Cited by 229Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorReceptor Mechanisms and Signaling

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All Roads to Schizophrenia Lead to Dopamine Supersensitivity and Elevated Dopamine D2High Receptors

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Seeman, Philip·2011·CNS Neuroscience & Therapeutics

DOI 10.1111/j.1755-5949.2010.00162.xPMC PMC6493870

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Abstract

BACKGROUND: The dopamine D2 receptor is the common target for antipsychotics, and the antipsychotic clinical doses correlate with their affinities for this receptor. Antipsychotics quickly enter the brain to occupy 60-80% of brain D2 receptors in patients (the agonist aripiprazole occupies up to 90%), with most clinical improvement occurring within a few days. The D2 receptor can exist in a state of high-affinity (D2(High) ) or in a state of low-affinity for dopamine (D2Low). AIM: The present aim is to review why individuals with schizophrenia are generally supersensitive to dopamine-like drugs such as amphetamine or methyphenidate, and whether the D2(High) state is a common basis for dopamine supersensitivity in the animal models of schizophrenia. RESULTS: All animal models of schizophrenia reveal elevations in D2(High) receptors. These models include brain lesions, sensitization by drugs (amphetamine, phencyclidine, cocaine, corticosterone), birth injury, social isolation, and gene deletions in pathways for NMDA, dopamine, GABA, acetylcholine, and norepinephrine. CONCLUSIONS: These multiple abnormal pathways converge to a final common pathway of dopamine supersensitivity and elevated D2(High) receptors, presumably responsible for psychotic symptoms. Although antipsychotics alleviate psychosis and reverse the elevation of D2(High) receptors, long-term antipsychotics can further enhance dopamine supersensitivity in patients. Therefore, switching from a traditional antipsychotic to an agonist antipsychotic (aripiprazole) can result in psychotic signs and symptoms. Clozapine and quetiapine do not elicit parkinsonism or tardive dyskinesia because they are released from D2 within 12 to 24 h. Traditional antipsychotics remain attached to D2 receptors for days, preventing relapse, but allowing accumulation that can lead to tardive dyskinesia. Future goals include imaging D2(High) receptors and desensitizing them in early-stage psychosis.

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Seeman, P. M., & Guan, H. (2009) · Synapse · doi:10.1002/syn.20704 · Cited by 27
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A Rating Scale for Psychotic Symptoms (RSPS)
Chouinard, G., & Miller, R. (1999) · Schizophrenia Research · doi:10.1016/s0920-9964(99)00012-2 · Cited by 26
Dopamine D2High receptors on intact cells
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Ex vivo [11C]‐(+)‐PHNO binding is unchanged in animal models displaying increased high‐affinity states of the D2receptor in vitro
McCormick, P. N., Kapur, S., Reckless, G. E., & Wilson, A. A. (2009) · Synapse · doi:10.1002/syn.20671 · Cited by 23
Evidence of Brain Dopamine Deficiency in Schizophrenia
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Increase of dopamine D2Highreceptors in the striatum of rats sensitized to caffeine motor effects
Simola, N., Morelli, M., & Seeman, P. M. (2008) · Synapse · doi:10.1002/syn.20507 · Cited by 23
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Repeated administration of a dopamine D1 receptor agonist reverses the increased proportions of striatal dopamine D1High and D2High receptors in methamphetamine‐sensitized rats
Shuto, T., Seeman, P. M., Kuroiwa, M., & Nishi, A. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06221.x · Cited by 22
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Increased dopamine D2High receptors in knockouts of the dopamine transporter and the vesicular monoamine transporter may contribute to spontaneous hyperactivity and dopamine supersensitivity
Seeman, P. M., Hall, F. S., & Uhl, G. R. (2007) · Synapse · doi:10.1002/syn.20402 · Cited by 22
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Psychotolysis with haloperidol. Rapid control of the acutely disturbed psychotic patient.
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Alcohol‐withdrawn animals have a prolonged increase in dopamine D2Highreceptors, reversed by general anesthesia: Relation to relapse?
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S.27.02 A partial D3 receptor agonist in schizophrenia
Lecrubier, Y. (2003) · European Neuropsychopharmacology · doi:10.1016/s0924-977x(03)91703-2 · Cited by 19
Increased proportion of high-affinity dopamine D2 receptors in rats with excitotoxic damage of the entorhinal cortex, an animal model of schizophrenia
Sumiyoshi, T., Seeman, P. M., Uehara, T., Itoh, H., Tsunoda, M., & Kurachi, M. (2005) · Molecular Brain Research · doi:10.1016/j.molbrainres.2005.07.001 · Cited by 18
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Seeman, P. M. (2009) · Schizophrenia Research · doi:10.1016/j.schres.2008.12.024 · Cited by 16
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Tassin, J., Torrens, Y., Salomon, L., Lanteri, C., & Seeman, P. M. (2007) · Synapse · doi:10.1002/syn.20401 · Cited by 8
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Seeman, P. M. (2007) · Scholarpedia · doi:10.4249/scholarpedia.3634 · Cited by 5
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See all 229

Authors: Seeman, P.
Affiliations: University of Toronto (CA)
Corresponding author: Seeman, Philip
ORCID: Seeman, Philip
Venue: CNS Neuroscience & Therapeutics
Publisher: Wiley
Published: 2011-03-15
Volume: 17
Issue: 2
Pages: 118-132
ISSN: 1755-5930 (ISSN-L)
DOI: 10.1111/j.1755-5949.2010.00162.x
PMC: PMC6493870
OpenAlex: W2113742168
Cited by: 228
References: 104
Citations by year: 2026: 11 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 16 · 2021: 12 · 2020: 17 · 2019: 9 · 2018: 9 · 2017: 18 · 2016: 23 · 2015: 22 · 2014: 16 · 2013: 23 · 2012: 21
FWCI: 13.34
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 1631 d)
Locations: CNS Neuroscience & Therapeutics (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: schizophrenia, dopamine D2 receptor, dopamine supersensitivity, animal models of schizophrenia, antipsychotic drugs, aripiprazole, tardive dyskinesia, parkinsonism, amphetamine sensitivity, phencyclidine, birth trauma, social isolation, gene deletion, NMDA receptor, GABA, acetylcholine, norepinephrine, receptor desensitization, psychosis
MeSH terms: Animals, Brain, Disease Models, Animal, Dopamine, Gene Expression Regulation, Humans, Schizophrenia, Antipsychotic Agents, Receptors, Dopamine D2

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All Roads to Schizophrenia Lead to Dopamine Supersensitivity and Elevated Dopamine D2High Receptors

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