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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Background
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Background
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Background
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Method
INHIBITION BY APOMORPHINE OF THE POTASSIUM‐EVOKED RELEASE OF [3H]‐γ‐AMINOBUTYRIC ACID FROM THE RAT SUBSTANTIA NIGRA in vitro
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“…had its incipience in the clinical observation in the 1970s that available neuroleptic medications targeted dopamine release, its receptors and downstream actions (Seeman and Lee, 1975; Carlsson, 1977), and the discovery of the dopaminergic innervation of rat medial PFC (Thierry et al., 1973).”
Background
5-HT2 receptors modulate the expression of antipsychotic-induced dopamine supersensitivity
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“Antipsychotic drugs suppress the symptoms of psychosis by attenuating dopamine-mediated neurotransmission at striatal dopamine D2/D3 receptors (Farde et al., 1988; Kapur and Remington, 2001; Seeman and Lee, 1975).”
Chronic clozapine selectively decreases prefrontal cortex dopamine as shown by simultaneous cortical, accumbens, and striatal microdialysis in freely moving rats
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Background
Synthesis and Atypical Antipsychotic Profile of Some 2-(2-Piperidinoethyl)benzocycloalkanones as Analogs of Butyrophenone
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“Clozapine is an atypical antipsychotic drug, whose effects are believed to be mediated partly through dopamine D4 receptor blockade (Seeman and Lee, 1975; Seeman and Van Tol, 1994; Wong and Van Tol, 2003): this effect is difficult to reconcile with the present study where activation of D4 receptors…”
Result
Impact of clozapine on the expression of miR-675-3p in plasma exosomes derived from patients with schizophrenia
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“Although several hypotheses, including dopamine and glutamate hypotheses, have been explored (Seeman and Lee 1975; Javitt and Zukin 1991), the critical aetiology and pathogenesis of SCZ remain unclear.”
Background
Could cannabidiol be used as an alternative to antipsychotics?
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“It draws evidence from the observation that a large number of antipsychotics have the ability to block dopamine D2 receptors (Seeman and Lee, 1975; Howes and Kapur, 2009).”
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Calcium and chlorpromazine interactions in rat synaptic plasma membranes
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The crosstalk between 5-HT2AR and mGluR2 in schizophrenia
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“This hypothesis has been indirectly supported by the effects of antipsychotic drugs on positive symptomatology, which correlate with their potency to block the striatal dopamine D2 receptor (Creese et al., 1976; Seeman and Lee, 1975).”
Background
Positron emission tomography and single photon emission CT molecular imaging in schizophrenia
Erritzøe, D., Talbot, P. S., Frankle, W. G., & Abi‐Dargham, A. (2003) · Neuroimaging Clinics of North America · doi:10.1016/s1052-5149(03)00089-3 · Cited by 31
When one’s sense of agency goes wrong: Absent modulation of time perception by voluntary actions and reduction of perceived length of intervals in passivity symptoms in schizophrenia
Graham-Schmidt, K., Martin-Iverson, M. T., Holmes, N. P., & Waters, F. (2016) · Consciousness and Cognition · doi:10.1016/j.concog.2016.08.006 · Cited by 34
“…current antipsychotic medications are competitive antagonists or partial agonists of the dopamine D2 receptor (Horacek et al., 2006; Seeman, 2006; Seeman & Lee, 1975; Seeman, Lee, Chau-Wong, & Wong, 1976) and antagonism of the D2 receptor leads to a decrease in the rate of the internal pacemaker…”
Neurodevelopmental concepts of schizophrenia in the genome-wide association era: AKT/mTOR signaling as a pathological mediator of genetic and environmental programming during development
Howell, K. R., & Law, A. J. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2019.08.036 · Cited by 30
“The presence of dopamine and the DRD2 receptor in the placenta is well described (Godziejewski and Maruchin, 1988; Kubota et al., 1979; Vaillancourt et al., 1994).”
BackgroundInfluential
Electrophysiologic interactions of antipsychotic drugs with central noradrenergic pathways
Marwaha, J., Hoffer, B. J., Geller, H. M., & Freedman, R. (1981) · Psychopharmacology · doi:10.1007/bf00429202 · Cited by 31
“Measurements of DA receptor binding (Creese et al. 1976) and DA release ( Seeman and Lee 1975 ) show similar ratios.”
