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ELSEVIER
Is schizophrenia a dopamine supersensitivity psychotic reaction?^
Mary V. Seeman a, Philip Seeman b'*
a Departments of Psychiatry, University of Toronto, 260 Heath St. West, Suite 605, Toronto, Ontario M5P 3L6, Canada b Departments of Pharmacology, University of Toronto, 260 Heath St. West, Suite 605, Toronto, Ontario M5P 3L6, Canada
ABSTRACT
Adolf Meyer (1866-1950) did not see schizophrenia as a discrete disorder with a specific etiology but, rather, as a reaction to a wide variety of biopsychosocial factors. He may have been right. Today, we have evidence that gene mutations, brain injury, drug use (cocaine, amphetamine, marijuana, phencyclidine, and steroids), prenatal infection and malnutrition, social isolation and marginalization, can all result in the signs and symptoms of schizophrenia. This clinical picture is generally associated with supersensitivity to dopamine, and activates dopamine neurotransmission that is usually alleviated or blocked by drugs that block dopamine D2 receptors. While the dopamine neural pathway may be a final common route to many of the clinical symptoms, the components of this pathway, such as dopamine release and number of D2 receptors, are approximately normal in schizophrenia patients who are in remission. Postmortem findings, however, reveal more dimers of D1D2 and D2D2 receptors in both human schizophrenia brains and in animal models of schizophrenia. Another finding in animal models is an elevation of high-affinity state D2High receptors, but no radioactive ligand is yet available to selectively label D2High receptors in humans.
It is suggested that synaptic dopamine supersensitivity in schizophrenia is an attempt at compensation for the original damage by heightening dopamine neurotransmission pathways (preparing the organism for fight or flight). The dopamine overactivity is experienced subjectively as overstimulation, which accounts for some of the clinical symptoms, with attempts at dampening down the stimulation leading to still other symptoms. Reaction and counter-reaction may explain the symptoms of schizophrenia.
© 2013 The Authors. Published by Elsevier Inc. All rights reserved.
Contents
1. Introduction............................................................................................................................156
2. The historical view of schizophrenia as a reaction..........................................................................................156
3. The dopamine supersensitive reaction....................................................................................................156
4. The schizophrenia supersensitive reaction and presynaptic neuron pruning..................................................................157
5. The schizophrenia supersensitive reaction via dopamine release..............................................................................157
6. The schizophrenia supersensitive reaction via dopamine D2 receptors..................................................................157
7. The schizophrenia supersensitive reaction, dopamine D2High receptors, and dimers..........................................................157
8. Idiopathic supersensitivity in schizophrenia, and antipsychotic-induced supersensitivity........................................................157
9. The schizophrenia experiential/behavioral reaction to the supersensitive synapse..............................................................157
9.1. Misattributions or delusions........................................................................................................158
9.2. Hallucinations....................................................................................................................158
9.3. Cognitive deficits..................................................................................................................158
9.4. Thought disorder................................................................................................................158
9.5. Negative signs and symptoms......................................................................................................158
9.6. Mood changes....................................................................................................................158
9.7. Movement disorder..............................................................................................................158
10. Psychotogens............................................................................................................................158
11. Clinical treatment implications............................................................................................................158
Funding......................................................................................................................................159
References....................................................................................................................................159
☆ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
* Corresponding author. Tel.: +1 416 486 3456. E-mail address: Philip.Seeman@utoronto.ca (P. Seeman).
0278-5846/$ - see front matter © 2013 The Authors. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.! 016/j.pnpbp.2013.10.003
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ARTICLE INFO
Article history:
Received 30 August 2013
Received in revised form 3 October 2013
Accepted 3 October 2013
Available online 12 October 2013
Keywords:
D1D2 receptor dimer
D2 receptor
D2D2 receptor dimer
Dopamine release
Mutation
Psychosis
Psychotogens
1. Introduction
Most investigators acknowledge that there are many risk factors that contribute to schizophrenia. These include various gene mutations (both new and inherited), prenatal malnutrition or infection, birth anoxia/injury, brain trauma, drug abuse (cocaine, amphetamine, marijuana, phencyclidine, and steroids), social isolation and marginalization. Nevertheless, despite the impact of many different factors, the brain can react to them all similarly to produce the signs and symptoms of schizophrenia, the specific experiential and behavioral expression of which can, and does, vary from patient to patient.
This common general reaction is associated with supersensitivity to dopamine (Lieberman et al., 1987; Seeman, 2011), and overactivity of dopamine neurotransmission, which is usually alleviated or blocked by drugs that block dopamine D2 receptors (Madras, 2013).
