Generic placeholder image

Current Drug Targets

Editor-in-Chief

ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

Review Article (Mini-Review)

A Review on Emerging Drug Targets in Treatment of Schizophrenia

Author(s): Hemen S. Ved and Gaurav M. Doshi*

Volume 21 , Issue 15 , 2020

Page: [1593 - 1605] Pages: 13

DOI: 10.2174/1389450121666200615150429

Price: $65

Abstract

Schizophrenia is a multifactorial, highly complex behavioral and cognitive disorder caused by disruptions of neurotransmitters in the brain, consequently affecting its functioning. The disorder is known to affect approximately 1% of the adult population worldwide. Antipsychotics used in the treatment have considerable drawbacks as they primarily aim to alleviate the positive symptoms of different aspects of the disorder and fail to treat the negative and cognitive symptoms. Considering the poor functional outcome of conventional antipsychotic therapy, the recent development of effective targets is of clinical importance. In this review, we summarize perspective on recent approaches and advances on schizophrenia. New therapeutically potential compounds for the treatment of schizophrenia act on metabotropic glutamate receptor, Matrix metalloproteinase, endocannabinoid receptor, nicotinic acetylcholine receptor, muscarinic acetylcholine cholinergic receptor and Dynorphin /Kappa Opioid receptor systems. This review explores the functions of different receptors other than dopaminergic systems to treat and manage schizophrenia effectively. The article would provide readers guidance on newer targets related to schizophrenia.

Keywords: Schizophrenia, novel treatment, metabotropic glutamate (mGlu), matrix metalloproteinase (MMP), endocannabinoid (eCB), nicotinic acetylcholine receptor (nAChR), muscarinic, kappa-opioid receptor (KOR).

Graphical Abstract
[1]
Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet 2016; 388(10039): 86-97.
[http://dx.doi.org/10.1016/S0140-6736(15)01121-6] [PMID: 26777917]
[2]
Millan MJ, Andrieux A, Bartzokis G, et al. Altering the course of schizophrenia: progress and perspectives. Nat Rev Drug Discov 2016; 15(7): 485-515.
[http://dx.doi.org/10.1038/nrd.2016.28] [PMID: 26939910]
[3]
Marder SR, Cannon TD. Schizophrenia. N Engl J Med 2019; 381(18): 1753-61.
[http://dx.doi.org/10.1056/NEJMra1808803] [PMID: 31665579]
[4]
[5]
He H, Liu Q, Li N, et al. Trends in the incidence and DALYs of schizophrenia at the global, regional and national levels: Results from the Global Burden of Disease Study. Epidemiol Psychiatr Sci 2017; 29e91
[6]
Morris BJ, Pratt JA. Novel treatment strategies for schizophrenia from improved understanding of genetic risk. Clin Genet 2014; 86(5): 401-11.
[http://dx.doi.org/10.1111/cge.12485] [PMID: 25142969]
[7]
Lally J, Maccabe JH. Antipsychotic medication in schizophrenia: a review. Br Med Bull 2015; 114: 169-79.
[http://dx.doi.org/10.1093/bmb/ldv017]
[8]
Maric NP, Jovicic MJ, Mihaljevic M, Miljevic C. Improving Current Treatments for Schizophrenia. Drug Dev Res 2016; 77(7): 357-67.
[http://dx.doi.org/10.1002/ddr.21337] [PMID: 27633376]
[9]
Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry 2012; 17(12): 1206-27.
[http://dx.doi.org/10.1038/mp.2012.47] [PMID: 22584864]
[10]
Zhang JP, Gallego JA, Robinson DG, Malhotra AK, Kane JM, Correll CU. Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol 2013; 16(6): 1205-18.
[http://dx.doi.org/10.1017/S1461145712001277] [PMID: 23199972]
[11]
Tarricone I, Casoria M, Gozzi BF, et al. Metabolic risk factor profile associated with use of second generation antipsychotics: A cross sectional study in a community mental health centre. BMC Psychiatry 2006; (11): 6.
