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Monday, 25.01.2021

Philip Seeman and Mary V. Seeman: The Dopamine Hypothesis of Schizophrenia in Historical Perspective


        Psychosis refers to a set of symptoms that include recurrent misperceptions and entrenched misinterpretations of the world. Psychosis is not one illness because these same symptoms can be seen in a number of different illnesses, notably schizophrenia. There are many hypotheses about what causes psychosis, but the one that has best stood the test of time is the “dopamine hypothesis.”

        The hypothesis is attributed to Jacques M. Van Rossum. Noticing that drugs such as L-dopa or amphetamine, which enhance dopaminergic activity, are able to induce or exacerbate psychosis, and that drugs such as chlorpromazine and related drugs (then called neuroleptics) reversed psychosis, Van Rossum (1967) wrote:

        “When the hypothesis of dopamine blockade by neuroleptic agents can be further substantiated, it may have far going consequences for the pathophysiology of schizophrenia. Overstimulation of dopamine receptors could then be part of the aetiology. Obviously such an overstimulation might be caused by overproduction of dopamine, production of substances with dopamine actions (methoxy derivatives), abnormal susceptibility of the receptors, etc.”

        As it refers to schizophrenia, the hypothesis posits that the over-transmission of dopamine in subcortical and limbic brain regions contributes to the positive, negative and cognitive symptoms of the disease.

        That neuroleptic or antipsychotic drugs exert their therapeutic action by blocking brain dopamine receptors was later directly confirmed by Philip Seeman’s in vitro experiments (Seeman, Chau-Wong, Tedesco and Wong 1975). The in vitro work found that all antipsychotic drugs block specific dopamine receptors (D2 receptors) in direct relation to their clinical potency (Seeman 2010, 2011).

        In line with Van Rossum’s speculation that over-stimulation might be caused by abnormal susceptibility of receptors, Seeman searched for potential causes of such susceptibility. His research group initially found an elevated number of D2 receptors in post-mortem human brain tissues from schizophrenia patients, but the participants had all been treated with antipsychotic drugs so the elevation was most likely attributable to treatment rather than to disease.  More recent brain imaging data on never-medicated patients show only a very small increase in the number of dopamine D2 receptors, about 6%.

        The dopamine D2 receptor is a G-protein-linked receptor and, like other G-protein-linked receptors,  it can exist in a state of high affinity for dopamine, D2High, or in a state of low affinity for dopamine, D2Low. The high-affinity and low-affinity states rapidly convert into each other in a matter of seconds or less. This can be experimentally shown.

        It is, therefore, possible that, while the overall density of D2 receptors in never-medicated schizophrenia is only increased by approximately 6%, the number of D2High receptors may be significantly elevated in psychotic conditions.

        There are many animal models of psychosis that indicate D2High receptors are elevated in association with psychotic-like behaviour. For example, prolonged administration of methamphetamine causes rats to become hyperactive and develop stereotyped behaviour. This occurs in association with a two-fold or three-fold increase in the proportion of D2 receptors in the D2High state (Shuto, Seeman, Kuroiwa and Nishi 2008).

        In addition, a wide variety of drugs (cocaine, amphetamine, phencyclidine, glucocorticoids), brain injuries, Caesarian birth, genetic mutations and social isolation all elicit psychotic-like behaviour and elevation of D2High receptors in animals (Seeman, Schwarz, Chen et al. 2006).     

        What is needed to show D2High receptors in vivo is radioactive dopamine-like ligands that selectively labels D2High receptors but this is difficult for a number of technical reasons (Shalgunov, van Waarde, Booij et al. 2019).

        At least three molecular components could theoretically form the basis of dopamine supersensitivity. These are:

1. An increase in D2D2 dimers that is known to occur in amphetamine-sensitized rat striata, as well as in post-mortem striata from schizophrenia patients (Wang M, Pei L, Fletcher et al. 2010). Some of the D2 units within the D2D2 dimer likely exist in the D2High state.

2. An increase in D1D2 dimers that occur in amphetamine-treated rats, as well as in post-mortem striata of schizophrenia patients. Many of the D2 units within the D1D2 dimer are likely to exist in the D2High state.

3. A decrease in the affinity between monomers that constitute each D2 protein such that more of the monomers can now exist in the high-affinity state and, therefore, bind more dopamine (Seeman, Schwarz, Chen et al. 2006).

        Most recently, Kubota, Nagashima, Takano et al. (2017) in Japan found that dopamine D2High receptors were significantly elevated in 11 untreated schizophrenia patients, as measured by positron emission tomography, using two radioactive compounds on each patient.     

        In summary, the current (2020) dopamine hypothesis of psychosis centers on the nature of the high-affinity dopamine state and growing evidence for its association with the presence of psychotic symptoms in unmedicated patients. Understanding the function of the dopamine receptor is generally viewed as the cornerstone of the dopamine hypothesis of schizophrenia (Madras 2013).


Kubota M, Nagashima T, Takano H, Kodaka F, Fujiwara H, Takahata K, Moriguchi S, Kimura Y, Higuchi M, Okubo Y, Takahashi H, Ito H, Suhara T. Affinity states of striatal dopamine D2 receptors in antipsychotic-free patients with schizophrenia. Int J Neuropsychopharmacol. 2017; 20(11):928-35.

Madras BK. History of the discovery of the antipsychotic dopamine D2 receptor: A basis for the dopamine hypothesis of schizophrenia. J Hist Neurosci. 2013; 22:62-78.

Seeman P, Chau-Wong M, Tedesco J, Wong K. Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad Sci USA. 1975; 72:4376–80

Seeman P. All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2High receptors. CNS Neurosci Ther. 2011; 17:118-32.

Seeman P.  Dopamine D2 receptors as treatment targets in schizophrenia. Clin. Schizophr  Relat Psychoses. 2010; 4:56-73.

Seeman P, Schwarz J, Chen JF, Szechtman H, Perreault M, McKnight GS, Roder JC, Quirion R, Boksa P, Srivastava LK, Yanai K, Weinshenker D, Sumiyoshi T. Psychosis pathways converge via D2High dopamine receptors. Synapse. 2006; 60:319‐346.

Shalgunov V, van Waarde A, Booij J, Michel MC, Dierckx RAJO, Elsinga PH. Hunting for the high‐affinity state of G‐protein‐coupled receptors with agonist tracers: Theoretical and practical considerations for positron emission tomography imaging. Medicinal Res Rev. 2019; 39:1014-52.

Shuto T, Seeman P, Kuroiwa M, Nishi A. Eur J Neurosci. 2008; 27:2551-7.

Van Rossum JM.  The significance of dopamine-receptor blockade for the action of neuroleptic drugs. In: Brill H, Cole JO, Deniker P, Hippius H, Bradley PB, editors. Neuro-Psycho-Pharmacology, Proceedings of the Fifth International Congress of the Collegium Internationale Neuro-Psycho-pharmacologicum, March 1966.  Amsterdam: Excerpta Medica Foundation. 1967, pp. 321-9.

Wang M, Pei L, Fletcher, Kapur S, Seeman P, Liu F. Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: Increased dopamine D2 receptor dimerization. Mol Brain. 2010; 3:25.


December 3, 2020