NEUROTRANSMITTER AND BRAIN PARTS INVOLVED IN SCHIZOPHRENIA
DOI:
https://doi.org/10.22159/ajpcr.2018.v11i6.24557Keywords:
Schizophrenia, Memory, Cognitive dysfunction, Dopamine, GlutamateAbstract
Schizophrenia (SCZ) is a major debilitating, complex, and costly illness that strikes 1% of the world's population. It is characterized by three general types of symptoms: Atypical symptoms (aggressiveness, agitation, delusions, hallucinations), depressive symptoms (alogia, avolition, anhedonia, apathy), and cognitive symptoms (impaired attention, learning, memory). The etiology of SCZ has still not been fully understood. Alteration in various neurochemical systems such as dopamine, serotonin, norepinephrine, gamma-aminobutyric acid, and glutamate are involved in the pathophysiology of SCZ. The lack of understanding regarding the exact pathogenic process may be the likely a reason for the non-availability of effective treatment, which can prevent onset and progression of the SCZ. The tools of modern neuroscience, drawing from neuroanatomy, neurophysiology, brain imaging, and psychopharmacology, promise to provide a host of new insights into the etiology and treatment of SCZ. In this review, we will discuss the role of the various neurotransmitter concerned and brain parts exaggerated in the SCZ.
Downloads
References
Andreasen NC. Symptoms, signs, and diagnosis of schizophrenia. Lancet 1995;346:477-81.
Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE, et al. Schizophrenia: Manifestations, incidence and course in different cultures. A World health organization ten-country study. Psychol Med Monogr Suppl 1992;20:1-97.
Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron 2006;52:139-53.
Singh SM, O’Reilly R. (Epi) genomics and neurodevelopment in schizophrenia: Monozygotic twins discordant for schizophrenia augment the search for diseaserelated (epi) genomic alterations. Genome Natl Res Council Canada 2009;52:8-19.
Jaaro-Peled H, Hayashi-Takagi A, Seshadri S, Kamiya A, Brandon NJ, Sawa A, et al. Neurodevelopmental mechanisms of schizophrenia: Understanding disturbed postnatal brain maturation through neuregulin-1-erbB4 and DISC1. Trends Neurosci 2009;32:485-95.
Hayashi-Takagi A, Sawa A. Disturbed synaptic connectivity in schizophrenia: Convergence of genetic risk factors during neurodevelopment. Brain Res Bull 2010;83:140-6.
Keshavan MS, Tandon R, Boutros NN, Nasrallah HA. Schizophrenia ‘‘just the facts’’: What we know in 2008 Part 3: Neurobiology. Schizophr Res 2008;106:89-107.
Rice DP. The economic impact of schizophrenia. J Clin Psychiatry 1999;60 Suppl 1:4-6.
Andreasen NC. Schizophrenia: The fundamental questions. Brain Res Brain Res Rev 2000;31:106-12.
Erlenmeyer-Kimling L, Rock D, Roberts SA, Janal M, Kestenbaum C, Cornblatt B, et al. Attention, memory, and motor skills as childhood predictors of schizophrenia-related psychoses: The new york high-risk project. Am J Psychiatry 2000;157:1416-22.
Vishnupriya R, Ezhilramya B, Meenakshi B. Metformin in the prevention of metabolic syndrome associated with initiation of atypical antipsychotic therapy in adolescents and young adults-a randomized, open labelled, single centered study. Int J Pharm Pharm Sci 2016;8:200-6.
Leonard BE. Fundamentals of Psychopharmacology. 3rd ed. New York: John Wiley and Sons, Ltd.; 2003. p. 1-445.
Parle MA. Anti-psychotic activity of Pyrus communis Juice. Int J Pharm Pharm Sci 2017;9:113-20.
Weickert TW, Goldberg TE, Gold JM, Bigelow LB, Egan MF, Weinberger DR, et al. Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect. Arch Gen Psychiatry 2000;57:907-13.