[http://dx.doi.org/10.1186/1471-244X-6-11]
[12]
Muench J, Hamer AM. Adverse Effects of Antipsychotic Medications www.aafp.org/afpAmericanFamilyPhysician6172010
[13]
Aguilar L, Lorenzo C, Fernández-Ovejero R, Roncero C, Montejo AL. Tardive Dyskinesia After Aripiprazole Treatment That Improved With Tetrabenazine, Clozapine, and Botulinum Toxin. Front Pharmacol 2019; 10: 281.
[http://dx.doi.org/10.3389/fphar.2019.00281] [PMID: 30949057]
[14]
Maksymetz J, Moran SP, Conn PJ. Targeting metabotropic glutamate receptors for novel treatments of schizophrenia. Mol Brain 2017; 10(1): 15.
[http://dx.doi.org/10.1186/s13041-017-0293-z] [PMID: 28446243]
[15]
Simões AP, Silva CG, Marques JM, et al. Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation. Cell Death Dis 2018; 9(3): 297.
[http://dx.doi.org/10.1038/s41419-018-0351-1] [PMID: 29463792]
[16]
Stansley BJ, Conn PJ. The therapeutic potential of metabotropic glutamate receptor modulation for schizophrenia. Curr Opin Pharmacol 2018; 38: 31-6.
[http://dx.doi.org/10.1016/j.coph.2018.02.003] [PMID: 29486374]
[17]
Nicoletti F, Orlando R, Di Menna L, et al. Targeting mGlu receptors for optimization of antipsychotic activity and disease-modifying effect in schizophrenia. Front Psychiatry 2019; 10: 49.
[http://dx.doi.org/10.3389/fpsyt.2019.00049] [PMID: 30890967]
[18]
Walker AG, Conn PJ. Group I and group II metabotropic glutamate receptor allosteric modulators as novel potential antipsychotics. Curr Opin Pharmacol 2015; 20: 40-5.
[http://dx.doi.org/10.1016/j.coph.2014.11.003] [PMID: 25462291]
[19]
Geyer MA, Gross G. Novel antischizophrenia treatments. Springer 2012.
[http://dx.doi.org/10.1007/978-3-642-25758-2]
[20]
Skolnick P. Glutamate-based therapies for psychiatric disorders. Springer 2010.
[http://dx.doi.org/10.1007/978-3-0346-0241-9]
[21]
Xiang Z, Lv X, Maksymetz J, et al. mGlu5 Positive Allosteric Modulators Facilitate Long-Term Potentiation via Disinhibition Mediated by mGlu5-Endocannabinoid Signaling. ACS Pharmacol Transl Sci 2019; 2(3): 198-209.
[http://dx.doi.org/10.1021/acsptsci.9b00017] [PMID: 31259318]
[22]
Rook JM, Xiang Z, Lv X, et al. Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents. Neuron 2015; 86(4): 1029-40.
[http://dx.doi.org/10.1016/j.neuron.2015.03.063] [PMID: 25937172]
[23]
Sengmany K, Gregory KJ. Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias. Br J Pharmacol 2016; 173(20): 3001-17.
[http://dx.doi.org/10.1111/bph.13281] [PMID: 26276909]
[24]
Celanire S, Poli S, Cesura AM. 2015.
[25]
Balu DT, Li Y, Takagi S, et al. An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia. Neuropsychopharmacology 2016; 41(8): 2052-61.
[http://dx.doi.org/10.1038/npp.2016.2] [PMID: 26741285]
[26]
Muguruza C, Meana JJ, Callado LF, Group II. Group II metabotropic glutamate receptors as targets for novel antipsychotic drugs. Front Pharmacol 2016; 7: 130.
