Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists

RationaleAlterations in the central cholinergic system of patients with schizophrenia such as reduced numbers of muscarinic and nicotinic receptors in the cortex and hippocampus may contribute to the cognitive impairment of schizophrenia. Therefore, pharmacological treatments that enhance central cholinergic function may be useful as cognitive enhancers in schizophrenia.MethodsSearches were conducted for articles which investigated alterations of central cholinergic systems in patients with schizophrenia. Additional searches were conducted for animal and human trials of potential cognitive enhancing compounds that target the cholinergic system and any preliminary trials conducted with schizophrenic patients.ResultsCurrently available treatments which are potentially suitable for this purpose include acetylcholinesterase inhibitors, muscarinic agonists, nicotinic agonists, and allosteric potentiators of nicotinic receptor function. Although some open label studies demonstrate modest cognitive improvements of schizophrenic patients treated with donepezil, data from a blinded, placebo controlled study demonstrate no effect. Data from a controlled trial of galantamine, a combined acetylcholinesterase inhibitor and allosteric potentiator of the nicotinic receptor, indicates that this may be an effective alternative. In addition, some preclinical data indicates that selective M1 muscarinic agonists under development may have potential as cognitive enhancers and antipsychotic treatments for schizophrenic patients.ConclusionsA cholinergic approach to ameliorating the cognitive dysfunction of schizophrenia appears viable. There is some preliminary data to support the efficacy of combined acetylcholinesterase inhibitors and allosteric potentiators of the nicotinic receptor, whereas future trials are awaited for more specific muscarinic agonists currently under development.

[1]  D. Mash,et al.  Differential Regulation of Molecular Subtypes of Muscarinic Receptors in Alzheimer's Disease , 1995, Journal of neurochemistry.

[2]  H. Meltzer,et al.  Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. , 1989, The Journal of pharmacology and experimental therapeutics.

[3]  M. Caulfield.  Muscarinic receptors--characterization, coupling and function. , 1993, Pharmacology & therapeutics.

[4]  R. Mohs,et al.  Cognitive functioning in late-life schizophrenia: a comparison of elderly schizophrenic patients and patients with Alzheimer's disease. , 1996, The American journal of psychiatry.

[5]  M. Benwell,et al.  Desensitization of the nicotine‐induced mesolimbic dopamine responses during constant infusion with nicotine , 1995, British journal of pharmacology.

[6]  D. Wong,et al.  Xanomeline: a novel muscarinic receptor agonist with functional selectivity for M1 receptors. , 1994, The Journal of pharmacology and experimental therapeutics.

[7]  A. Cudennec,et al.  Deficits in passive-avoidance learning following atropine in the developing rat , 1977, Psychopharmacology.

[8]  R. Freedman,et al.  Improvement in Smooth Pursuit Eye Movements after Cigarette Smoking in Schizophrenic Patients , 1998, Neuropsychopharmacology.

[9]  H. Tecle,et al.  Milameline (CI-979/RU35926): a muscarinic receptor agonist with cognition-activating properties: biochemical and in vivo characterization. , 1999, The Journal of pharmacology and experimental therapeutics.

[10]  L. Thal,et al.  Continuous physostigmine infusion in rats with excitotoxic lesions of the nucleus basalis magnocellularis: effects on performance in the water maze task and cortical cholinergic markers. , 1989, The Journal of pharmacology and experimental therapeutics.

[11]  F. Gage,et al.  Essential role of neocortical acetylcholine in spatial memory , 1995, Nature.

[12]  B. Dean,et al.  The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia. , 1996, Molecular psychiatry.

[13]  R. Harbaugh,et al.  Continuous ICV infusion of scopolamine impairs sustained attention of rhesus monkeys , 1993, Neurobiology of Aging.

[14]  Robert C. Smith,et al.  Effects of Cigarette Smoking and Nicotine Nasal Spray on Psychiatric Symptoms and Cognition In Schizophrenia , 2002, Neuropsychopharmacology.

[15]  Philip D. Harvey,et al.  A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia , 2002, Biological Psychiatry.

[16]  P. Watkins,et al.  Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. , 1994, JAMA.