Ohnuma T, Arai H. Pathophysiology of patients with schizophrenia: Genetic and Environmental factors. Juntendo Med J 2017;63:8-16.
Lieberman JA, Perkins D, Belger A, Chakos M, Jarskog F, Boteva K, et al. The early stages of schizophrenia: Speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry 2001;50:884-97.
Glatt SJ, Jönsson EG. The cys allele of the DRD2 ser311Cys polymorphism has a dominant effect on risk for schizophrenia: Evidence from fixed-and random-effects meta-analyses. Am J Med Genet B Neuropsychiatr Genet 2006;141B:149-54.
Toth M, Tecott L. Transgenic approach to epilepsy. Adv Neurol 1999;79:291-6.
Willins DL, Berry SA, Alsayegh L, Backstrom JR, Sanders-Bush E, Friedman L, et al. Clozapine and other 5-hydroxytryptamine-2A receptor antagonists alter the subcellular distribution of 5-hydroxytryptamine-2A receptors in vitro and in vivo. Neuroscience 1999;91:599-606.
Clinton SM, Meador-Woodruff JH. Abnormalities of the NMDA receptor and associated intracellular molecules in the thalamus in schizophrenia and bipolar disorder. Neuropsychopharmacology 2004;29:1353-62.
Pilowsky LS, Bressan RA, Stone JM, Erlandsson K, Mulligan RS, Krystal JH, et al. First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry 2006;11:118-9.
Benes FM. Emerging principles of altered neural circuitry in schizophrenia. Brain Res Brain Res Rev 2000;31:251-69.
Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology and therapy of schizophrenia. Pharmacol Biochem Behav 2012;100:665-77.
Grace AA. Dopamine system dysregulation by the hippocampus: Implications for the pathophysiology and treatment of schizophrenia. Neuropharmacology 2012;62:1342-8.
Toda M, Abi-Dargham A. Dopamine hypothesis of schizophrenia: Making sense of it all. Curr Psychiatry Rep 2007;9:329-36.
Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005;6:312-24.
Moghaddam B. Bringing order to the glutamate chaos in schizophrenia. Neuron 2003;40:881-4.
Fallon JH, Opole IO, Potkin SG. The neuroanatomy of schizophrenia: Circuitry and neurotransmitter systems. Clin Neurosci Res 2003;3:77-107.
Perez-Costas E, Melendez-Ferro M, Roberts RC. Basal ganglia pathology in schizophrenia: Dopamine connections and anomalies. J Neurochem 2010;113:287-302.
Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: Version III–the final common pathway. Schizophr Bull 2009;35:549-62.
Cazorla M, de Carvalho FD, Chohan MO, Shegda M, Chuhma N, Rayport S, et al. Dopamine D2 receptors regulate the anatomical and functional balance of basal ganglia circuitry. Neuron 2014;81:153-64.
Seeman P, Seeman MV. Schizophrenia and the supersensitive synapse. Neuropsychiatry 2011;1:233-42.
Brittain JS, Brown P. Oscillations and the basal ganglia: Motor control and beyond. Neuroimage 2014;85 Pt 2:637-47.
Harrington D, Hening W, Poizner H. Basal Ganglia: Motor Functions. New Jersey: University of Medicine and Dentistry of New Jersey; 2009. p. 346-50.
Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL. Effects of S-ketamine on striatal dopamine: A [11C]-raclopride PET study of a model psychosis in humans. J Psychiatr Res 2000;34:35-43.
Huang EJ, Reichardt LF. Neurotrophins: Roles in neuronal development and function. Annu Rev Neurosci 2001;24:677-736.
Spenger C, Hyman C, Studer L, Egli M, Evtouchenko L, Jackson C,et al. Effects of BDNF on dopaminergic, serotonergic, and GABAergic neurons in cultures of human fetal ventral mesencephalon. Exp Neurol 1995;133:50-63.