[http://dx.doi.org/10.3389/fphar.2016.00130] [PMID: 27242534]
[27]
Ellaithy A, Younkin J, González-Maeso J, Logothetis DE. Positive allosteric modulators of metabotropic glutamate 2 receptors in schizophrenia treatment. Trends Neurosci 2015; 38(8): 506-16.
[http://dx.doi.org/10.1016/j.tins.2015.06.002] [PMID: 26148747]
[28]
Farinha A, Lavreysen H, Peeters L, et al. Molecular determinants of positive allosteric modulation of the human metabotropic glutamate receptor 2. Br J Pharmacol 2015; 172(9): 2383-96.
[http://dx.doi.org/10.1111/bph.13065] [PMID: 25571949]
[29]
Cieślik P, Woźniak M, Rook JM, et al. Mutual activation of glutamatergic mGlu4 and muscarinic M4 receptors reverses schizophrenia-related changes in rodents. Psychopharmacology (Berl) 2018; 235(10): 2897-913.
[http://dx.doi.org/10.1007/s00213-018-4980-y] [PMID: 30054675]
[30]
Kalinichev M, Le Poul E, Boléa C, et al. Characterization of the novel positive allosteric modulator of the metabotropic glutamate receptor 4 ADX88178 in rodent models of neuropsychiatric disorders. J Pharmacol Exp Ther 2014; 350(3): 495-505.
[http://dx.doi.org/10.1124/jpet.114.214437] [PMID: 24947466]
[31]
Woźniak M, Acher F, Marciniak M, et al. Involvement of GABAB Receptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu4 Receptor, LSP4-2022. Curr Neuropharmacol 2016; 14(5): 413-26.
[http://dx.doi.org/10.2174/1570159X13666150516000630] [PMID: 26769224]
[32]
Cieślik P, Woźniak M. 2018.
[33]
Robbins MJ, Starr KR, Honey A, et al. Evaluation of the mGlu8 receptor as a putative therapeutic target in schizophrenia. Brain Res 2007; 1152: 215-27.
[http://dx.doi.org/10.1016/j.brainres.2007.03.028] [PMID: 17434465]
[34]
Crupi R, Impellizzeri D, Cuzzocrea S. Role of metabotropic glutamate receptors in neurological disorders. Front Mol Neurosci 2019; 12: 20.
[http://dx.doi.org/10.3389/fnmol.2019.00020] [PMID: 30800054]
[35]
Lindsley CW, Stauffer SR. Metabotropic glutamate receptor 5-positive allosteric modulators for the treatment of schizophrenia (2004-2012). Pharm Pat Anal 2013; 2(1): 93-108.
[http://dx.doi.org/10.4155/ppa.12.82] [PMID: 24236973]
[36]
Krystal JH, Abi-Saab W, Perry E, et al. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology (Berl) 2005; 179(1): 303-9.
[http://dx.doi.org/10.1007/s00213-004-1982-8] [PMID: 15309376]
[37]
Li ML, Hu XQ, Li F, Gao WJ. Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end? Prog Neuropsychopharmacol Biol Psychiatry 2015; 60: 66-76.
[http://dx.doi.org/10.1016/j.pnpbp.2015.02.012] [PMID: 25724760]
[38]
McGregor N, Thompson N, O’Connell KS, Emsley R, van der Merwe L, Warnich L. Modification of the association between antipsychotic treatment response and childhood adversity by MMP9 gene variants in a first-episode schizophrenia cohort. Psychiatry Res 2018; 262: 141-8.
[http://dx.doi.org/10.1016/j.psychres.2018.01.044] [PMID: 29448178]
[39]
Chopra K, Baveja A, Kuhad A. MMPs: a novel drug target for schizophrenia. Expert Opin Ther Targets 2015; 19(1): 77-85.
[http://dx.doi.org/10.1517/14728222.2014.957672] [PMID: 25214056]
[40]
Kim Y-S, Joh T-H. Matrix metalloproteinases, new insights into the understanding of neurodegenerative disorders. Biomol Ther (Seoul) 2012; 20(2): 133-43.
