Progress in Neuro-Psychopharmacology & Biological Psychiatry 48 (2014) 155–160

Contents lists available at ScienceDirect

Progress in Neuro-Psychopharmacology & Biological

Psychiatry
journal homepage: www.elsevier.com/locate/pnp

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

a r t i c l e i n f o a b s t r a c t

Article history: Adolf Meyer (1866–1950) did not see schizophrenia as a discrete disorder with a specific etiology but, rather, as a
Received 30 August 2013 reaction to a wide variety of biopsychosocial factors. He may have been right. Today, we have evidence that gene
Received in revised form 3 October 2013 mutations, brain injury, drug use (cocaine, amphetamine, marijuana, phencyclidine, and steroids), prenatal
Accepted 3 October 2013
infection and malnutrition, social isolation and marginalization, can all result in the signs and symptoms of
Available online 12 October 2013
schizophrenia. This clinical picture is generally associated with supersensitivity to dopamine, and activates
Keywords:
dopamine neurotransmission that is usually alleviated or blocked by drugs that block dopamine D2 receptors.
D1D2 receptor dimer While the dopamine neural pathway may be a final common route to many of the clinical symptoms, the
D2 receptor components of this pathway, such as dopamine release and number of D2 receptors, are approximately normal
D2D2 receptor dimer in schizophrenia patients who are in remission. Postmortem findings, however, reveal more dimers of D1D2
Dopamine release and D2D2 receptors in both human schizophrenia brains and in animal models of schizophrenia. Another finding
Mutation in animal models is an elevation of high-affinity state D2High receptors, but no radioactive ligand is yet available to
Psychosis selectively label D2High receptors in humans.
Psychotogens
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. Open access under CC BY license.

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

⁎ Corresponding author. Tel.: +1 416 486 3456.

E-mail address: Philip.Seeman@utoronto.ca (P. Seeman).

0278-5846 © 2013 The Authors. Published by Elsevier Inc. Open access under CC BY license.
http://dx.doi.org/10.1016/j.pnpbp.2013.10.003
156 M.V. Seeman, P. Seeman / Progress in Neuro-Psychopharmacology & Biological Psychiatry 48 (2014) 155–160
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 D2High 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.
 M.V. Seeman, P. Seeman / Progress in Neuro-Psychopharmacology & Biological Psychiatry 48 (2014) 155–160
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,
157
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 (Sromek et 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).
158 M.V. Seeman, P. Seeman / Progress in Neuro-Psychopharmacology & Biological Psychiatry 48 (2014) 155–160
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 Brébion 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 (Elvevåg 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 et al., 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 hyper-
transmission 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
 M.V. Seeman, P. Seeman / Progress in Neuro-Psychopharmacology & Biological Psychiatry 48 (2014) 155–160
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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