Xiu MH, Hui L, Dang YF, Hou TD, Zhang CX, Zheng YL, et al. Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:1508-12.
Laruelle M. The role of endogenous sensitization in the pathophysiology of schizophrenia: Implications from recent brain imaging studies. Brain Res Brain Res Rev 2000;31:371-84.
Burnet PW, Eastwood SL. Harrison PJ 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 1996;15:442-55.
Raymond JR, Mukhin YV, Gelasco A, Turner J, Collinsworth G, Gettys TW, et al. Multiplicity of mechanisms of serotonin receptor signal transduction. Pharmacol Ther 2001;92:179-212.
Harrison PJ. Neurochemical alterations in schizophrenia affecting the putative receptor targets of atypical antipsychotics. Focus on dopamine (D1, D3, D4) and 5-HT2a receptors. Br J Psychiatry Suppl 1999;38:12-22.
Lodge D. The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclature. Neuropharmacology 2009;56:6-21.
Kalia LV, Kalia SK, Salter MW. NMDA receptors in clinical neurology: Excitatory times ahead. Lancet Neurol 2008;7:742-55.
Labrie V, Roder JC. The involvement of the NMDA receptor D-serine/glycine site in the pathophysiology and treatment of schizophrenia. Neurosci Biobehav Rev 2010;34:351-72.
Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature 2004;429:761-6.
Quinlan EM, Olstein DH, Bear MF. Bidirectional, experience-dependent regulation of Nmethyl-D-aspartate receptor subunit composition in the rat visual cortex during postnatal development. Proc Natl Acad Sci USA 1999;96:12876-80.
Yashiro K, Philpot BD. Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity. Neuropharmacology 2008;55:1081-94.
van Zundert B, Yoshii A, Constantine-Paton M. Receptor compartmentalization and trafficking at glutamate synapses: A developmental proposal. Trends Neurosci 2004;27:428-37.
Javitt DC. Glycine transport inhibitors and the treatment of schizophrenia. Biol Psychiatry 2008;63:6-8.
McDonald JW, Johnston MV. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Brain Res Rev 1990;15:41-70.
Carlsson A, Waters, N, Waters S, Carlsson ML. Network interactions in schizophrenia: Therapeutic implications. Brain Res Brain Res Rev 2000;31:342-9.
Jentsch JD, Roth RH. The neuropsychopharmacology of phencyclidine: From NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 1999;20:201-25.
Coyle JT. The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 1996;3:241-53.
Ayano G. Dopamine: Receptors, functions, synthesis, pathways, locations and mental disorders: Review of literatures. J Ment Disord Treat 2016;2:120.
Goto Y, Yang CR, Otani S. Functional and dysfunctional synaptic plasticity in prefrontal cortex: Roles in psychiatric disorders. Biol Psychiatry 2010;67:199-207.
Lisman J, Grace AA, Duzel E. A neoHebbian framework for episodic memory; Role of dopamine-dependent late LTP. Trends Neurosci 2011;34:536-47.
Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL, et al. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: Implications for schizophrenia. Biol Psychiatry 2000;48:627-40.
Wobrock T, Kadovic D, Falkai P. Cortical excitability in schizophrenia. Studies using transcranial magnetic stimulation. Nervenarzt 2007;78:753-4, 756-63.
Perry E, Walker M, Grace J, Perry R. Acetylcholine in mind: A neurotransmitter correlate of consciousness? Trends Neurosci 1999;22:273-80.
Dean B. Evolution of the human CNS cholineric system: Has this resulted in the emergence of psychiatric disease? Aust N Z J Psychiatry 2009;43:1016-28.
Thiele A. Muscarinic signaling in the brain. Annu Rev Neurosci 2013;36:271-94.
Dean B, Crook JM, Opeskin K, Hill C, Keks N, Copolov DL, et al. The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia. Mol Psychiatry 1996;1:54-8.