[http://dx.doi.org/10.4062/biomolther.2012.20.2.133] [PMID: 24116286]
[41]
Beroun A, Mitra S, Michaluk P, Pijet B, Stefaniuk M, Kaczmarek L. MMPs in learning and memory and neuropsychiatric disorders. Cell Mol Life Sci 2019; 76(16): 3207-28.
[http://dx.doi.org/10.1007/s00018-019-03180-8] [PMID: 31172215]
[42]
Devanarayanan S, Nandeesha H, Kattimani S, Sarkar S. Relationship between matrix metalloproteinase-9 and oxidative stress in drug-free male schizophrenia: a case control study. Clin Chem Lab Med 2016; 54(3): 447-52.
[http://dx.doi.org/10.1515/cclm-2015-0212] [PMID: 26351924]
[43]
Lepeta K, Kaczmarek L. Matrix metalloproteinase-9 as a novel player in synaptic plasticity and schizophrenia. Schizophr Bull 2015; 41(5): 1003-9.
[http://dx.doi.org/10.1093/schbul/sbv036] [PMID: 25837304]
[44]
Zhang L, Zhao J. Profile of minocycline and its potential in the treatment of schizophrenia. Neuropsychiatr Dis Treat 2014; 10: 1103-11.
[http://dx.doi.org/10.2147/NDT.S64236] [PMID: 24971013]
[45]
Oya K, Kishi T, Iwata N. Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol 2014; 29(5): 483-91.
[http://dx.doi.org/10.1002/hup.2426] [PMID: 25087702]
[46]
Miyaoka T. Clinical potential of minocycline for schizophrenia. CNS Neurol Disord Drug Targets 2008; 7(4): 376-81.
[http://dx.doi.org/10.2174/187152708786441858] [PMID: 18991666]
[47]
Deakin B, Suckling J, Barnes TRE, et al. BeneMin Study team. The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial. Lancet Psychiatry 2018; 5(11): 885-94.
[http://dx.doi.org/10.1016/S2215-0366(18)30345-6] [PMID: 30322824]
[48]
Ben-Azu B, Omogbiya IA, Aderibigbe AO, Umukoro S, Ajayi AM, Iwalewa EO. Doxycycline prevents and reverses schizophrenic-like behaviors induced by ketamine in mice via modulation of oxidative, nitrergic and cholinergic pathways. Brain Res Bull 2018; 139: 114-24.
[http://dx.doi.org/10.1016/j.brainresbull.2018.02.007] [PMID: 29425796]
[49]
Shrivastava A, Johnston M, Tsuang M. Cannabis use and cognitive dysfunction. Indian J Psychiatry 2011; 53(3): 187-91.
[http://dx.doi.org/10.4103/0019-5545.86796] [PMID: 22135433]
[50]
Fakhoury M. Role of the Endocannabinoid System in the Pathophysiology of Schizophrenia. Mol Neurobiol 2017; 54(1): 768-78.
[http://dx.doi.org/10.1007/s12035-016-9697-5] [PMID: 26768595]
[51]
O’Neill A, Bhattacharyya S. Investigating the Role of the Endocannabinoid System in Early Psychosis. J Explor Res Pharmacol 2017; 2: 85-92.
[http://dx.doi.org/10.14218/JERP.2017.00009]
[52]
Ferretjans R, Moreira FA, Teixeira AL, Salgado JV. The endocannabinoid system and its role in schizophrenia: a systematic review of the literature. Br J Psychiatry 2012; 34(Suppl. 2): S163-77.
[http://dx.doi.org/10.1016/j.rbp.2012.07.003] [PMID: 23429846]
[53]
Basavarajappa BS. Neuropharmacology of the endocannabinoid signaling system-molecular mechanisms, biological actions and synaptic plasticity. Curr Neuropharmacol 2007; 5(2): 81-97.
[http://dx.doi.org/10.2174/157015907780866910] [PMID: 18084639]
[54]
Giuffrida A, Leweke FM, Gerth CW, et al. Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology 2004; 29(11): 2108-14.
