Dopamine hypothesis of schizophrenia: Making sense of it all

The dopamine (DA) hypothesis of schizophrenia has evolved over the last decade from the stage of circumstantial evidence related to clinical observations and empirical validation from antipsychotic treatment to finally reach more direct testing and validation from imaging studies. These have provided much information that allows us at this point to assemble all the pieces and attempt to synthesize them and integrate them with the other neurotransmitter alterations observed in this illness. Although clearly not sufficient to explain the complexity of this disorder, the DA dysregulation offers a direct relationship to symptoms and to their treatment. We will review here its history, validation, and implications for treatment.

[1]  H. Crew RECENT ADVANCES IN THE TEACHING OF PHYSICS. , 1904, Science.

[2]  W. Scoville,et al.  Paranoid Psychosis in Narcolepsy and the Possible Danger of Benzedrine Treatment , 1938 .

[3]  J. Delay,et al.  [Therapeutic use in psychiatry of phenothiazine of central elective action (4560 RP)]. , 1952, Annales medico-psychologiques.

[4]  A. Carlsson,et al.  EFFECT OF CHLORPROMAZINE OR HALOPERIDOL ON FORMATION OF 3METHOXYTYRAMINE AND NORMETANEPHRINE IN MOUSE BRAIN. , 2009, Acta pharmacologica et toxicologica.

[5]  Van Rossum Jm The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. , 1966 .

[6]  E. Ellinwood Amphetamine psychosis : description of the individuals and processes , 1967 .

[7]  B. Angrist,et al.  The phenomenology of experimentally induced amphetamine psychosis--preliminary observations. , 1970, Biological psychiatry.

[8]  D. Bell The experimental reproduction of amphetamine psychosis. , 1973, Archives of general psychiatry.

[9]  E. Ellinwood,et al.  Evolving behavior in the clinical and experimental amphetamine (model) psychosis. , 1973, The American journal of psychiatry.

[10]  P. Seeman,et al.  Brain receptors for antipsychotic drugs and dopamine: direct binding assays. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[11]  S H Snyder,et al.  Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs , 1976, Science.

[12]  C. Carter,et al.  Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats , 1980, Nature.

[13]  B. Angrist,et al.  CNS stimulants as tools in the study of schizophrenia , 1984, Trends in Neurosciences.

[14]  G. E. Alexander,et al.  Parallel organization of functionally segregated circuits linking basal ganglia and cortex. , 1986, Annual review of neuroscience.

[15]  J. Lieberman,et al.  Prediction of relapse in schizophrenia. , 1987, Archives of general psychiatry.

[16]  D. Weinberger Implications of normal brain development for the pathogenesis of schizophrenia. , 1987, Archives of general psychiatry.

[17]  P. Seeman Brain dopamine receptors in schizophrenia: PET problems. , 1988, Archives of general psychiatry.

[18]  D. Weinberger,et al.  Mesocortical Dopaminergic Function and Human Cognition , 1988, Annals of the New York Academy of Sciences.

[19]  P. Seeman,et al.  Endogenous dopamine lowers the dopamine D2 receptor density as measured by [3H]raclopride: Implications for positron emission tomography of the human brain , 1989, Synapse.

[20]  A. Grace Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: A hypothesis for the etiology of schizophrenia , 1991, Neuroscience.

[21]  K. Davis,et al.  Dopamine in schizophrenia: a review and reconceptualization. , 1991, The American journal of psychiatry.

[22]  Douglas W. Jones,et al.  The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[23]  G. Sedvall,et al.  Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. , 1992, Archives of general psychiatry.

[24]  P. Strick,et al.  Multiple output channels in the basal ganglia. , 1993, Science.

[25]  A. Boulton,et al.  Regulation of striatal aromatic L-amino acid decarboxylase: effects of blockade or activation of dopamine receptors. , 1993, European journal of pharmacology.

[26]  Christer Halldin,et al.  Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: A double-blind PET study of schizophrenic patients , 1993, Biological Psychiatry.

[27]  Philip D. Harvey,et al.  Neuropsychological correlates of central monoamine function in chronic schizophrenia: relationship between CSF metabolites and cognitive function , 1994, Schizophrenia Research.

[28]  G. Reynolds,et al.  Are Striatal Dopamine D4 Receptors Increased in Schizophrenia? , 1994, Journal of neurochemistry.

[29]  Alan C. Evans,et al.  Elevated dopa decarboxylase activity in living brain of patients with psychosis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[30]  P. Goldman-Rakic Working memory dysfunction in schizophrenia. , 1994, The Journal of neuropsychiatry and clinical neurosciences.

[31]  J. Hietala,et al.  Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients , 1995, The Lancet.