[17]  I. Williams,et al.  Correlation of brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioral changes. , 1989, European journal of pharmacology.

[18]  Gastone G. Celesia,et al.  A 30-Week Randomized Controlled Trial of High-Dose Tacrine in Patients With Alzheimer's Disease , 1994 .

[19]  A. Baddeley,et al.  Memory impairment in schizophrenia: its extent, affiliations and neuropsychological character , 1992, Psychological Medicine.

[20]  Xingbao Li,et al.  Augmenting Atypical Antipsychotics with a Cognitive Enhancer (Donepezil) Improves Regional Brain Activity in Schizophrenia Patients: A Pilot Double-blind Placebo Controlled BOLD fMRI Study , 2003, Neurocase.

[21]  K. Perry,et al.  The muscarinic agonist xanomeline increases monoamine release and immediate early gene expression in the rat prefrontal cortex , 2001, Biological Psychiatry.

[22]  J R Hughes,et al.  Prevalence of smoking among psychiatric outpatients. , 1986, The American journal of psychiatry.

[23]  D. Chen,et al.  Distributions of nicotinic acetylcholine receptor α7 and β2 subunits on cultured hippocampal neurons , 1999, Neuroscience.

[24]  R. Mohs,et al.  Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. , 1998, Archives of internal medicine.

[25]  S. Dunnett.  Comparative effects of cholinergic drugs and lesions of nucleus basalis or fimbria-fornix on delayed matching in rats , 2004, Psychopharmacology.

[26]  D. Vistica,et al.  Differential competition with cytotoxic agents: an approach to selectivity in cancer chemotherapy. , 1979, Science.

[27]  Robert Freedman,et al.  Cholinergic gating of response to auditory stimuli in rat hippocampus , 1992, Brain Research.

[28]  R. Polinsky,et al.  Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. , 1998, Clinical therapeutics.

[29]  Jin Dai,et al.  Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum , 2002, Neuropsychopharmacology.

[30]  H. Barz,et al.  Inhibition of Acetylcholinesterase Activity in Human Brain Tissue and Erythrocytes by Galanthamine, Physostigmine and Tacrine , 1991, European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies.

[31]  T. Nishikawa,et al.  Increased muscarinic cholinergic receptors in prefrontal cortices of medicated schizophrenics. , 1983, Life sciences.

[32]  A. C. Collins,et al.  Abnormal Regulation of High Affinity Nicotinic Receptors in Subjects with Schizophrenia , 2000, Neuropsychopharmacology.

[33]  M. Mishkin,et al.  The effects of physostigmine and scopolamine on recognition memory in monkeys. , 1986, Behavioral and neural biology.

[34]  Abraham Weizman,et al.  Beneficial Effect of Donepezil Augmentation for the Management of Comorbid Schizophrenia and Dementia , 2003, Clinical neuropharmacology.

[35]  Y. Iga,et al.  (+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate (SNI-2011, cevimeline hydrochloride) induces saliva and tear secretions in rats and mice: the role of muscarinic acetylcholine receptors. , 1998, Japanese journal of pharmacology.

[36]  A. Wiser,et al.  Normalization of auditory physiology by cigarette smoking in schizophrenic patients. , 1993, The American journal of psychiatry.

[37]  M. Wienrich,et al.  Pharmacodynamic profile of the M1 agonist talsaclidine in animals and man. , 2001, Life sciences.

[38]  J. O’Brien,et al.  Design and development of selective muscarinic agonists for the treatment of Alzheimer's disease: characterization of tetrahydropyrimidine derivatives and development of new approaches for improved affinity and selectivity for M1 receptors. , 2000, Pharmaceutica acta Helvetiae.

[39]  Jeremy M Crook,et al.  Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation , 2000, Biological Psychiatry.

[40]  S. Lightowler,et al.  The muscarinic receptor agonist xanomeline has an antipsychotic-like profile in the rat. , 2001, The Journal of pharmacology and experimental therapeutics.

[41]  J. Kleinman,et al.  The nucleus basalis of Meynert, senile plaques, and intellectual impairment in schizophrenia. , 1991, The Journal of neuropsychiatry and clinical neurosciences.