[http://dx.doi.org/10.1038/sj.npp.1300558] [PMID: 15354183]
[55]
Fervaha G, Zakzanis KK, Foussias G, Graff-Guerrero A, Agid O, Remington G. Motivational deficits and cognitive test performance in schizophrenia. JAMA Psychiatry 2014; 71(9): 1058-65.
[http://dx.doi.org/10.1001/jamapsychiatry.2014.1105] [PMID: 25075930]
[56]
Rohleder C, Müller JK, Lange B, Leweke FM. Cannabidiol as a potential new type of an antipsychotic. A critical review of the evidence. Front Pharmacol 2016; 7: 422.
[http://dx.doi.org/10.3389/fphar.2016.00422] [PMID: 27877130]
[57]
Gururajan A, Malone DT. Does cannabidiol have a role in the treatment of schizophrenia? Schizophr Res 2016; 176(2-3): 281-90.
[http://dx.doi.org/10.1016/j.schres.2016.06.022] [PMID: 27374322]
[58]
Almeida V, Peres FF, Levin R, et al. Effects of cannabinoid and vanilloid drugs on positive and negative-like symptoms on an animal model of schizophrenia: the SHR strain. Schizophr Res 2014; 153(1-3): 150-9.
[http://dx.doi.org/10.1016/j.schres.2014.01.039] [PMID: 24556469]
[59]
Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2012; 2: e94-4.
[http://dx.doi.org/10.1038/tp.2012.15] [PMID: 22832859]
[60]
McGuire P, Robson P, Cubala WJ, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: A multicenter randomized controlled trial. Am J Psychiatry 2018; 175(3): 225-31.
[http://dx.doi.org/10.1176/appi.ajp.2017.17030325] [PMID: 29241357]
[61]
Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf 2011; 6(4): 237-49.
[http://dx.doi.org/10.2174/157488611798280924] [PMID: 22129319]
[62]
Taylor P. Nicotinic Receptors
[63]
Tregellas JR, Wylie KP. Alpha7 Nicotinic Receptors as Therapeutic Targets in Schizophrenia. Nicotine Tob Res 2019; 21(3): 349-56.
[http://dx.doi.org/10.1093/ntr/nty034] [PMID: 30137618]
[64]
Smucny J, Tregellas JR. Targeting neuronal dysfunction in schizophrenia with nicotine: Evidence from neurophysiology to neuroimaging. J Psychopharmacol (Oxford) 2017; 31(7): 801-11.
[http://dx.doi.org/10.1177/0269881117705071] [PMID: 28441884]
[65]
Yang T, Xiao T, Sun Q, Wang K. The current agonists and positive allosteric modulators of α7 nAChR for CNS indications in clinical trials. Acta Pharm Sin B 2017; 7(6): 611-22.
[http://dx.doi.org/10.1016/j.apsb.2017.09.001] [PMID: 29159020]
[66]
Harris JG, Kongs S, Allensworth D, et al. Effects of nicotine on cognitive deficits in schizophrenia. Neuropsychopharmacology 2004; 29(7): 1378-85.
[http://dx.doi.org/10.1038/sj.npp.1300450] [PMID: 15138435]
[67]
Hashimoto K. Targeting of α7 Nicotinic Acetylcholine Receptors in the Treatment of Schizophrenia and the Use of Auditory Sensory Gating as a Translational Biomarker. Curr Pharm Des 2015; 21(26): 3797-806.
[http://dx.doi.org/10.2174/1381612821666150605111345] [PMID: 26044974]
[68]
Kem WR, Olincy A, Johnson L, et al. Pharmacokinetic Limitations on Effects of an Alpha7-Nicotinic Receptor Agonist in Schizophrenia: Randomized Trial with an Extended-Release Formulation. Neuropsychopharmacology 2018; 43(3): 583-9.