At present, there is no diagnostic test or unique biological marker for schizophrenia, either associated with or extraneous to the dopamine system. For example, while all antipsychotics target the dopamine D2 receptor, the number of these receptors has been found to be approximately normal in the cerebral cortex of patients, as long as they have not been medicated with antipsychotics (Seeman, 2013a, in press). Numbers may differ, however, in specific parts of the brain, such as an apparent reduction in presynaptic D2 receptors in the thalamus (reviewed by Seeman, in press).
The psychopathology and molecular mechanisms that trigger overactivity at the D2 receptor, either by presynaptic or postsynaptic events, offer a potential pathway that might unravel the vulnerable elements that underlie schizophrenia. For over half a century, a door into the psychotic brain has been opened via the strategy of searching for the mechanism of antipsychotic drug action and working backwards to identify the brain networks involved in psychosis. The first effective drugs were chlorpromazine (Delay et al., 1952) and the related phenothiazines, followed by the haloperidol-type antipsychotics and the more recent second generation antipsychotics, with their diverse structures and receptor binding profiles. Despite the different chemical structures and the multi-receptor affinity of many of the effective drugs, a common target for all the antipsychotics is now recognized to be the so-called antipsychotic receptor, more commonly known as the dopamine D2 receptor (Seeman et al., 1975).
While D2-blocking drugs usually alleviate delusions and hallucinations within a matter of a few days (Delay et al., 1952; Kapur et al., 2005), the dissipation of negative symptoms, such as apathy, and the cognitive difficulties associated with schizophrenia, may require antipsychotics that act on targets other than the D2 receptor. At present, however, potentially new antipsychotic drugs acting on other targets such as receptors for dopamine D1, D3, D4, D5, cannabinoid-1, neurokinin-3, serotonin, neurotensin, ampakines, and sigma sites have not been shown to be clinically effective.
While there is renewed interest in the hypoglutamate theory of psychosis based on the fact that glutamate antagonists such as phencyclidine and ketamine trigger psychosis, it is known clinically that haloperidol (which has high affinity for D2, but low affinity for glutamate receptors) effectively alleviates the psychosis secondary to phencyclidine or ketamine (Giannini et al., 1984-1985, 2000). Moreover, it is uncertain whether glutamate receptor agonists such as pomaglumetad methionil or LY404,039 have any antipsychotic efficacy. A four-week trial had little or no efficacy against positive symptoms or negative signs when compared to olanzapine (Kinon et al., 2011; Seeman, 2012a).
2. The historical view of schizophrenia as a reaction
The view of schizophrenia as a reaction to a variety of potential causes was promoted by the Swiss American psychiatrist, Adolf Meyer (1866-1950), in the early 1900s (Noll, 2011; Yuhas, 2013). Meyer
reframed mental illness in terms of biopsychosocial "reaction types" rather than biologically-specific disease entities. As early as 1906, Meyer considered dementia praecox to be a "reaction type," a cluster of maladaptations that, together, constituted an attempt to cope with biopsychosocial stressors.
The present suggestion that schizophrenia may be a hyperactive dopamine supersensitive reaction to a variety of possible causes fits Meyer's general framework of schizophrenia as a reactive disorder.
3. The dopamine supersensitive reaction
The present work develops the idea that synaptic dopamine supersensitivity compensates for an original early injury (or mutation) by heightening dopamine neurotransmission pathways. Subjectively, the patient experiences this as overstimulation, a generally unpleasant sensation that leads to symptoms and to attempts at adaptation. Out of such attempts at compensation arise the variety of signs and symptoms that have been identified with schizophrenia. Patients with schizophrenia, whether treated or untreated, are known to be supersensitive to dopamine-like compounds (Lieberman et al., 1987), with intensification of symptoms or the development of new symptoms following the administration of dopamine-like agonists. The present mini-review outlines "the schizophrenia reaction" in terms of the molecular components of synaptic dopamine receptor sensitivity and the patient's automatic compensation.
While there are many molecular components underlying the biological basis of the schizophrenia reaction, it is not known, of course, in what sequence such components become active. Nevertheless, for the present purpose of this mini-review, the order of these components is organized as follows (see also Fig. 1):
a. Neuron cell pruning.
b. Activation of dopamine release.
c. Activation of dopamine D2 receptors.
d. Induction of dopamine D2High receptors.