[42]  E X Albuquerque,et al.  Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands. , 1996, Molecular pharmacology.

[43]  D. Middlemiss,et al.  Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry , 1999, British journal of pharmacology.

[44]  J. Buccafusco,et al.  m1–m5 Muscarinic Receptor Distribution in Rat CNS by RT‐PCR and HPLC , 1994, Journal of neurochemistry.

[45]  M. Stanton,et al.  Memory and the septo-hippocampal cholinergic system in the rat , 2004, Psychopharmacology.

[46]  K. Davis,et al.  Physostigmine: improvement of long-term memory processes in normal humans. , 1978, Science.

[47]  R. Lukas,et al.  Dependence of nicotinic acetylcholine receptor recovery from desensitization on the duration of agonist exposure. , 1999, The Journal of pharmacology and experimental therapeutics.

[48]  B. Dean,et al.  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. , 2001, The American journal of psychiatry.

[49]  L Kruglyak,et al.  Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[50]  E. Richelson,et al.  Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells. , 1992, The Journal of pharmacology and experimental therapeutics.

[51]  J. N. P. Rawlins,et al.  Removal of the hippocampus and transection of the fornix produce comparable deficits on delayed non-matching to position by rats , 1992, Behavioural Brain Research.

[52]  T. Goldberg,et al.  Recall memory deficit in schizophrenia A possible manifestation of prefrontal dysfunction , 1989, Schizophrenia Research.

[53]  Martin Radina,et al.  Galantamine Is an Allosterically Potentiating Ligand of Neuronal Nicotinic but Not of Muscarinic Acetylcholine Receptors , 2003, Journal of Pharmacology and Experimental Therapeutics.

[54]  R. Murray,et al.  High marker-density analyses of the α7-nicotinic cholinergic receptor subunit (CHRNA7) gene region on chromosome 15q13-q14 and 5′-rage cloning of fragments specific to CHRNA7 or its partial duplication , 2000, Schizophrenia Research.

[55]  Charles R. Breese,et al.  Acetylcholine Activates an α-Bungarotoxin-Sensitive Nicotinic Current in Rat Hippocampal Interneurons, But Not Pyramidal Cells , 1998, The Journal of Neuroscience.

[56]  T. Werge,et al.  The Muscarinic M1/M4 Receptor Agonist Xanomeline Exhibits Antipsychotic-Like Activity in Cebus apella Monkeys , 2003, Neuropsychopharmacology.

[57]  K. Davis,et al.  Postmortem studies in schizophrenia , 2000, Schizophrenia bulletin.

[58]  H. Weingartner,et al.  Human serial learning: enhancement with arecholine and choline impairment with scopolamine. , 1978, Science.

[59]  T. Robbins,et al.  The Effects of AMPA‐induced Lesions of the Septo‐hippocampal Cholinergic Projection on Aversive Conditioning to Explicit and Contextual Cues and Spatial Learning in the Water Maze , 1995, The European journal of neuroscience.

[60]  W. J. Jackson,et al.  Functional Characterization of the Novel Neuronal Nicotinic Acetylcholine Receptor Ligand GTS-21 In Vitro and In Vivo , 1997, Pharmacology Biochemistry and Behavior.

[61]  T. Sotnikova,et al.  Hyperactivity, elevated dopaminergic transmission, and response to amphetamine in M1 muscarinic acetylcholine receptor-deficient mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[62]  T. Robbins,et al.  Attentional functions of the forebrain cholinergic systems: effects of intraventricular hemicholinium, physostigmine, basal forebrain lesions and intracortical grafts on a multiple-choice serial reaction time task , 2004, Experimental Brain Research.

[63]  J. Hagan,et al.  Blockade of spatial learning by the M1 muscarinic antagonist pirenzepine , 2004, Psychopharmacology.

[64]  Alcino J. Silva,et al.  Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice , 2003, Nature Neuroscience.

[65]  P. Tariot,et al.  A 5-month, randomized, placebo-controlled trial of galantamine in AD , 2000, Neurology.

[66]  A. Maelicke,et al.  Noncompetitive agonism at nicotinic acetylcholine receptors; functional significance for CNS signal transduction. , 1995, Journal of receptor and signal transduction research.