[http://dx.doi.org/10.1038/npp.2017.182] [PMID: 28825423]
[70]
Toyohara J, Hashimoto K. α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease. Open Med Chem J 2010; 4: 37-56.
[http://dx.doi.org/10.2174/1874104501004010037] [PMID: 21249164]
[71]
Rezvani AH, Kholdebarin E, Brucato FH, Callahan PM, Lowe DA, Levin ED. Effect of R3487/MEM3454, a novel nicotinic α7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33(2): 269-75.
[http://dx.doi.org/10.1016/j.pnpbp.2008.11.018] [PMID: 19110025]
[72]
Hauser TA, Kucinski A, Jordan KG, et al. TC-5619: an alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia. Biochem Pharmacol 2009; 78(7): 803-12.
[http://dx.doi.org/10.1016/j.bcp.2009.05.030] [PMID: 19482012]
[73]
Walling D, Marder SR, Kane J, et al. Phase 2 Trial of an Alpha-7 Nicotinic Receptor Agonist (TC-5619) in Negative and Cognitive Symptoms of Schizophrenia. Schizophr Bull 2016; 42(2): 335-43.
[http://dx.doi.org/10.1093/schbul/sbv072] [PMID: 26071208]
[74]
Kohnomi S, Suemaru K, Goda M, et al. Ameliorating effects of tropisetron on dopaminergic disruption of prepulse inhibition via the α(7) nicotinic acetylcholine receptor in Wistar rats. Brain Res 2010; 1353: 152-8.
[http://dx.doi.org/10.1016/j.brainres.2010.07.037] [PMID: 20673759]
[75]
Zhang XY, Liu L, Liu S, et al. Short-term tropisetron treatment and cognitive and P50 auditory gating deficits in schizophrenia. Am J Psychiatry 2012; 169(9): 974-81.
[http://dx.doi.org/10.1176/appi.ajp.2012.11081289] [PMID: 22952075]
[76]
Preskorn SH, Gawryl M, Dgetluck N, Palfreyman M, Bauer LO, Hilt DC. Normalizing effects of EVP-6124, an α-7 nicotinic partial agonist, on event-related potentials and cognition: a proof of concept, randomized trial in patients with schizophrenia. J Psychiatr Pract 2014; 20(1): 12-24.
[http://dx.doi.org/10.1097/01.pra.0000442935.15833.c5] [PMID: 24419307]
[77]
Prickaerts J, van Goethem NP, Chesworth R, et al. EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors. Neuropharmacology 2012; 62(2): 1099-110.
[http://dx.doi.org/10.1016/j.neuropharm.2011.10.024] [PMID: 22085888]
[78]
Ng HJ, Whittemore ER, Tran MB, et al. Nootropic α7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators. Proc Natl Acad Sci USA 2007; 104(19): 8059-64.
[http://dx.doi.org/10.1073/pnas.0701321104] [PMID: 17470817]
[79]
Gee KW, Olincy A, Kanner R, et al. First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: Pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288. J Psychopharmacol (Oxford) 2017; 31(4): 434-41.
[http://dx.doi.org/10.1177/0269881117691590] [PMID: 28196430]
[80]
Winterer G, Gallinat J, Brinkmeyer J, et al. Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: a proof-of-mechanism study. Neuropharmacology 2013; 64: 197-204.
[http://dx.doi.org/10.1016/j.neuropharm.2012.06.040] [PMID: 22766391]
[81]
Abrams P, Andersson KE, Buccafusco JJ, et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol 2006; 148(5): 565-78.
[http://dx.doi.org/10.1038/sj.bjp.0706780] [PMID: 16751797]
[82]
Carruthers SP, Gurvich CT, Rossell SL. The muscarinic system, cognition and schizophrenia. Neurosci Biobehav Rev 2015; 55: 393-402.
[http://dx.doi.org/10.1016/j.neubiorev.2015.05.011] [PMID: 26003527]
[83]
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(5): 381-8.