Scarr E, Sundram S, Keriakous D, Dean B. Altered hippocampal muscarinic M4, but not M1, receptor expression from subjects with schizophrenia. Biol Psychiatry 2007;61:1161-70.
Mancama D, Arranz MJ, Landau S, Kerwin R. Reduced expression of the muscarinic 1 receptor cortical subtype in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2003;119B:2-6.
Beck AT, Reactor NA, Stolar N, Grant P. Biological Contribution in Schizophrenia: Cognitive Theory, Research and Therapy. New York: Guilford Press; 2009. p. 30-61.
Schwartz JH, Javitch JA. Neurotransmitter: Principles of Neural Science. 5th ed. New York: McGraw Hill; 2013. p. 28-305.
Izawa J, Asai T, Imamizu H. Computational motor control as a window to schizophrenia. Neurosci Res 2016;104:44-51.
Woodcock EA, Wadehra S, Diwadkar VA. Network profiles of the dorsal anterior cingulate and dorsal prefrontal cortex in schizophrenia during hippocampal-based associative memory. Front Syst Neurosci 2016;10:32.
Witt ST, Laird AR, Meyerand ME. Functional neuroimaging correlates of finger-tapping task variations: An ALE meta-analysis. Neuroimage 2008;42:343-56.
Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: A review and reconceptualization. Am J Psychiatry 1991;148:1474-86.
Bogerts B. Recent advances in the neuropathology of schizophrenia. Schizophr Bull 1993;19:431-45.
Shenton ME, Kikinis R, Jolesz FA, Pollak SD, LeMay M, Wible CG, et al. Abnormalities of the left temporal lobe and thought disorder in schizophrenia. A quantitative magnetic resonance imaging study. N Engl J Med 1992;327:604-12.
Vita A, Bressi S, Perani D, Invernizzi G, Giobbio GM, Dieci M, et al. High-resolution SPECT study of regional cerebral blood flow in drug-free and drug-naive schizophrenic patients. Am J Psychiatry 1995;152:876-82.
Zaidel DW, Esiri MM, Harrison PJ. The hippocampus in schizophrenia: Lateralized increase in neuronal denstiy and altered cytoarchitectural asymmetry. Psychol Med 1997;27:703-13.
Middleton FA, Strick PL. Basal gangilia and cerebellar loops: Motor and cognitive circuits. Brain Res Brain Res Rev 2000;31:236-50.
Bombin I, Arango C, Buchanan RW. Significance and meaning of neurological signs in schizophrenia: Two decades later. Schizophr Bull 2005;31:962-77.
Yang H, He H, Zhong J, Multimodal MR. Characterisation of schizophrenia: 851 A discriminative analysis. Lancet 2016;388:S36.
Friston K, Brown HR, Siemerkus J, Stephan KE. The dysconnection hypothesis 595 (2016). Schizophr Res 2016;176:83-94.
Patel N, Jankovic J, Hallett M. Sensory aspects of movement disorders. Lancet Neurol 2014;13:100-12.
Picazio S, Koch G. Is motor inhibition mediated by cerebello-cortical interactions? Cerebellum 2015;14:47-9.
Salman MS, Tsai P. The role of the pediatric cerebellum in motor functions, cognition, and behavior: A Clinical perspective. Neuroimaging Clin N Am 2016;26:317-29.
Ivry RB, Spencer RM. The neural representation of time. Curr Opin Neurobiol 2004;14:225-32.
Graybiel AM. The basal ganglia. Trends Neurosci 1995;18:60-2.
Weinberger DR, Gallhofer B. Cognitive function in schizophrenia. Int Clin Psychopharmacol 1997;12 Suppl 4:S29-36.
Heckers S. Neuroimaging studies of the hippocampus in schizophrenia.Hippocampus 2001;11:520-8.
Squire LR, Zola-Morgan S. The medial temporal lobe memory system. Science 1991;253:1380-6.
