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Cited by 279Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

Schizophrenia: More dopamine, more D 2 receptors

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Seeman, Philip, Kapur, Shitij·2000·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.97.14.7673PMC PMC33999
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Abstract

Schizophrenia is a major therapeutic challenge of modern medicine, and one of the last frontiers of brain research. The illness is defined by delusions, hallucinations, disorganized behavior, and cognitive difficulties such as memory loss. It occurs in ≈1% of the world population and usually first appears in early adulthood. Although antipsychotic medications have dramatically improved the lives of patients with schizophrenia, the causes of the illness remain unknown. Of the many contemporary theories of schizophrenia, the most enduring has been the dopamine hypothesis. As originally put by Van Rossum in 1967 (ref. 1, p. 321), “When the hypothesis of dopamine blockade by neuroleptic agents can be further substantiated, it may have fargoing consequences for the pathophysiology of schizophrenia. Overstimulation of dopamine receptors could be part of the aetiology … [emphasis added].” Indeed, this speculative sentence by Van Rossum foreshadows the title of the important work by Abi-Dargham et al . (2) in this issue of PNAS: “Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.” The discovery of the antipsychotic/dopamine receptor (3, 4), now commonly known as the dopamine D2 receptor, led to repeated confirmation that it is the primary site of action for all antipsychotics (3–5), including clozapine and quetiapine (6). All these drugs have different potencies at the receptor. The potency depends on the drug's dissociation constant at D2, which, in turn, relates to the rate of release of the drug from the D2 receptor. For example, the dopamine D2 receptor releases clozapine and quetiapine more rapidly than it does any of the other antipsychotic drugs (7, 8). Given the tight correlation between the clinical potency and the D2-blocking action of the antipsychotic medications, dopamine overactivity could be the common denominator in the …

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  • On a neurophysiological level, a prediction error of this nature could cause an increase in phasic activity of midbrain dopaminergic neurons, given their role in signaling salience and prediction errors.

    “However, on a neurophysiological level, a prediction error of this nature could cause an increase in the phasic activity of midbrain dopaminergic neurons, given the role that these particular neurons are believed to play in signaling salience in general and prediction errors in particular.[62][63][64][65]”

    From Schizophrenia, myelination, and delayed corollary discharges: a hypothesis (2012) · cites this paper as [64]

  • The prediction errors hypothesized in schizophrenia may be more relevant to non-reward salient stimuli than to reward-conditioned prediction errors.

    “This scenario may be more relevant to the prediction errors we hypothesize to occur in schizophrenia patients, given that it is not clear that these particular predictions (eg, regarding the sensory consequences of self-generated actions) necessarily relate to reward conditioning.”

    From Schizophrenia, myelination, and delayed corollary discharges: a hypothesis (2012) · cites this paper as [64]

  • Dopaminergic neurons increase firing rates in response to unpredictable and salient stimuli that are not conditioned to reward.

    “dopaminergic neurons have also been found to ''increase'' their firing rates in response to unpredictable and salient stimuli that are not conditioned to reward.63,64”

    From Schizophrenia, myelination, and delayed corollary discharges: a hypothesis (2012) · cites this paper as [64]

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Research works printed but not linked: 2

  1. [13]Laruelle, M., Abi-Dargham, A., van Dyck, C. H., Gil, R., De Souza, C. D., Erdos, J., McCance, E., Rosenblatt, W., Fingado, C., Zoghbi, S. S., et al . (1996) Proc. Natl. Acad. Sci. USA 93, 92359240.
  2. [14]Breier, A., Su, T. P., Saunders, R., Carson, R. E., Kolachana, B. S., de Bartolomeis, A., Weinberger, D. R., Weisenfeld, N., Malhotra, A. K., Eckelman, W. C., et al . (1997) Proc. Natl. Acad. Sci. USA 94, 2569-2574.

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Authors
Seeman, P., & Kapur, S.
Affiliations
University of Toronto (CA)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2000-07-05
Volume
97
Issue
14
Pages
7673-7675
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.97.14.7673
PMC
PMC33999
OpenAlex
W2022725791
Cited by
279
References
22
Citations by year
2026: 1 · 2025: 14 · 2024: 8 · 2023: 9 · 2022: 10 · 2021: 15 · 2020: 5 · 2019: 12 · 2018: 9 · 2017: 4 · 2016: 11 · 2015: 15 · 2014: 19 · 2013: 14 · 2012: 13
FWCI
6.28
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (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 › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
schizophrenia, dopamine hypothesis, dopamine D2 receptor, receptor occupancy, antipsychotic drugs, clozapine, quetiapine, receptor dissociation constant, schizophrenia pathophysiology
MeSH terms
Benzamides, Dopamine, Models, Biological, Psychotic Disorders, Pyrrolidines, Schizophrenia, Receptors, Dopamine D2, Dopamine Antagonists

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