[http://dx.doi.org/10.1016/S0006-3223(00)00918-5] [PMID: 10978721]
[84]
Scarr E, Dean B. Role of the cholinergic system in the pathology and treatment of schizophrenia. Expert Rev Neurother 2009; 9(1): 73-86.
[http://dx.doi.org/10.1586/14737175.9.1.73] [PMID: 19102670]
[85]
Shannon HE, Rasmussen K, Bymaster FP, et al. Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr Res 2000; 42(3): 249-59.
[http://dx.doi.org/10.1016/S0920-9964(99)00138-3] [PMID: 10785583]
[86]
Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry 2008; 165(8): 1033-9.
[http://dx.doi.org/10.1176/appi.ajp.2008.06091591] [PMID: 18593778]
[87]
Grant MKO, El-Fakahany EE. Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor. J Pharmacol Exp Ther 2005; 315(1): 313-9.
[http://dx.doi.org/10.1124/jpet.105.090134] [PMID: 16002459]
[88]
Bridges TM, LeBois EP, Hopkins CR, et al. The antipsychotic potential of muscarinic allosteric modulation. Drug News Perspect 2010; 23(4): 229-40.
[http://dx.doi.org/10.1358/dnp.2010.23.4.1416977] [PMID: 20520852]
[89]
Jones CK, Brady AE, Davis AA, et al. Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats. J Neurosci 2008; 28(41): 10422-33.
[http://dx.doi.org/10.1523/JNEUROSCI.1850-08.2008] [PMID: 18842902]
[90]
Bradley SR, Lameh J, Ohrmund L, et al. AC-260584, an orally bioavailable M(1) muscarinic receptor allosteric agonist, improves cognitive performance in an animal model. Neuropharmacology 2010; 58(2): 365-73.
[http://dx.doi.org/10.1016/j.neuropharm.2009.10.003] [PMID: 19835892]
[91]
Nathan PJ, Watson J, Lund J, et al. The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction. Int J Neuropsychopharmacol 2013; 16(4): 721-31.
[http://dx.doi.org/10.1017/S1461145712000752] [PMID: 22932339]
[92]
Lange HS, Cannon CE, Drott JT, Kuduk SD, Uslaner JM. The M1 muscarinic positive allosteric modulator PQCA improves performance on translatable tests of memory and attention in rhesus monkeys. J Pharmacol Exp Ther 2015; 355(3): 442-50.
[http://dx.doi.org/10.1124/jpet.115.226712] [PMID: 26446308]
[93]
Ghoshal A, Rook JM, Dickerson JW, et al. Potentiation of M1 muscarinic receptor reverses plasticity deficits and negative and cognitive symptoms in a schizophrenia mouse model. Neuropsychopharmacology 2016; 41(2): 598-610.
[http://dx.doi.org/10.1038/npp.2015.189] [PMID: 26108886]
[94]
Khajehali E, Valant C, Jörg M, et al. Probing the binding site of novel selective positive allosteric modulators at the M1 muscarinic acetylcholine receptor. Biochem Pharmacol 2018; 154: 243-54.
[http://dx.doi.org/10.1016/j.bcp.2018.05.009] [PMID: 29777683]
[95]
Shirey JK, Xiang Z, Orton D, et al. An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission. Nat Chem Biol 2008; 4(1): 42-50.
[http://dx.doi.org/10.1038/nchembio.2007.55] [PMID: 18059262]
[96]
Hoyos Flight M. Tuning muscarinic receptor signalling. Nat Rev Drug Discov 2008; 7: 806-6.
[http://dx.doi.org/10.1038/nrd2689]
[97]
Yohn SE, Conn PJ. Positive allosteric modulation of M1 and M4 muscarinic receptors as potential therapeutic treatments for schizophrenia. Neuropharmacology 2018; 136(Pt C): 438-48.
[http://dx.doi.org/10.1016/j.neuropharm.2017.09.012] [PMID: 28893562]
[98]
Bubser M, Bridges TM, Dencker D, et al. Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents. ACS Chem Neurosci 2014; 5(10): 920-42.
