Cited by 878Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

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Antipsychotic Drugs: Direct Correlation Between Clinical Potency and Presynaptic Action on Dopamine Neurons

Seeman, P., Lee, T.·1975·Science

DOI 10.1126/science.1145194

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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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Powell, S. B., Zhou, X., & Geyer, M. A. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.04.021 · Cited by 218
Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine
Ben-Shachar, D. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01263.x · Cited by 232
The effects of vitamin D on brain development and adult brain function
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“Although haloperidol is not highly specific, antipsychotic drug efficacy is believed to be via the blockade of dopamine 2 receptors (Creese et al., 1976; Seeman and Lee, 1975).”
Background
Dopamine receptor binding in the corpus striatum of mammalian brain.
Burt, D. R., Enna, S. J., Creese, I., & Snyder, S. H. (1975) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.72.11.4655 · Cited by 220
Anti-schizophrenic drugs—Membrane receptor sites of action
Seeman, P. M. (1977) · Biochemical Pharmacology · doi:10.1016/0006-2952(77)90340-9 · Cited by 218
Self-citation
Catatonic Reactions to High-Potency Neuroleptic Drugs
Gelenberg, A. J. (1977) · Archives of General Psychiatry · doi:10.1001/archpsyc.1977.01770200085010 · Cited by 216
Brain NMDA Receptors in Schizophrenia and Depression
Adell, A. (2020) · Biomolecules · doi:10.3390/biom10060947 · Cited by 225
“Since the finding that the therapeutic efficacy of antipsychotic drugs was directly correlated to their affinity for dopamine D2 receptors [80,81], it was first postulated that altered dopamine D2-like receptors was responsible for schizophrenia symptoms.”
Background
The role of serotonin in the pathophysiology and treatment of schizophrenia
Abi‐Dargham, A., Laruelle, M. A., Aghajanian, G. K., Charney, D. S., & Krystal, J. H. (1997) · Journal of Neuropsychiatry · doi:10.1176/jnp.9.1.1 · Cited by 210
Haloperidol versus chlorpromazine for schizophrenia
Leucht, C., Kitzmantel, M., Kane, J. M., Leucht, S., & Chua, W. L. L. (2008) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd004278.pub2 · Cited by 206
Presynaptic regulation of dopaminergic neurotransmission
Schmitz, Y., Benoit‐Marand, M., Gonon, F., & Sulzer, D. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02050.x · Cited by 202
Antipsychotic drugs and neuroplasticity: insights into the treatment and neurobiology of schizophrenia
Konradi, C. L., & Heckers, S. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(01)01267-7 · Cited by 201
“Conventional antipsychotic drugs influence protein phosphorylation via their ability to inhibit dopamine D2 receptors (Seeman and Lee 1975).”
Background
Morphine and β-endorphin inhibit release of noradrenaline from cerebral cortex but not of dopamine from rat striatum
Arbilla, S., & Langer, S. Z. (1978) · Nature · doi:10.1038/271559a0 · Cited by 200
Marked disparity between age‐related changes in dopamine and other presynaptic dopaminergic markers in human striatum
Haycock, J. W., Becker, L. E., Ang, L. C., Furukawa, Y., Hornykiewicz, O., & Kish, S. J. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02017.x · Cited by 195
“A hypothetical role for brain DA has also been suggested in other conditions such as schizophrenia (Seeman and Lee 1975), drug abuse (DiChiara 1995), and the mild motor impairment which accompanies normal senescence (cf. Kish et al. 1992).”
Background
Controlled Study of Pimozide vs. Placebo in Tourette's Syndrome
Shapiro, A. K., & Shapiro, E. (1984) · Journal of the American Academy of Child Psychiatry · doi:10.1097/00004583-198403000-00007 · Cited by 194
Prevalence and clinical correlates of extrapyramidal signs and spontaneous dyskinesia in never-medicated schizophrenic patients
Chatterjee, A., Chakos, M., Koreen, A., Geisler, S., Sheitman, B., Woerner, M. G., Kane, J. M., Alvir, J. M., & Lieberman, J. A. (1995) · American Journal of Psychiatry · doi:10.1176/ajp.152.12.1724 · Cited by 198
Prolactin Responses to Neuroleptics in Normal and Schizophrenic Subjects
GRUEN, P. H. (1978) · Archives of General Psychiatry · doi:10.1001/archpsyc.1978.01770250110011 · Cited by 193
Pimozide
Pinder, R. M., Brogden, R. N., Sawyer, P. R., Speight, T. M., Spencer, R., & Avery, G. S. (1976) · Drugs · doi:10.2165/00003495-197612010-00001 · Cited by 189
Antipsychotic-Induced Weight Gain and Therapeutic Response: A Differential Association