Background
Presynaptic Receptors on Catecholamine Neurones
Langer, S. Z., & Lehmann, J. C. (1988) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-46625-0_8 · Cited by 31
Regional brain volume changes following chronic antipsychotic administration are mediated by the dopamine D2 receptor
Guma, E., Rocchetti, J., Devenyi, G. A., Tanti, A., Mathieu, A., Lerch, J., Elgbeili, G., Courcot, B., Mechawar, N., Chakravarty, M., et al. (2018) · NeuroImage · doi:10.1016/j.neuroimage.2018.04.054 · Cited by 33
“The clinical efficacy of APDs was quickly linked with their ability to block D2-like receptors (Creese et al., 1976; Seeman and Lee, 1975).”
Predicting Brain Occupancy from Plasma Levels using PET: Superiority of Combining Pharmacokinetics with Pharmacodynamics while Modeling the Relationship
Kim, E., Howes, O. D., Kim, B., Jeong, J. M., Lee, J. S., Jang, I., Shin, S., Turkheimer, F., Kapur, S., & Kwon, J. S. (2011) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2011.180 · Cited by 30
“The affinity of antipsychotic drugs for dopamine D2 receptors closely parallels their clinical potency (Seeman and Lee, 1975), and antipsychotic dopamine D2 receptor occupancy in vivo predicts both the clinical response of patients and their risk of side effects during antipsychotic treatment…”
Background
Activation of GABAB receptors inhibits protein kinase B /Glycogen Synthase Kinase 3 signaling
Lu, F. F., Su, P., Liu, F., & Daskalakis, Z. J. (2012) · Molecular Brain · doi:10.1186/1756-6606-5-41 · Cited by 30
“Available evidence suggests that antipsychotic drugs exert their antipsychotic effects in schizophrenia through the blockade of dopamine D2 receptors (D2R) or D2R in combination with the serotonin receptor 2A (5-HT2AR) [25,26,41].”
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State-dependent effects of the D2 partial agonist aripiprazole on dopamine neuron activity in the MAM neurodevelopmental model of schizophrenia
Sonnenschein, S. F., Gill, K. M., & Grace, A. A. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0219-1 · Cited by 32
Neurochemistry of schizophrenia: the contribution of neuroimaging postmortem pathology and neurochemistry in schizophrenia.
Dean, B. (2012) · Current Topics in Medicinal Chemistry · doi:10.2174/156802612805289935 · Cited by 30
“It has long been recognized that DADR2 were critical to the therapeutic benefits obtained when using antipsychotic drugs [12] and, it was proposed, to the pathophysiology of schizophrenia [7].”
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Behavioral Effects of Clozapine and Dopamine Receptor Subtypes
Josselyn, S. A., Miller, R. J., & Beninger, R. J. (1997) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(96)00051-6 · Cited by 30
Time-Resolved Resonance Raman and Density Functional Study of the Radical Cation of Chlorpromazine
Pan, D., Shoute, L. C. T., & Phillips, D. L. (2000) · The Journal of Physical Chemistry A · doi:10.1021/jp992196z · Cited by 30
Effects of haloperidol and apomorphine on the K+-depolarized overflow of [3H] dopamine from rat striatal slices
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The biochemical basis of relapse and drug response in schizophrenia: review and hypothesis
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A high performance liquid chromatographic assay of cis- and trans- isomers of tricyclic neuroleptic drugs
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Influence of monoamine oxidase inhibition on the release of 3H-dopamine elicited by potassium and by amphetamine from the rat substantia nigra and corpus striatum
Arbilla, S., & Langer, S. Z. (1980) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/bf00500301 · Cited by 30
“Monoamine oxidase inhibitors are imployed systematically by some authors in studies of stimulation-evoked release of 3H-dopamine from the central nervous system (Azzaro and Rutledge, 1973; Seeman and Lee, 1975; Paden et al., 1976; Dismukes and Mulder, 1977; Stool and Mulder, 1977; Arbilla et al., 1978 ; De Belleroche…”
Background
The striatonigral fibres and the feedback control of dopamine metabolism
Tulloch, I. F., Arbuthnott, G. W., Wright, A. K., Garcia-Munoz, M., & Nicolaou, N. M. (1978) · Psychological Medicine · doi:10.1017/s0033291700016159 · Cited by 30
A Case for Thalamic Mechanisms of Schizophrenia: Perspective From Modeling 22q11.2 Deletion Syndrome
Jiang, Y., Patton, M. H., & Zakharenko, S. S. (2021) · Frontiers in Neural Circuits · doi:10.3389/fncir.2021.769969 · Cited by 32
“, 2017) that inhibit D2 dopamine receptors (DRD2s) (Seeman and Lee, 1975; Carlsson, 1988).”
Clozapine does not require 5-HT1A receptors to block the locomotor hyperactivity induced by MK-801
Scorza, M. C., Castañé, A., Bortolozzi, A. A., & Artigas, F. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.04.012 · Cited by 29
“First generation (classical) antipsychotic drugs exert their therapeutic action by blocking dopamine (DA) D2 receptors (Seeman and Lee, 1975; Creese et al., 1976).”