At present, the evidence indicates that the signs and symptoms of psychosis, originating from whatever cause, are associated with an overactive dopamine system. This may result from a combination of increased presynaptic neural pruning, a high release of dopamine (Howes et al., 2012), altered numbers of dopamine D2 receptors (Seeman, 2013a, in press), and/or an increased sensitivity of the D2 receptor to dopamine (Seeman, 2011). This view is supported by the
1. Lesion (mutation, injury, drugs)
2. Increased release of dopamine
3. Receptor sensitization via more D2Hlgh receptors
4. More D2D2 or D2HighD2High dimers
5. More D1D2 or D1D2High dimers
6. Supersensitive behavior
7. Subjective awareness of internal over-stimulation
8. Psychotic signs and symptoms
Fig. 1. Biochemical progression from lesion to psychosis.
fact that the positive symptoms of delusions and hallucinations are alleviated in the majority of patients by D2-blocking medications.
4. The schizophrenia supersensitive reaction and presynaptic neuron pruning
The automatic reduction of central nervous system neurons, known as pruning, is a well-known phenomenon (see Maor-Nof and Yaron, 2013, for refs.). In humans, pruning of dopamine neurons occurs between 2 and 20 years of age and then slowly continues at between 2% and 3% per decade (Seeman et al., 1987a,b).
However, in the schizophrenia thalamus, several reports show evidence that suggest that there may be fewer than normal presynaptic D2 receptors and fewer presynaptic terminals, as monitored by benzamide ligands (Buchsbaum et al., 2006; Kegeles et al., 2010; Talvik et al., 2003, 2006; Tuppurainen et al., 2006; Yasuno et al., 2004), especially in association with a genetic variant in the dopamine D2 receptor (with a T in rs 1076560 in intron 6) (reviewed by Seeman, in press). Such reductions may be a result of neural pruning in the thalamus.
Neural presynaptic pruning would be expected to lead to denervation supersensitivity in a given specific brain region, analogous to that which occurs in early stages of Parkinson's disease.
5. The schizophrenia supersensitive reaction via dopamine release
It has been established that patients with schizophrenia release more endogenous dopamine than do individuals without schizophrenia, as measured by a challenge with a low dose of amphetamine (Laruelle et al., 1999). This effect of amphetamine occurs during the acute stages of schizophrenia but not when the patients are in clinical remission.
In the case of animal studies, it is not known whether dopamine release is increased in all of the many animal models of psychotic activity.
6. The schizophrenia supersensitive reaction via dopamine D2 receptors
As for the number of dopamine D2 receptors in the human brain striatum, these have finally been determined to be approximately normal (reviewed by Seeman, 2013a, in press), following an extensive number of earlier reports (e.g., Corripio et al., 2011; Farde et al., 1990).
However, as mentioned above, there is consistent suggestive evidence of reduced presynaptic terminals and reduced presynaptic numbers of dopamine D2 receptors in the schizophrenia thalamus (Seeman, in press). Such reductions would inevitably lead to denervation supersensitivity in this region.
7. The schizophrenia supersensitive reaction, dopamine D2High receptors, and dimers
Although the total number of D2 receptors in the human striatum may be normal, animal models of psychotic behavior (brain lesions, gene mutations, or harm from psychotogens) all lead to an increase in D2High receptors, which is the high-affinity state or the functional state of the D2 receptor (Seeman, 2011). Such factors include brain lesions in the hippocampus, frontal cortex, or substantia nigra, and various gene knock-out mutations in mice, including those for the metabotropic glutamate receptors 2 and 3, the GABA B1 receptor, the trace amine 1 receptor, the dopamine D4 receptor, the beta-adrenoceptor, and genes for dopamine-beta-hydroxylase, G-protein receptor kinase, the postsynaptic density 95, catecholamine-O-methyl-transferase, the dopamine transporter, and RGS-9 (Regulator of G-protein signaling 9).
In addition, the proportion of D2High receptors increased in rat striata after administration of the following drugs: corticosterone,
amphetamine, methamphetamine, phencyclidine, cocaine, caffeine, marijuana congeners, and quinpirole.
Such an elevation of D2High receptors in more than twenty animal models of psychosis (Seeman, 2011) is consistent with the long-standing observation that schizophrenia patients are more sensitive than control subjects to dopamine-like stimulants such as methylphenidate (Lieberman et al., 1987).
However, at present, the functional state of the D2 receptor cannot be measured in humans. The agonists (such as [11C]PHNO) that have been used to study this issue (Graff-Guerrero et al., 2009) do not selectively label D2High receptors. Radioactive agonists such as [11C] PHNO label both D2High and D2Low receptors, which may explain the inability to selectively measure D2High receptor numbers in human brain scans (Seeman, 2012b). However, the new long-lived [18F]-agonist ligand may be able to label D2High sites successfully in the future (Sromeket al., 2011).