[32]  A. Parent,et al.  Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop , 1995, Brain Research Reviews.

[33]  Karl J. Friston,et al.  Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia , 1995, Nature.

[34]  T. Hyde,et al.  Distribution of putative D4 dopamine receptors in postmortem striatum from patients with schizophrenia , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[35]  Tomiki Sumiyoshi,et al.  Dopamine D4 receptors and effects of guanine nucleotides on [3H]raclopride binding in postmortem caudate nucleus of subjects with schizophrenia or major depression , 1995, Brain Research.

[36]  R. Conley,et al.  Dopamine D2, D3, D4 receptors in human postmortem brain sections: Comparison between normals and schizophrenics , 1996, Schizophrenia Research.

[37]  J. Krystal,et al.  Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[38]  N H Neff,et al.  Regulation of tyrosine hydroxylase and aromatic L-amino acid decarboxylase by dopaminergic drugs. , 1997, European journal of pharmacology.

[39]  D. Copolov,et al.  [3H]Nemonapride Binding in Human Caudate and Putamen , 1997, Brain Research Bulletin.

[40]  M. Iyo,et al.  Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET , 1997, Nature.

[41]  A. Getson,et al.  The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group. , 1997, Archives of general psychiatry.

[42]  Marc Laruelle,et al.  Imaging D2 Receptor Occupancy by Endogenous Dopamine in Humans , 1997, Neuropsychopharmacology.

[43]  P. Goldman-Rakic,et al.  Down-regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs. , 1997, The Journal of pharmacology and experimental therapeutics.

[44]  R. Gur,et al.  Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study. , 1997, Archives of general psychiatry.

[45]  C. Crouzel,et al.  Presynaptic dopaminergic function in the striatum of schizophrenic patients , 1997, Schizophrenia Research.

[46]  A. Malhotra,et al.  Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[47]  P B Hoffer,et al.  Microdialysis and SPECT measurements of amphetamine‐induced dopamine release in nonhuman primates , 1997, Synapse.

[48]  D. Weinberger,et al.  Dopamine, the prefrontal cortex and schizophrenia , 1997, Journal of psychopharmacology.

[49]  J. M. Ollinger,et al.  Positron Emission Tomography , 2018, Handbook of Small Animal Imaging.

[50]  G. Antoni,et al.  Effect of apomorphine infusion on dopamine synthesis rate relates to dopaminergic tone , 1998, Neuropharmacology.

[51]  J. Krystal,et al.  Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. , 1998, The American journal of psychiatry.

[52]  M Laruelle,et al.  Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil. , 1998, The American journal of psychiatry.

[53]  R. Conley,et al.  Direct determination of dopamine D4 receptors in normal and schizophrenic postmortem brain tissue: a [3H]NGD-94-1 study , 1998, Molecular Psychiatry.

[54]  D. Wong,et al.  GBR12909 attenuates amphetamine‐induced striatal dopamine release as measured by [11C]raclopride continuous infusion PET scans , 1999, Synapse.

[55]  J. Hietala,et al.  Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia , 1999, Schizophrenia Research.

[56]  M. Bergström,et al.  Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(β-11C) DOPA and PET , 1999, Biological Psychiatry.

[57]  M. Laruelle,et al.  Increased dopamine transmission in schizophrenia: relationship to illness phases , 1999, Biological Psychiatry.

[58]  S. Kapur,et al.  Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. , 2000, The American journal of psychiatry.

[59]  R. V. Van Heertum,et al.  Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[60]  J. Krystal,et al.  Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [123I]β-CIT , 2000, Biological Psychiatry.

[61]  M. Laruelle,et al.  Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia , 2000, Biological Psychiatry.

[62]  F. Gonon,et al.  Dopamine tone regulates D1 receptor trafficking and delivery in striatal neurons in dopamine transporter-deficient mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[63]  P. Goldman-Rakic,et al.  D1 receptors in prefrontal cells and circuits , 2000, Brain Research Reviews.

[64]  D. Doudet,et al.  6-18F-DOPA PET study in patients with schizophrenia , 2000, Psychiatry Research: Neuroimaging.

[65]  J. Hietala,et al.  Striatal dopamine transporter binding in neuroleptic-naive patients with schizophrenia studied with positron emission tomography. , 2000, The American journal of psychiatry.

[66]  M. Laruelle Imaging Synaptic Neurotransmission with in Vivo Binding Competition Techniques: A Critical Review , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[67]  J. Price,et al.  Prefrontal cortical projections to the striatum in macaque monkeys: Evidence for an organization related to prefrontal networks , 2000, The Journal of comparative neurology.

[68]  D. Joel,et al.  The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum , 2000, Neuroscience.