Nelson MD, Saykin AJ, Flashman LA, Riordan HJ. Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: A meta-analytic study. Arch Gen Psychiatry 1998;55:433-40.
Torres IJ, Flashman LA, O’Leary DS, Swayze V 2nd, Andreasen NC. Lack of an association between delayed memory and hippocampal and temporal lobe size in patients with schizophrenia and healthy controls. Biol Psychiatry 1997;42:1087-96.
Ohtani T, Bouix S, Hosokawa T, Saito Y, Eckbo R, Ballinger T, et al. Abnormalities in white matter connections between orbitofrontal cortex and anterior cingulate cortex and their associations with negative symptoms in schizophrenia: A DTI study. Schizophr Res 2014;157:190-7.
GarcÃa-Martà G, Aguilar EJ, MartÃ-Bonmatà L, Escartà MJ, Sanjuán J. Multimodal morphometry and functional magnetic resonance imaging in schizophrenia and auditory hallucinations. World J Radiol 2012;4:159-66.
Haukvik UK, Hartberg CB, Agartz I. Schizophrenia–what does structural MRI show? Tidsskr Nor Laegeforen 2013;133:850-3.
Rajarethinam R, DeQuardo JR, Miedler J, Arndt S, Kirba R, Brunberg JA, et al. Hippocampus and amygdala in schizophrenia: Assessment of the relationship of neuroanatomy to psychopathology. Psychiatry Res 2001;108:79-87.
Agarwal N, Rambaldelli G, Perlini C, Dusi N, Kitis O, Bellani M, et al. Microstructural thalamic changes in schizophrenia: A combined anatomic and diffusion weighted magnetic resonance imaging study. J Psychiatry Neurosci 2008;33:440-8.
Minzenberg MJ, Lesh TA, Niendam TA, Yoon JH, Rhoades RN, Carter CS, et al. Frontal cortex control dysfunction related to long-term suicide risk in recent-onset schizophrenia. Schizophr Res 2014;157:19-25.
Anticevic A, Hu X, Xiao Y, Hu J, Li F, Bi F, et al. Early-course unmedicated schizophrenia patients exhibit elevated prefrontal connectivity associated with longitudinal change. J Neurosci 2015;35:267-86.
Frascarelli M, Tognin S, Mirigliani A, Parente F, Buzzanca A, Torti MC, et al. Medial frontal gyrus alterations in schizophrenia: Relationship with duration of illness and executive dysfunction. Psychiatry Res 2015;231:103-10.
Pollok B, Butz M, Gross J, Südmeyer M, Timmermann L, Schnitzler A, et al. Coupling between cerebellar hemispheres: Behavioural, anatomic, and functional data. Cerebellum 2006;5:212-9.
Batson MA, Petridou N, Klomp DW, Frens MA, Neggers SF. Single session imaging of cerebellum at 7 tesla: Obtaining structure and function of multiple motor subsystems in individual subjects. PLoS One 2015;10:e0134933.
Morris LS, Kundu P, Dowell N, Mechelmans DJ, Favre P, Irvine MA, et al. Fronto-striatal organization: Defining functional and microstructural substrates of behavioural flexibility. Cortex 2016;74:118-33.
Nachev P, Kennard C, Husain M. Functional role of the supplementary and pre-supplementary motor areas. Nat Rev Neurosci 2008;9:856-69.
Dum RP, Levinthal DJ, Strick PL. Motor, cognitive, and affective areas of the cerebral cortex influence the adrenal medulla. Proc Natl Acad Sci U S A 2016;113:9922-7.
Dum RP, Strick PL. Motor areas in the frontal lobe of the primate. Physiol Behav 2002;77:677-82.
Hutchison RM, Womelsdorf T, Gati JS, Leung LS, Menon RS, Everling S, et al. Resting-state connectivity identifies distinct functional networks in macaque cingulate cortex. Cereb Cortex 2012;22:1294-308.
Published
How to Cite
Issue
Section
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.