In addition to an increase in the proportion of D2High receptors, there is an increase in the proportion of D2D2 dimers (Wang et al., 2010) and D1D2 dimers (Perreault et al., 2010) in postmortem schizophrenia brain striatal tissue (compared to non-affected brains), findings that are associated with an elevation in D2High receptors.
While it is well established that long-term administration of antipsychotic medication can increase the number of dopamine D2 and D2High receptors and their sensitivity to dopamine (Samaha, 2013; Silvestri et al., 2000), the antipsychotics at the same time effectively reduce the number of D2High receptors that have previously been induced by a psychotogen such as amphetamine (Seeman, 2009).
8. Idiopathic supersensitivity in schizophrenia, and antipsychotic-induced supersensitivity
Moreover, while the schizophrenia reaction may be based on dopamine supersensitivity, prolonged antipsychotic treatment can also add to such supersensitivity. This view is supported by the general clinical observation that sudden withdrawal of antipsychotics can precipitate an acute episode of psychosis (Chouinard and Chouinard, 2008).
Because the dopamine supersensitive reaction in schizophrenia is somewhat similar to the dopamine supersensitivity that is induced by antipsychotic drugs, clarifications have been made by Chouinard and colleagues. For example, these authors earlier hypothesized that schizophrenia was an idiopathic dopamine deficiency disease associated with dopamine supersensitivity (Chouinard and Jones, 1978; Reith et al., 1994). They later suggested that some severe and persistent psychotic symptoms could emerge in association with antipsychotic-induced dopamine supersensitivity (Chouinard, 1990; see also Iyo et al., 2013; Kimura et al., 2013; Tadokoro et al., 2012).
In addition, antipsychotic-induced dopamine supersensitivity can occur together with tardive dyskinesia, which appears to be associated with a loss of cholinergic neurons as well as dopamine neurons (Miller and Chouinard, 1993; Seeman and Tinazzi, 2013).
9. The schizophrenia experiential/behavioral reaction to the supersensitive synapse
Supersensitivity at the level of the synapse can lead to clinical symptoms either directly or via compensation to dopamine overactivity. This is seen in the core symptoms of schizophrenia such as a) misattributions or delusions, b) altered perceptions or hallucinations, c) cognitive deficits, d) disorganization (thought disorder), e) isolation and amotivation (negative signs), and also in symptoms that frequently accompany schizophrenia, such as f) altered mood (depression, ecstasy, and terror) and g) altered movement (agitation, dyskinesia, and catatonia).
9.1. Misattributions or delusions
The dopamine supersensitive state can lead to excess thoughts and excess speed of thoughts, which makes them especially vivid. These actions can be replicated by a variety of hallucinogen agonists known to be active at the dopamine D2 receptor (Seeman et al., 2009). The vividness of the thoughts lends to them a sense of urgency and an aura of certainty. Delusions are misattributions that are experienced as imperative and believed in with unshakeable conviction. There is evidence that overactivity of the dopamine system can kick start the procession of events that leads to delusion formation (Howes and Kapur, 2009).
9.2. Hallucinations
Hallucinations are most frequently understood as defects of source monitoring (Garrett and Silva, 2003). Memories and inner thoughts that flood the brain through supersensitive D2 receptors are experienced as coming from the outside. This has been empirically validated by Brebion et al. (2009). The more rapid the perceptions, the more errors in context processing and subsequent experience of attributing inner sensations to external stimuli. Abnormal perceptions such as voices heard in one's head, visions, smells, and somatic sensations may all result from dopamine overactivity.
9.3. Cognitive deficits
The probability that dopamine supersensitivity can lead to cognitive difficulties is shown by the fact that D2 receptors, selectively genetically elevated in the striatum, reduce cognitive performance in animals (Kellendonk et al., 2006). Attention and memory problems in schizophrenia may directly result from dopamine overstimulation and are worsened by the lowered self-confidence that ensues from them.
