Antipsychotic Drugs: Direct Correlation Between Clinical Potency and Presynaptic Action on Dopamine Neurons
Abstract
Neuroleptic (antipsychotic) drugs inhibited the electrically stimulated release of [3 H]dopamine from rat striatal slices. The concentrations for 50 percent inhibition (ranging from 11.5 nanomolar for spiroperidol to 800 nanomolar for thioridazine) correlated closely with the average daily dosages of 25 neuroleptic drugs used clinically for schizophrenia. The correlation includes butyrophenones, phenothiazines, reserpine, pimozide, clozapine, and (+)-butaclamol. Clinically inactive isomers [trans-thiothixene,trans-flupenthixol, and (-)-butaclamol] required 20 to 1000 times higher concentrations than the active isomers to inhibit release. Compared to the inhibition of [3 H]dopamine release, much higher neuroleptic concentrations were needed to inhibit the electrically stimulated release of other neurotransmitters—[3 H]acetylcholine, [3 H]GABA (γ-aminobutyric acid). The neuroleptic drugs may block the presynaptic coupling between impulse and neurosecretion.
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The DA hypothesis of schizophrenia suggests that excess DA transmission may be pro-psychotic, and originally gained support from pharmacological evidence that drugs decreasing DA activity are antipsychotic whereas drugs promoting DA activity are psychotomimetic.
“The DA hypothesis of schizophrenia suggests that excess DA transmission may be pro-psychotic, and originally gained support from pharmacological evidence that drugs that decrease DA activity (for example,, the phenothiazine neuroleptics) are antipsychotic, whereas drugs that promote DA activity (for example,, amphetamines) are psychotomimetic [76,357].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [76]
Medications that have proven successful for treating schizophrenia/psychosis are drugs that primarily antagonize D2 receptors.
“the medications that have proven successful for treating schizophrenia/psychosis are drugs that primarily antagonize D2 receptors [76,358]”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [76]
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- Authors
- Seeman, P., & Lee, T.
- Affiliations
- University of Toronto (CA)
- ORCID
- Venue
- Science
- Published
- 1975-06-20
- Volume
- 188
- Issue
- 4194
- Pages
- 1217-1219
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2006122360
- Cited by
- 869
- References
- 35
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 13 · 2023: 16 · 2022: 22 · 2021: 13 · 2020: 18 · 2019: 36 · 2018: 21 · 2017: 30 · 2016: 26 · 2015: 28 · 2014: 37 · 2013: 23 · 2012: 32
- FWCI
- 62.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (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
- antipsychotic drugs, presynaptic dopamine release, striatum, spiperone, thioridazine, butyrophenones, phenothiazines, reserpine, pimozide, clozapine, butaclamol, stereoisomers, acetylcholine release, GABA release, schizophrenia
- MeSH terms
- Acetylcholine, Animals, Corpus Striatum, Dopamine, Dose-Response Relationship, Drug, Electric Stimulation, gamma-Aminobutyric Acid, Haloperidol, Humans, Male, Neurons, Neurosecretion, Schizophrenia, Tranquilizing Agents, Tritium, Rats
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