Czobor, P., Volavka, J., Sheitman, B., Lindenmayer, J., Citrome, L., McEvoy, J. P., Cooper, T. B., Chakos, M., & Lieberman, J. A. (2002) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-200206000-00003 · Cited by 185
Mechanisms of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies
Abi-Dargham, A., & Laruelle, M. (2005) · European Psychiatry · doi:10.1016/j.eurpsy.2004.11.003 · Cited by 179
“This hypothesis was based on the correlation between clinical doses of antipsychotic drugs and their potency to block DA D2 receptors [23,140] and on the psychotogenic effects of DA enhancing drugs (for reviews see [8,98]).”
Method
Major attenuation of food reward with performance-sparing doses of pimozide in the rat.
Wise, R. A., Spindler, J., & Legault, L. (1978) · Canadian Journal of Psychology/Revue Canadienne de Psychologie · doi:10.1037/h0081678 · Cited by 175
Detection and characterization of additional DNA polymorphisms in the dopamine D2 receptor gene
Hauge, X. Y., Grandy, D. K., Eubanks, J. H., Evans, G. A., Civelli, O., & Litt, M. J. (1991) · Genomics · doi:10.1016/0888-7543(91)90431-d · Cited by 173
Schizophrenia: from dopaminergic to glutamatergic interventions
Laruelle, M. A. (2014) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2014.01.001 · Cited by 181
The role of microRNAs in the regulation of cancer stem cells
Takahashi, R.-U., Miyazaki, H., & Ochiya, T. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2013.00295 · Cited by 118
“A CD44+/CD24−/low cell population purified from cancer tissues shows the features of an EMT phenotype, and human cancer cells induced to undergo EMT exhibit a CD44+/CD24−/low antigen phenotype and high tumorigenicity.”
Background
Does dopamine play a role in schizophrenia?
Carlsson, A. (1977) · Psychological Medicine · doi:10.1017/s003329170000622x · Cited by 163
Biochemical evidence for the presence of presynaptic receptors on dopaminergic nerve terminals
de Belleroche, J., & Bradford, H. F. (1978) · Brain Research · doi:10.1016/0006-8993(78)90176-2 · Cited by 163
Early Detection and Preventive Intervention in Schizophrenia: From Fantasy to Reality
Lieberman, J. A., Small, S. A., & Girgis, R. R. (2019) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.19080865 · Cited by 165
Feedback loop or output pathway in striato-nigral fibres?
Garcia-Munoz, M., Nicolaou, N., Tulloch, I. F., WRIGHT, A. K., & Arbuthnott, G. W. (1977) · Nature · doi:10.1038/265363a0 · Cited by 160
The effect of treatment with antipsychotic drugs on brain N-acetylaspartate measures in patients with schizophrenia
Bertolino, A., Callicott, J. H., Mattay, V. S., Weidenhammer, K. M., Rakow‐Penner, R., Egan, M. F., & Weinberger, D. R. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(00)00997-5 · Cited by 156
“Considerable evidence has accumulated over several decades that the efficacy of antipsychotic drugs in patients with schizophrenia involves antagonistic effects at dopamine D2 receptors (Seeman and Lee 1975).”
Background
Ritanserin, a Selective 5-HT2/1CAntagonist, and Negative Symptoms in Schizophrenia
Duinkerke, S. J., Botter, P. A., Jansen, A. A. I., van Dongen, P. A. M., Haaften, A. J. V., Boom, A. J., Laarhoven, J. H. M. V., & Busard, H. L. S. M. (1993) · The British Journal of Psychiatry · doi:10.1192/bjp.163.4.451 · Cited by 154
Role of cannabis and endocannabinoids in the genesis of schizophrenia
Fernández‐Espejo, E., Viveros, M., Núñez, L., Ellenbroek, B. A., & de Fonseca, F. R. (2009) · Psychopharmacology · doi:10.1007/s00213-009-1612-6 · Cited by 155
“Schizophrenia has consistently been related to increased dopamine function in the striatum (Seeman and Lee 1975; Angrist and Van Kammen 1984), possibly caused by a disinhibition of striatal dopamine transmission (Laruelle et al. 1996).”
Background
A comparison of pimozide and haloperidol in the treatment of Gilles de la Tourette's syndrome
Ross, M. S., & Moldofsky, H. (1978) · American Journal of Psychiatry · doi:10.1176/ajp.135.5.585 · Cited by 152
Mechanism of action of antipsychotic drugs: From dopamine D2 receptor antagonism to glutamate NMDA facilitation
Laruelle, M. A., Frankle, W. G., Narendran, R., Kegeles, L. S., & Abi‐Dargham, A. (2005) · Clinical Therapeutics · doi:10.1016/j.clinthera.2005.07.017 · Cited by 150

Authors: Seeman, P., & Lee, T.
Affiliations: University of Toronto (CA)
ORCID: Seeman, P.
Lee, T.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 1975-06-20
Volume: 188
Issue: 4194
Pages: 1217-1219
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1145194
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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Antipsychotic Drugs: Direct Correlation Between Clinical Potency and Presynaptic Action on Dopamine Neurons

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