E, Copolov DL, 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.
Dean B, McLeod M, Keriakous D, et al.:Decreased muscarinic(1) receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia.Mol Psychiatry 2002,7:1083–1091.
Scarr E, Keriakous D, Crossland N, Dean B:No change in cortical muscarinic M2, M3 receptors or [(35)S] GTPgammaS binding in schizophrenia.Life Sci 2005, [Epub ahead of print].
Katerina Z, Andrew K, Filomena M, Xu-Feng H:Investigation of m1/m4 muscarinic receptors in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression disorder.Neuropsychopharmacology 2004,29:619–625.
Kelly C, McCreadie RG:Smoking habits, current symptoms, and premorbid characteristics of schizophrenic patients in Nithsdale, Scotland.Am J Psychiatry 1999,156:1751–1757.
de Leon J, Diaz FJ:A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors.Schizophr Res 2005,76:135–157.
Kumari V, Postma P:Nicotine use in schizophrenia: the self medication hypotheses.Neurosci Biobehav Rev 2005,29:1021–1034.
Tidey JW, Rohsenow DJ, Kaplan GB, Swift RM:Cigarette smoking topography in smokers with schizophrenia and matched non-psychiatric controls.Drug Alcohol Depend 2005,80:259–265.
Williams JM, Ziedonis DM, Abanyie F, et al.:Increased nicotine and cotinine levels in smokers with schizophrenia and schizoaffective disorder is not a metabolic effect.Schizophr Res 2005,79:323–335.
Patkar AA, Gopalakrishnan R, Lundy A, et al.:Relationship between tobacco smoking and positive and negative symptoms in schizophrenia.J Nerv Ment Dis 2002,190:604–610.
Weiser M, Reichenberg A, Grotto I, et al.:Higher rates of cigarette smoking in male adolescents before the onset of schizophrenia: a historical-prospective cohort study.Am J Psychiatry 2004,161:1219–223.
Zammit S, Allebeck P, Dalman C, et al.:Lewis G. Investigating the association between cigarette smoking and schizophrenia in a cohort study.Am J Psychiatry 2003,160:2216–2221.
Barak Y, Achiron A, Mandel M, et al.:Reduced cancer incidence among patients with schizophrenia.Cancer 2005,104:2817–2821.
Addington J, el-Guebaly N, Campbell W, et al.:Smoking cessation treatment for patients with schizophrenia.Am J Psychiatry 1998,155:974–976.
Dalack GW, Becks L, Hill E, et al.:Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia.Neuropsychopharmacology 1999,21:195–202.
George TP, Ziedonis DM, Feingold A, et al.:Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia.Am J Psychiatry 2000,157:1835–1842.
Harris JG, Kongs S, Allensworth D, et al.:Effects of nicotine on cognitive deficits in schizophrenia.Neuropsychopharmacology 2004,29:1378–1385.
Sacco KA, Termine A, Seyal A, et al.:Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms.Arch Gen Psychiatry 2005,62:649–659.
Smith RC, Warner-Cohen J, Matute M, et al.:Effects of nicotine nasal spray on cognitive function in schizophrenia.Neuropsychopharmacology 2005, [Epub ahead of print].
Jacobsen LK, D’Souza DC, Mencl WE, et al.:Nicotine effects on brain function and functional connectivity in schizophrenia.Biol Psychiatry 2004,55:850–858.
Marenco S, Carson RE, Berman KF, et al.:Nicotine-induced dopamine release in primates measured with [11C] raclopride PET.Neuropsychopharmacology 2004,29:259–268.
Rao TS, Correa LD, Adams P, et al.:characterization of dopamine, norepinephrine and serotonin release in the rat prefrontal cortex by neuronal nicotinic acetylcholine receptor agonists.Brain Res 2003,990:203–208.
Decina P, Caracci G, Sandik R, et al.:Cigarette smoking and neuroleptic-induced parkinsonism.Biol Psychiatry 1990,28:502–508.
Yang YK, Nelson L, Kamaraju L, Wilson W, McEvoy JP:Nicotine decreases bradykinesia-rigidity in haloperidol-treated patients with schizophrenia.Neuropsychopharmacology 2002,27:684–686.
Silver H, Shlomo N, Hiemke C, et al.:Schizophrenic patients who smoke have a faster finger tapping rate than non-smokers.Eur Neuropsychopharmacology 2002,12:141–144.
Fowler JS, Logan J, Wang GJ, et al.:Comparison of monoamine oxidase a in peripheral organs in nonsmokers and smokers.J Nucl Med 2005,46:1414–1420.
Fowler JS, Volkow ND, Wang GJ, et al.:Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition.J Addict Dis 1998,17:23–34.
de Haan L, Booij J, Lavalaye J, et al:Occupancy of dopamine D(2) receptors by antipsychotic drugs is related to nicotine addiction in young patients with schizophrenia.Psychopharmacology (Berl) 2006,183:500–505.
Freedman R, Hall M, Adler LE, Leonard S:Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia.Biol Psychiatry 1995,38:22–33.
Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, Marks MJ, Collins AC, Leonard S:Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia.Neuropsychopharmacology 2000,23:351–364.
Durany N, ZÖchling R, Boissl KW, et al.:Human post-mortem striatal alpha4beta2 nicotinic acetylcholine receptor density in schizophrenia and Parkinson’s syndrome.Neurosci Lett 2000,287:109–112.
Guan ZZ, Zhang X, Blennow K, Nordberg A:Decreased protein level of nicotinic receptor alpha7 subunit in the frontal cortex from schizophrenic brain.Neuroreport 1999,10:1779–1782.
Freedman R, Coon H, Myles-Worsley M, et al.:Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus.Proc Natl Acad Sci U S A 1997,94:587–592.
Adler LE, Hoffer LD, Wiser A, Freedman R:Normalization of auditory physiology by cigarette smoking in schizophrenic patients.Am J Psychiatry 1993,150:1856–1861.
Leonard S, Breese C, Adams C, et al.:Smoking and schizophrenia: abnormal nicotinic receptor expression.Eur J Pharmacol 2000,393:237–242.
Leonard S, Gault J, Hopkins J, et al.:Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia.Arch Gen Psychiatry 2002,59:1085–1096.
Perl O, Ilani T, Strous RD, et al.:The alpha7 nicotinic acetylcholine receptor in schizophrenia: decreased mRNA levels in peripheral blood lymphocytes.FASEB J 2003,17:1948–1950.
Martin LF, Kem WR, Freedman R:Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia.Psychopharmacology (Berl) 2004,174:54–64.
About this article
Cite this article
Raedler, T.J., Tandon, R. Cholinergic mechanisms in schizophrenia: Current concepts. Current Psychosis & Therapeutics Reports 4, 20–26 (2006). https://doi.org/10.1007/BF02629410