9.4. Thought disorder
Thought disorder may fall into the category of compensation rather than result directly from overstimulated synapses. Patients frequently appear to be playing with words, rearranging them idiosyncratically as poets do. This has been referred to as 'swerves and cryptic references' (Byerley et al., 2005), a form of juggling thoughts that come too swiftly, perhaps to make them more manageable. A problem with communication or 'unconventional discourse' is a hallmark of schizophrenia (Elvevag et al., 2010). Many of the brain regions where dopamine sensitivity occurs are intimately associated with the language. In addition to Broca's area, these regions include Wernicke's area (comprehension), the left temporal gyrus (language storage and retrieval), the insula, the anterior cingulate gyrus, the left inferior frontal cortex, as well as portions of the thalamus, and cerebellum (Chouvardas, 1996; Nieuwenhuys et al., 2008). All these brain regions contain dopamine D2 receptors, but at densities that are between 20% and 50% of the densities found in the caudate/putamen region (Charuchinda et al., 1987; Hall etal., 1995).
9.5. Negative signs and symptoms
The negative signs and symptoms of schizophrenia, such as social isolation, amotivation, lethargy, can be understood as wholly reactive — compensations designed to ward off dopamine overstimulation (Corin and Lauzon, 1992).
9.6. Mood changes
Many individuals with schizophrenia suffer from oscillations of mood. The biochemical basis may well be the existence of high- and
low-affinity states of the D2 receptor, with the D2High and D2Low receptors rapidly interconverting, depending on the metabolism of GDP and GTP within the cell (Seeman, 2013b). It should be noted that the two states of D2High and D2Low are constantly interconverting, and that synaptic and clinical dopamine sensitivity can change in a matter of minutes, depending on the metabolism of these two guanine nucleotides. Ups and downs of mood are dealt with differently by different individuals. Routinization and stereotypy are one way, accounting for the prevalence of obsessive-compulsive symptoms (nearly one third of patients) in schizophrenia (Byerly et al., 2005). Some strategies for dealing with mood oscillation, such as quickly jumping to conclusions' (which, incidentally, encourages delusion formation) may be an attempt to rapidly establish certainty in order to ward off the chaos and ambiguity that results from supersensitive synapses.
9.7. Movement disorder
Adventitious movements such as exaggerated or purposeless arm and leg motions, tics, grimacing, repetitive activity, and altered reflexes occur in patients with schizophrenia even when they are not taking antipsychotic drugs. They are probably a direct result of hypertransmission at dopamine synapses (Van Rossum, 1967) whereas, after drugs, they reflect dopamine/cholinergic imbalance (Campos et al., 2010; Pappa and Dazzan, 2009; Peluso et al., 2012). Psychomotor slowing and catatonia are further examples of movement problems associated with schizophrenia and can be viewed as compensations.
10. Psychotogens
Another way of attempting to control chaos is through the use of mind-altering substances. Supersensitivity at the dopamine receptor enhances the reward from nicotine and alcohol, and possibly to marijuana and its congeners (see also Seeman, 2011), further reinforcing the abuse of these compounds. A high proportion of patients with schizophrenia also develop substance use disorder with common street drugs (Volkow, 2009).
A possible biochemical progression from brain injury or gene mutation to the psychotic state is summarized in Fig. 1. The original brain anomaly leads to elevated numbers of D2, D2High, D2D2 dimers, and D1D2 dimers. In addition, there is abnormal pruning and the heightened release of endogenous dopamine. These factors combine to induce abnormal sensations and behaviors. The patient attempts to compensate as best he or she can, and this results in the various manifestations of schizophrenia.
11. Clinical treatment implications
Adolf Meyer did not believe that schizophrenia was something that a person "had" or "was born with" but, rather, that it was a pattern of symptoms and behaviors that evolved from multiple original causes and to which the person tried to adapt, sometimes successfully, sometimes not (Meyer, 1922).
Like Meyer, it is here suggested that patterns of clinical expression in schizophrenia evolve in recurrent cycles of event, reaction and counter-reaction. As such they are relatively unique to every individual and unpredictable in terms of course. There is no finality to a diagnosis of schizophrenia. As Meyer wrote: "... it is also important to lay stress upon traits of personality, cultural influences, environmental stressors, evasive and regressive modes of adaptation" (Double, 2007).
It is further here suggested that dopaminergic overdrive is a necessary step on the path between initial causation and symptom expression. As such, therapeutic interventions need to focus on preventing dopamine overstimulation through a combination of means: biological (dampening dopamine release and transmission), psychological (muting stress that is mediated through dopamine
pathways), and sociological (alleviating poverty and discrimination, which raise dopamine activity in large swaths of the population).
Funding
This work was supported by the Dr. Karolina Jus estate, the Medland family, Pamela and Desmond O'Rorke, Janet Marsh Frosst, David Medland, Judith Rockert, and Constance E. Lieber and Stephen Lieber.
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