Potential role of adenosine A2A receptors in the treatment of schizophrenia
Wardas, J. (2008) · Frontiers in bioscience · doi:10.2741/2995 · Cited by 31
“based on experimental observations that antipsychotic drugs served as functional dopamine receptor antagonists, and their clinical efficacy correlated with their potency to block dopamine D2 receptors (3, 8).”
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An Adenylate Cyclase of Brain Reflects Propensity for Breast Cancer in Mice
Cotzias, G. C., & Tang, L. (1977) · Science · doi:10.1126/science.887942 · Cited by 29
ACUTE ENDOCRINE PROFILE OF SULPIRIDE IN THE HUMAN*
L'Hermite, M., Denayer, P., GOLSTEIN, J., Virasoro, E., Vanhaelst, L., Copinschi, G., & ROBYN, C. (1978) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1978.tb02200.x · Cited by 29
Psychosis as a disorder of muscarinic signalling: psychopathology and pharmacology
McCutcheon, R. A., Weber, L. A. E., Nour, M. M., Cragg, S. J., & McGuire, P. K. (2024) · The Lancet Psychiatry · doi:10.1016/s2215-0366(24)00100-7 · Cited by 29
Emerging roles of striatal dopamine D2 receptors in motivated behaviour: Implications for psychiatric disorders
Olivetti, P. R., Balsam, P. D., Simpson, E. H., & Kellendonk, C. (2019) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13271 · Cited by 28
Developing New Drugs for Schizophrenia: From Animals to the Clinic
Jones, D. N. C., Gartlon, J. E., Minassian, A., Perry, W., & Geyer, M. A. (2008) · Elsevier eBooks · doi:10.1016/b978-0-12-373861-5.00008-4 · Cited by 30
Acute effects of chlorpromazine in a monkey operant behavioral test battery
Ferguson, S. A., & Paule, M. G. (1992) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(92)90536-o · Cited by 28
β-Adrenergic-control of cyclic AMP-generating systems in cerebellum: Pharmacological heterogeneity confirmed by destruction of interneurons
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Stress-induced alterations of cyclic nucleotide levels in brain: Effects of centrally acting drugs
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Antipsychotic drug action: targets for drug discovery with neurochemical imaging
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Intervention, causal reasoning, and the neurobiology of mental disorders: Pharmacological drugs as experimental instruments
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“…implicated the role of dopamine in schizophrenia was the finding that clinical effectiveness of typical antipsychotic drugs (e.g., chlorpromazine, haloperidol) is directly related to their affinity for dopamine receptors (Seeman & Lee, 1975; Creese, Burt, & Snyder, 1976; Seeman et al., 1976).”
Background
Unique pharmacological actions of atypical neuroleptic quetiapine: possible role in cell cycle/fate control
Kondo, M., Tajinda, K., Colantuoni, C., Hiyama, H., Seshadri, S., Huang, B., Pou, S., Furukori, K., Hookway, C., Jaaro-Peled, H., et al. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.19 · Cited by 27
Potential drug targets and treatment of schizophrenia
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“…of dopaminergic transmission in the mesolimbic system triggers the positive symptoms, and the hypoactivity of dopamine within mesocortical system mediates negative symptoms, cognitive symptoms and affective symptoms of schizophrenia (Snyder et al. 1974; Seeman and Lee 1975; Carlsson 1988).”
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Glutathione Levels and Glutathione-Glutamate Correlation in Patients With Treatment-Resistant Schizophrenia
Iwata, Y., Nakajima, S., Plitman, E., Truong, P., Bani‐Fatemi, A., Caravaggio, F., Kim, J., Shah, P., Mar, W., Chavez, S., et al. (2021) · Schizophrenia Bulletin Open · doi:10.1093/schizbullopen/sgab006 · Cited by 29
“21 Further, we classified patients with schizophrenia into the following 3 groups based on their response to antipsychotics: (1) CLZ nonresponders, (2) CLZ responders, and (3) FLR.”
BackgroundMethodResultInfluential
Reversal of ethanol intoxication in humans: An assessment of the efficacy of propranolol
Alkana, R. L., Parker, E. S., Cohen, H. B., Birch, H., & Noble, E. P. (1976) · Psychopharmacology · doi:10.1007/bf00426317 · Cited by 27
Effects of antipsychotics and selective D3 antagonists on PPI deficits induced by PD 128907 and apomorphine
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In vitro findings of alterations in intracellular calcium homeostasis in schizophrenia
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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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