[69]  R. Koeppe,et al.  In Vivo Measurement of the Vesicular Monoamine Transporter in Schizophrenia , 2000, Neuropsychopharmacology.

[70]  R. Parsey,et al.  Dopamine D2 receptor availability and amphetamine-induced dopamine release in unipolar depression , 2001, Biological Psychiatry.

[71]  A. Gjedde,et al.  Acute neuroleptic stimulates DOPA decarboxylase in porcine brain in vivo , 2001, Synapse.

[72]  J. Yelnik Functional anatomy of the basal ganglia , 2002, Movement disorders : official journal of the Movement Disorder Society.

[73]  Marc Laruelle,et al.  The role of in vivo molecular imaging with PET and SPECT in the elucidation of psychiatric drug action and new drug development , 2002, European Neuropsychopharmacology.

[74]  Dennis S. Charney,et al.  Neuropsychopharmacology : The Fifth Generation of Progress , 2002 .

[75]  S. Tanada,et al.  Decreased dopamine D2 receptor binding in the anterior cingulate cortex in schizophrenia. , 2002, Archives of general psychiatry.

[76]  Hans Forssberg,et al.  Selective up-regulation of dopamine D1 receptors in dendritic spines by NMDA receptor activation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[77]  R. V. Van Heertum,et al.  Prefrontal Dopamine D1 Receptors and Working Memory in Schizophrenia , 2002, The Journal of Neuroscience.

[78]  G. Sedvall,et al.  PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia. , 2002, The American journal of psychiatry.

[79]  A. Meyer-Lindenberg,et al.  Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia , 2002, Nature Neuroscience.

[80]  Albert Gjedde,et al.  Subchronic Haloperidol Downregulates Dopamine Synthesis Capacity in the Brain of Schizophrenic Patients In Vivo , 2003, Neuropsychopharmacology.

[81]  Kun-Ju Lin,et al.  Dopamine transporter change in drug-naı̈ve schizophrenia: an imaging study with 99mTc-TRODAT-1 , 2003, Schizophrenia Research.

[82]  M. Laruelle,et al.  Glutamate, Dopamine, and Schizophrenia , 2003 .

[83]  C. Halldin,et al.  Decreased thalamic D2/D3 receptor binding in drug-naive patients with schizophrenia: a PET study with [11C]FLB 457. , 2003, The international journal of neuropsychopharmacology.

[84]  J. Tiihonen,et al.  Extrastriatal dopamine D2/3 receptor density and distribution in drug-naive schizophrenic patients , 2003, Molecular Psychiatry.

[85]  H. Moore,et al.  Prefrontal DA Transmission at D1 Receptors and the Pathology of Schizophrenia , 2003, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[86]  A. Lawrence,et al.  Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study. , 2004, Archives of general psychiatry.

[87]  J. Lieberman,et al.  Provocative tests with psychostimulant drugs in schizophrenia , 2004, Psychopharmacology.

[88]  T. Goldberg,et al.  Genes and the parsing of cognitive processes , 2004, Trends in Cognitive Sciences.

[89]  Mark Slifstein,et al.  Altered prefrontal dopaminergic function in chronic recreational ketamine users. , 2005, The American journal of psychiatry.

[90]  Tyrone D. Cannon,et al.  Increased caudate dopamine D2 receptor availability as a genetic marker for schizophrenia. , 2005, Archives of general psychiatry.

[91]  Tyrone D. Cannon,et al.  Brain dopamine d1 receptors in twins discordant for schizophrenia. , 2006, The American journal of psychiatry.

[92]  G. González-Burgos,et al.  Pathophysiologically based treatment interventions in schizophrenia , 2006, Nature Medicine.

[93]  Mark Slifstein,et al.  Schizophrenia is associated with increased synaptic dopamine in associative rather than limbic regions of the striatum: Implications for mechanisms of action of antipsychotic drugs , 2006 .

[94]  C. Svarer,et al.  Frontal Dopamine D2/3 Receptor Binding in Drug-Naive First-Episode Schizophrenic Patients Correlates with Positive Psychotic Symptoms and Gender , 2006, Biological Psychiatry.

[95]  Christer Halldin,et al.  Dopamine D2 receptor binding in drug-naïve patients with schizophrenia examined with raclopride-C11 and positron emission tomography , 2006, Psychiatry Research: Neuroimaging.

[96]  Alan A. Wilson,et al.  Striatal Vs Extrastriatal Dopamine D2 Receptors in Antipsychotic Response—A Double-Blind PET Study in Schizophrenia , 2007, Neuropsychopharmacology.

[97]  Mark Slifstein,et al.  In Vivo DA D1 Receptor Selectivity of NNC 112 and SCH 23390 , 2007, Molecular Imaging and Biology.