Localization of dopamine D4 receptors in GABAergic neurons of the primate brain
Abstract
Dopamine receptors are the principal targets of drugs used in the treatment of schizophrenia. Among the five mammalian dopamine-receptor subtypes, the D4 subtype is of particular interest because of its high affinity for the atypical neuroleptic clozapine. Interest in clozapine stems from its effectiveness in reducing positive and negative symptoms in acutely psychotic and treatment-resistant schizophrenic patients without eliciting extrapyramidal side effects. We have produced a subtype-specific antibody against the D4 receptor and localized it within specific cellular elements and synaptic circuits of the central nervous system. The D4-receptor antibody labelled GABAergic neurons in the cerebral cortex, hippocampus, thalamic reticular nucleus, globus pallidus and the substantia nigra (pars reticulata). Labelling was also observed in a subset of cortical pyramidal cells. Our findings suggest that clozapine's beneficial effects in schizophrenia may be achieved, in part, through D4-mediated GABA modulation, possibly implicating disinhibition of excitatory transmission in intrinsic cortical, thalamocortical and extrapyramidal pathways.
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Dopamine acts at D4-receptors in the PFC, where it inhibits interneurons.
“DA also acts at D4-receptors in the PFC, where it inhibits interneurons (Mrzljak et al., 1996; Wang et al., 2002).”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Mrzljak et al., 1996
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- Authors
- Mrzljak, L., Bergson, C., Pappy, M., Huff, R., Levenson, R., & Goldman-Rakic, P. S.
- Affiliations
- Yale University (US)
- Pennsylvania State University (US)
- Pfizer (United States) (US)
- Venue
- Nature
- Published
- 1996-05
- Volume
- 381
- Issue
- 6579
- Pages
- 245-248
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1979179687
- Cited by
- 494
- References
- 0
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 9 · 2022: 9 · 2021: 9 · 2020: 7 · 2019: 6 · 2018: 5 · 2017: 8 · 2016: 16 · 2015: 18 · 2014: 17 · 2013: 14 · 2012: 12
- FWCI
- 11.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- dopamine D4 receptor, GABAergic neurons, schizophrenia, clozapine, atypical antipsychotics, receptor localization, GABA modulation, thalamic reticular nucleus, globus pallidus, substantia nigra, cerebral cortex, hippocampus, cortical pyramidal neurons, synaptic circuits
- MeSH terms
- Animals, Antibody Specificity, Basal Ganglia, Base Sequence, Brain Chemistry, Cell Line, Escherichia coli, gamma-Aminobutyric Acid, Humans, Immunologic Techniques, Interneurons, Macaca mulatta, Molecular Sequence Data, Neurons, Recombinant Proteins, Thalamus, Receptors, Dopamine D2, DNA Primers, Receptors, Dopamine D4
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