[67]  W W Offen,et al.  Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. , 1997, Archives of neurology.

[68]  R. Bartus.  Physostigmine and recent memory: effects in young and aged nonhuman primates. , 1979, Science.

[69]  T. Robbins,et al.  Comparative effects of ibotenic acid- and quisqualic acid-induced lesions of the substantia innominata on attentional function in the rat: further implications for the role of the cholinergic neurons of the nucleus basalis in cognitive processes , 1989, Behavioural Brain Research.

[70]  B. Dean,et al.  Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia , 2002, Molecular Psychiatry.

[71]  R. Church,et al.  Nucleus basalis magnocellularis and medial septal area lesions differentially impair temporal memory , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[72]  R. Mohs,et al.  A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease , 1998, Neurology.

[73]  S. Tye,et al.  Enhanced performance of spatial and visual recognition memory tasks by the selective acetylcholinesterase inhibitor E2020 in rhesus monkeys , 1997, Psychopharmacology.

[74]  R. Freedman,et al.  Selective α7-nicotinic agonists normalize inhibition of auditory response in DBA mice , 1998, Psychopharmacology.

[75]  R. Freedman,et al.  Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia , 1995, Biological Psychiatry.

[76]  P. F. M. Janssen,et al.  Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding , 1996, Psychopharmacology.

[77]  A. Maelicke,et al.  New approach to drug therapy in Alzheimer's dementia Alfred Maelicke and Edson X. Albuquerque , 1996 .

[78]  P. Solomon,et al.  A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. , 1994, JAMA.

[79]  Philip D. Harvey,et al.  Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. , 2001, The American journal of psychiatry.

[80]  R. Lester,et al.  Upregulation of surface alpha4beta2 nicotinic receptors is initiated by receptor desensitization after chronic exposure to nicotine. , 1999, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[81]  Y. Agid,et al.  Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trialCommentary: Another piece of the Alzheimer's jigsaw , 1999 .

[82]  P. Sanberg,et al.  Improved learning and memory in aged rats with chronic administration of the nicotinic receptor agonist GTS-21 , 1995, Brain Research.

[83]  H. Yamashita,et al.  Characterization of a novel muscarinic receptor agonist, YM796: comparison with cholinesterase inhibitors in in vivo pharmacological studies. , 1994, European journal of pharmacology.

[84]  D. Price,et al.  Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[85]  T. Robbins,et al.  Dissociable effects on spatial maze and passive avoidance acquisition and retention following AMPA- and ibotenic acid-induced excitotoxic lesions of the basal forebrain in rats: Differential dependence on cholinergic neuronal loss , 1991, Neuroscience.

[86]  P Dal-Bianco,et al.  Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. , 1999, BMJ.

[87]  D. Wong,et al.  Neurochemical effects of the M1 muscarinic agonist xanomeline (LY246708/NNC11-0232). , 1994, The Journal of pharmacology and experimental therapeutics.

[88]  H. Eichenbaum,et al.  Two functional components of the hippocampal memory system , 1994, Behavioral and Brain Sciences.

[89]  R. Gur,et al.  Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. , 1994, Archives of general psychiatry.

[90]  F. Fadda,et al.  Increased hippocampal acetylcholine release during a working memory task. , 1996, European journal of pharmacology.

[91]  K. Davis,et al.  Pharmacological Alleviation of Combined Cholinergic/Noradrenergic Lesion‐Induced Memory Deficits in Rats , 1991, Clinical neuropharmacology.

[92]  M. Emmerling,et al.  CI-1017, a functionally M1-selective muscarinic agonist: design, synthesis, and preclinical pharmacology. , 2000, Pharmaceutica acta Helvetiae.

[93]  Robert W. Buchanan,et al.  An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia , 2003, Schizophrenia Research.

[94]  R. Lester,et al.  Upregulation of Surface α4β2 Nicotinic Receptors Is Initiated by Receptor Desensitization after Chronic Exposure to Nicotine , 1999, The Journal of Neuroscience.

[95]  Douglas W. Jones,et al.  In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia. , 2003, The American journal of psychiatry.