[http://dx.doi.org/10.1021/cn500128b] [PMID: 25137629]
[99]
Galloway CR, Lebois EP, Shagarabi SL, Hernandez NA, Manns JR. Effects of selective activation of M1 and M4 muscarinic receptors on object recognition memory performance in rats. Pharmacology 2014; 93(1-2): 57-64.
[http://dx.doi.org/10.1159/000357682] [PMID: 24480931]
[100]
Shekhar A. Role of Kappa Opioid Receptors in Symptoms of Schizophrenia: What Is the Neurobiology? Biol Psychiatry 2019; 86(7): 494-6.
[http://dx.doi.org/10.1016/j.biopsych.2019.08.004] [PMID: 31521206]
[101]
Clark SD, Abi-Dargham A. The Role of Dynorphin and the Kappa Opioid Receptor in the Symptomatology of Schizophrenia: A Review of the Evidence. Biol Psychiatry 2019; 86(7): 502-11.
[http://dx.doi.org/10.1016/j.biopsych.2019.05.012] [PMID: 31376930]
[102]
Peckys D, Hurd YL. Prodynorphin and κ opioid receptor mRNA expression in the cingulate and prefrontal cortices of subjects diagnosed with schizophrenia or affective disorders. Brain Res Bull 2001; 55(5): 619-24.
[http://dx.doi.org/10.1016/S0361-9230(01)00525-1] [PMID: 11576758]
[103]
Tejeda HA, Shippenberg TS, Henriksson R. The dynorphin/κ-opioid receptor system and its role in psychiatric disorders. Cell Mol Life Sci 2012; 69(6): 857-96.
[http://dx.doi.org/10.1007/s00018-011-0844-x] [PMID: 22002579]
[104]
Carlezon WA Jr, Krystal AD. Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials. Depress Anxiety 2016; 33(10): 895-906.
[http://dx.doi.org/10.1002/da.22500] [PMID: 27699938]
[105]
Skrabanek P. Naloxone in schizophrenia. Lancet 1982; 2(8310): 1270.
[http://dx.doi.org/10.1016/S0140-6736(82)90118-0] [PMID: 6128561]
[106]
Verhoeven WMA, van Praag HM, de Jong JTVM. Use of naloxone in schizophrenic psychoses and manic syndromes. Neuropsychobiology 1981; 7(3): 159-68.
[http://dx.doi.org/10.1159/000117845] [PMID: 7231653]
[107]
Tatari F, Farnia V, Hossein Hashemian A. Naltrexone Augmentation of Risperidone in Treatment of Schizophrenia Symptoms https://www.researchgate.net/publication/2750234302014.
[108]
Marchesi GF, Santone G, Cotani P, Giordano A, Chelli F. Naltrexone in chronic negative schizophrenia. Clin Neuropharmacol 1992; 15(Suppl. 1 Pt A): 56A-7A.
[http://dx.doi.org/10.1097/00002826-199201001-00031] [PMID: 1498948]
[109]
Schmauss C, Yassouridis A, Emrich HM. Antipsychotic effect of buprenorphine in schizophrenia. Am J Psychiatry 1987; 144(10): 1340-2.
[http://dx.doi.org/10.1176/ajp.144.10.1340] [PMID: 3310672]
[110]
Groves S, Nutt D, Vieta E. Letters. Hum Psychopharmacol Clin Exp 1991; 6: 71-3.
[http://dx.doi.org/10.1002/hup.470060113]
[111]
Rapaport MH, Wolkowitz O, Kelsoe JR, Pato C, Konicki PE, Pickar D. Beneficial effects of nalmefene augmentation in neuroleptic-stabilized schizophrenic patients. Neuropsychopharmacology 1993; 9(2): 111-5.
[http://dx.doi.org/10.1038/npp.1993.49] [PMID: 8105790]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy