CURE FOR SCHIZOPHRENIA

A JOURNEY

CAN BIOLOGICAL CONTROL

SYSTEMS BE THE ANSWER TO
CHEMICAL REGULATION?

DOPAMINE AND ITS ROLE

Mushahid M
The Role of Dopamine Receptors in Schizophrenia
by: Rupinder Mann
for: Biochemistry II (CHEM 4420)
5/29/96 Two million people suffer from schizophrenia at some
point in their life, making it one of the most common health
problems in the United States. Schizophrenia has also been
found to be hereditary. This biological disorder of the brain is a
result of abnormalities which arise early in life and disrupt the
normal development of the brain. These abnormalities involve
structural differences between a schizophrenic brain and a
healthy brain. Schizophrenic brains tend to have larger lateral
ventricles and a smaller volume of tissue in the left temporal
lobe in comparison to healthy brains. The chemical nature of a
schizophrenic brain is also different in the manner the brain
handles dopamine, a neurotransmitter. Neurotransmitters
transmit impulses between neurons. (Brown 1994)

The disease schizophrenia can be characterized by

disturbances in the areas of the brain that are associated with
thought, perception, attention, motor behavior, emotion, and
life functioning. The symptoms are divided into negative and
positive categories. Negative symptoms consist of behavioral
deficits such as blunting of emotions, language deficits, and
lack of energy. Positron emission tomography (PET) has been
used to show that schizophrenics with negative symptoms have
reduced brain activity in the prefrontal cortex of the brain.
PET measures the blood flow in the brain by measuring
particles (positrons) that are emitted from a radioactive
chemical injected into the patient. The rate of positron
emission is used to evaluate the metabolic rate of nerve cells in
particular regions of the brain. PET allows scientists to
determine which areas of the brain are being used as people
perform certain tasks.
Positive symptoms are frightening, but they are not as
disabling in the long term as negative symptoms. These positive
symptoms consist of hallucinations, delusions, and bizarre
behavior. Single photon emission tomography (SPET)
measures a single photon's rate of emission. It has been used to
show that during the delusional hearing of voices, the blood
flow is greater than normal to Broca's area. This is the part of
the brain that has been linked to articulated language. Some
subcategories of schizophrenia include hebephrenic, catatonic,
and paranoid schizophrenia. Hebephrenic or disorganized
schizophrenia is characterized by profuse hallucinations and
delusions that often involve deterioration of the body.
Catatonic schizophrenia involves motor disturbances, which
alternate between immobility and wild excitement. A paranoid
schizophrenic has prominent delusions about persecution.
(Davison & Neale 1990) A number of these symptoms are
thought to be caused by biochemical factors. One of the most
prominent of these factors is the excessive activity of the
neurotransmitter dopamine. This excessive activity will be
explained by the chemistry of the brain and dopamine
receptors.

Thousands of chemical processes take place in a functioning

neuron. The transfer of information is mediated by
neurotransmitters that interact with certain receptors. (Sedvall
& Farde 1995) When drugs block dopamine receptors in the
basal ganglia, the symptoms of schizophrenia are reduced.
Amphetamines and other drugs that stimulate the receptors
produce schizophrenic symptoms in healthy people. (Brown
1994) Five dopamine receptors, D1, D2, D3, D4, and D5, have
been discovered. Each of the receptors contain about 400
amino acids, and they have seven regions spanning the neural
membrane. Their function is to bind to dopamine secreted by
presynaptic nerve cells. This binding triggers changes in the
metabolic activity of the postsynaptic nerve cells. A study was
conducted in which presynaptic dopamine function (measured
by the uptake of fluorodopa) was observed by PET in the
brains of seven schizophrenic patients and eight healthy people
(controls). The fluorodopa influx constant was higher in the
schizophrenic patients. Their receptors took up more
fluorodopa. In conclusion, these alterations in presynaptic
dopamine function constituted a part of the disrupted neural
circuits that predispose people to schizophrenia. (Hietala 1995)

The dopamine receptors involved in these processes can be

separated into the D1 and D2 families. The D1 family contains
the receptors D1 and D5. The D1 receptors in the brain are
linked to episodic memory, emotion, and cognition. These
functions are disturbed in schizophrenic patients. In addition,
D1 binding of dopamine was found to be lower in
schizophrenic patients as compared to healthy subjects of the
same age. The binding was lower as a result of fewer D1
receptors. Certain antipsychotic drugs stimulate D1 regulated
pathways, which increases the D1 to D2 activity balance in the
brain. This balance can also be regained by the release of
dopamine. Not much is known about D5 due to the lack of
drugs that are selective for it.

The D2 family contains the receptors D2, D3, and D4. D2 is the
second most abundant dopamine receptor in the brain. D2
receptor blockade is the main target for antipsychotic drugs,
because there is a higher density of D2 in schizophrenic brains.
(Sedvall & Farde 1995) A study conducted by Schmauss (1993)
found a selective loss of D3 mRNA expression in the parietal
and motor cortices of postmortem, schizophrenic brains. This
phenomena may be due to either the course of the disease or
the therapy given to the patient during the course of the
disease. Seeman (1993) found the density of D4 receptors was
elevated sixfold in schizophrenic patients.
These dopamine receptors are affected by alterations in the
neural cell membranes, which could disrupt communication
between cells. Abnormalities in two long-chain fatty acids in
the blood cells of people with negative symptoms have been
discovered. These substances breakdown into products that are
involved in the dopamine system. (Brown 1994) Dopamine is
secreted by cells in the midbrain that send their axons to the
basal ganglia and frontal lobe. Certain drugs used for
schizophrenia bind to the dopamine receptors. This blocks
dopamine binding to the receptor. This deactivates the
biochemical processes normally initiated by dopamine binding.
First dopamine binds to the receptor, and then the receptor
autophosphorylates. By phosphorylation, this receptor
activates adenylate cyclase, which then makes cAMP. These
processes involve the synthesis of cAMP and synaptic action at
synapses using dopamine as a transmitter. The dopamine
synapses are incapacitated by antipsychotic drugs. Dopamine
antagonists are drugs that block dopamine receptors. The
brain responds to this receptor blockade by making extra
dopamine receptors. This is the postsynaptic cells' attempt to
compensate for the weakening of synaptic transmission, which
is caused by the drugs. These extra receptors restore the cell's
sensitivity to dopamine. The brain also compensates by
increasing dopamine synthesis. The increase in dopamine
synthesis lasts one to two weeks of medication from the start of
therapy, which is the same time required for the medication to
become effective. Drugs have been discovered to alleviate the
upregulation of receptors and the increased synthesis of
dopamine. (Lickey & Gordon 1990)

Anti-schizophrenic drugs are called neuroleptics. A dopamine

antagonist is chlorpromazine (Thorazine), and reserpine
operates by depleting transmitter stores. Ligand-binding
techniques, which use neuroleptic drugs labelled with
radioisotopes demonstrate that such drugs bind to dopamine
receptors. A correlation exists between this ability to bind
dopamine and the dosage required to improve schizophrenic
symptoms in patients. This effect could also be directly
observed by PET in living subjects . (Sedvall & Farde 1995)

Controlling dopamine and dopamine receptors is essential for

the treatment of schizophrenia. Because schizophrenia is
hereditary, it is important to see progress for the next
generation. (Brown 1994) In the future there will be more
sophisticated drugs that do not merely suppress symptoms, but
also allow for normal cognitive functioning. Although
schizophrenics may never be normal, their lives can still be
made more tolerable.
INTRODUCTION

The last 10 years have witnessed far-reaching changes in the

understanding of dopamine (DA) and its possible role in the
pathogenesis of schizophrenia. Although the original
hypothesis that has so stimulated the study of DA in
schizophrenia has proven to be untenable, a role for DA in
schizophrenia appears even more likely than it did 10 years
ago.

The original DA hypothesis of schizophrenia postulated that

schizophrenia was characterized by increased DA function (1).
This hypothesis was based primarily on the correlation
between the ability of neuroleptics to displace DA antagonists
in vitro and their clinical potency (2). However, in the last
decade it has become increasingly evident that this hypothesis
was in need of revision. One of the principal reasons driving
the demand for reconceptualizing the original DA hypothesis
was the appreciation that some core symptoms of
schizophrenia are negative symptoms and cognitive deficits.
These symptoms, though amenable to some extent to
neuroleptic treatment, are far less responsive to treatment with
DA antagonists than are psychotic, positive symptoms. This, in
turn, suggests that some of the core symptoms of schizophrenia
may be unrelated to increased DA activity. Additionally,
knowledge about the DA system has expanded considerably
over the last decade and, combined with the above questions,
has stimulated further studies into DA and schizophrenia,
leading to an increased and refined understanding of its role in
that illness. (See Mesocorticolimbic Dopaminergic Neurons:
Functional and Regulatory Roles and Dopamine Receptors:
Clinical Correlates , for related discussion.)
IDENTIFICATION OF MULTIPLE DA RECEPTOR
SUBTYPES

The discovery of multiple DA receptors serves as a good

illustration of the progress made over the last decade in
understanding the DA system. Ten years ago, D2 and D1 were
the only DA receptors known, but now D3, D4, and D5
receptors have also been identified. D1 receptors are coupled to
adenylate cyclase, have a low binding affinity to [3H]spiperone,
and are found predominantly in the cortex of humans (3). D5
receptors resemble D1 (4), but they have a higher affinity for
DA than do D1 receptors (5). D2 receptors are negatively
coupled to adenylate cyclase, display high binding affinity to
[3H]spiperone (6), and are most prominent in the striatal and
limbic structures in humans; and their presence, if at all, in the
human cortex, is limited (3). The D2 receptor has also been
cloned and two D2 isoforms, labeled D2a and D2b, have been
identified (7). The D3 receptor has been cloned and is
primarily present in the nucleus accumbens with very low
levels in the caudate and putamen (8). It also exists in two
isoforms (9). [In one study, no linkage was found in four
Icelandic pedigrees between schizophrenia and the D3 receptor
gene (10).] It bears no resemblance to either the D1 or the D2
system (11). Finally, D4 receptors have been identified
displaying a higher affinity for the atypical neuroleptic,
clozapine (12). The identification of these various DA receptors
has important implications. The high affinity of clozapine to
the DA4 receptor, for instance, raises the issue of whether
atypical neuroleptics are effective by blocking D4 receptors
more effectively than they block D2 receptors. Indeed, it has
been argued that blockade of D4 receptors is related to the
efficacy of neuroleptics, whereas blockade of D2 receptors is
related to their extrapyramidal side-effect profile (13). The
anatomical localization of D3 receptors to limbic regions has
intriguing possibilities for the development of antipsychotic
compounds.

MODULATION OF THE DA SYSTEM

Another discovery of importance in understanding the role of

dopaminergic transmission in schizophrenia has been the
elucidation of an interaction between cortical and striatal DA
systems: An inhibitory regulation of cortical DA systems on
striatal DA neurons has been found. When DA neurons are
lesioned in the prefrontal cortex (PFC) in rats, increased levels
of DA and its metabolites as well as increased D2 receptor
binding sites and D2 receptor responsivity are found in
striatum (14, 15, 16, 17, 18). Conversely, injection of the DA
agonist, apomorphine, in the PFC of rats reduced the DA
metabolites, homovallic acid (HVA) and dihydroxyphenylacetic
acid (DOPAC), by about 20% in the striatum (19).

In a modification to the model proposed by Pycock et al. (14),

Deutch (20) proposed that the effect of DA depletion in the
PFC on striatal DA activity is particularly revealed after the
animal has been stressed. Specifically, when animals were
stressed, larger increases in striatal DA activity were found in
animals whose mesocortical DA neurons had been lesioned
than in animals with intact PFC DA systems (20). This suggests
that the sensitivity of striatal (mesolimbic) DA neurons to
physiological (i.e., stress) challenge is enhanced when DA
function in the PFC is decreased. These studies therefore
indicate that decreasing prefrontal cortical DA activity
increases striatal DA turnover, D2 receptor sensitivity, and D2
receptor function, whereas increased DA function in the PFC
decreases striatal DA activity particularly in response to stress.
Thus, it appears that DA systems in the PFC display an
inhibitory modulatory effect on subcortical, striatal DA
systems. Decreased activity in the PFC may render the subject
particularly sensitive to stress-induced increases in subcortical
DA activity.

Others suggest an additional link between (diminished) DA

activity in the PFC and stress-sensitive changes in subcortical
DA activity. It has been hypothesized that the release of DA in
subcortical sites is under the control of two independent
mechanisms: phasic and tonic DA release (21). Phasic DA
release appears associated with behavioral stimuli (stress, for
instance), whereas the degree of tonic DA activity determines
the magnitude of the phasic response to environmental stimuli.
Decreased prefrontal DA activity in schizophrenic patients is
hypothesized to reduce tonic DA release, leading to
compensatory increases in (for instance) receptor sensitivity,
resulting in exaggerated responses to phasic release of DA in
response to stress (21).

In summary, findings suggesting a regulatory effect for PFC

DA systems on subcortical DA function have changed the focus
from solely subcortical DA systems to the interaction between
the subcortical and cortical DA systems as one of the primary
regions of interest in schizophrenia. These findings have far-
reaching and important implications for the role of DA in
schizophrenia: Not only do they suggest the usefulness of
increasing DA activity (in the PFC), but even more
importantly, increasing DA function in the PFC may be used as
an intervention to prevent (stress-induced) increases in
subcortical DA activity (i.e., psychosis) and thus may be
considered as maintenance treatment in schizophrenia (see also
Schizophrenia and Glutamate).

METHODOLOGICAL ADVANCE

Understanding of the DA system in humans has also been

enhanced by the development of peripheral measures that
reflect central DA function. Measurement of the DA
metabolite, homovanillic acid (HVA), in plasma has proven to
be such a tool, appearing particularly useful when DA function
is putatively manipulated, as during administration of
neuroleptics. The HVA found in plasma is produced primarily
by brain DA neurons and peripheral noradrenergic (NA)
neurons. Secondary sources of HVA are peripheral DA and
brain NA neurons. Animal and human studies suggest that
brain DA turnover can be reflected by plasma HVA (pHVA)
concentrations (22, 23). Although the precise proportion of
pHVA deriving from brain HVA has not been fully elucidated
(24), measurement of this DA metabolite in plasma of
schizophrenic patients appears to be a valid method to
investigate DA in this disorder provided certain conditions are
met.

For example, highly consistent findings have been produced

when HVA is measured in plasma prior to and during
neuroleptic treatment in schizophrenic patients. All studies
found chronic neuroleptic treatment to lower pHVA, and all
found this decrement to relate to treatment outcome (Table 1).
Moreover, six out of eight studies found higher pretreatment
pHVA concentrations to be related to good neuroleptic
treatment response (Table 2). When HVA is measured during
the steady state, however, less consistent results have been
generated: pHVA differentiates patients from controls only in
some studies, and results of studies trying to link pHVA
concentrations to specific schizophrenic symptoms, or even to
severity of illness, have been inconsistent (Table 3).

Thus, while the results when HVA is used as an indication of

baseline DA function are conflicting, when HVA is used as an
index of change in DA function the results are quite consistent.
This may be the result of the relatively large changes in HVA
production when DA activity is manipulated as compared to
the steady state. For instance, when striatal HVA is reduced
(after administration of apomorphine) by about a third, pHVA
decreases by about 25% in rodents (22); when HVA increases
fourfold (after administration of haloperidol) in striatum, it
almost doubles in plasma of rats (25). A single administration
of haloperidol roughly doubles pHVA concentrations in human
subjects (26). Thus, the changes induced by perturbation of DA
function lead to large changes in both central and peripheral
HVA concentrations. Possibly, when DA function is
manipulated, the changes that occur are profound enough to
be detected in metabolite concentrations in plasma. In contrast,
when steady-state DA function is assessed, DA metabolite
concentrations may be much more prone to multiple
confounding factors (27).

MODULATION OF DA SYSTEMS IN ANIMALS

The distribution and development of the DA system in
primates have recently been elucidated. This may indirectly
help to understand the role of DA in schizophrenia (see ref. 28).
In contrast to those in rodents, DA fibers in adult monkeys are
widespread in every cortical region, although they are most
pronounced in layers I and III (28). Neonatal monkeys,
however, display a more uneven distribution of DA fibers—
that is, fewer DA axons in layers III–VI. Axonal growth in
these layers takes place during the first 2–3 months of life, so
that in early adult life the distribution of DA fibers resembles
that in adult monkeys. Interestingly, in monkeys that have
been socially isolated since birth, the neuronal growth in layers
III–VI appears to have been stunted (29), suggesting that early
age is critical for the normal development of DA neuronal
networks.

MODULATIONS OF DA SYSTEMS IN HUMANS

Evidence for Cortical Hypofunction

Anatomical Imaging Studies

Multiple studies using computerized tomography (CT) have

found evidence of enlarged ventricles in schizophrenic patients
as compared to healthy controls (for a review see ref. 30).
These studies provide only nonspecific evidence of diminished
brain tissue. With the advent of magnetic resonance imaging
(MRI), evidence of more localized abnormalities have
materialized. Decreased volume of the frontal and temporal
cortex have been found as well as decreased volume of the
hippocampus, although the findings have not been consistent
(see ref. 30). Differences in results may depend on imaging
techniques (resolution of MRI scanners) including the slice
thickness of the images. The potential significance of these
findings can best be viewed in relation to functional imaging
studies.

Functional Imaging Studies

Decreased function of the frontal lobes has been repeatedly

demonstrated with both measurements of cerebral blood flow
as measured by single photon emission computerized
tomography (SPECT) and positron emission tomography
(PET) (for a review see ref. 31). In a cognitive task linked to
frontal lobe function, the Wisconsin Card Sort Task (WCST),
schizophrenic patients failed to show an increase in cerebral
blood flow to the same degree as normal controls (32). Facility
at this task has been associated with the dorsolateral prefrontal
lobe. Similarly, schizophrenic patients showed decreased blood
flow and activation of the left mesial frontal cortex on
performing the "Tower of London" task (31). This lack of
activation and decreased blood flow was similar in drug-naive
and medicated patients, but occurred only in patients with high
negative symptoms scores (31). Indeed, negative
symptomatology has been associated with prefrontal
hypometabolism (33). Furthermore, decreased frontal blood
flow is not related to medication effects (34). Hence, frontal
hypofunction seems a key feature of schizophrenia,
particularly to patients with prominent negative or deficit
symptoms. However, a critical question is whether the findings
of decreased volume and function of the prefrontal cortex in
schizophrenia have any relationship to the role of DA in
schizophrenia. Obviously, atrophy of the frontal cortex could
affect various neurotransmitter systems. Similarly, decreased
function of the PFC may be the result of hypofunction of
multiple neurotransmitters. However, several lines of evidence
suggest that decreased function of the PFC may be related to
decreased activity of mesocortical DA neurons.

Relationship Between Cerebrospinal Fluid HVA (CSF HVA)

and Function of the PFC

Indirect evidence has suggested that cortical hypofunctionality

is associated with diminished cortical DA activity. For example,
a strong positive correlation was found between the ability to
activate the PFC (on the Wisconsin Card Sort Test) and CSF
HVA concentrations (32). Indeed, cognitive deficits attributed
to activity of the frontal cortex, such as WCST performance,
were associated with lowered CSF HVA concentrations,
suggesting a relationship between decreased DA function and
impaired frontally mediated cognitive function (35). Moreover,
blood flow in the prefrontal cortex increases in schizophrenic
patients after administration of the DA agonists amphetamine
(36) and apomorphine (37), suggesting that the hypofrontality
found in schizophrenic patients can be redressed by increasing
DA activity in the PFC. The increase in prefrontal blood flow
after amphetamine also correlated significantly with improved
performance on the WCST (36), indicating that increasing DA
activity improves a cognitive deficit linked to diminished
prefrontal cortical activity.

Effect of DA Agonists on Negative Symptoms

If negative symptoms were related to decreased function of the

mesocortical DA system, one would expect treatment with DA
agonists to improve negative symptoms of schizophrenia.
Various studies have attempted to improve schizophrenic
symptoms by increasing DA activity. Most have failed to find
clinically meaningful effects (see ref. 38). However, recently the
DA reuptake inhibitor, mazindole (2 mg/day), improved
negative symptoms as compared to placebo (39). In that study,
mazindole or placebo were added to neuroleptic treatment
after patients had been stabilized on neuroleptic for 4 weeks.
However, well-controlled large studies are needed to explore
the efficacy of increasing DA activity in the negative symptoms
of schizophrenia, although the data reviewed here certainly
encourage such an approach.

Conclusion

In summary, evidence suggests that the negative symptoms and

some of the cognitive deficits of schizophrenia may be related
to decreased PFC function which, in turn, based on indirect
evidence, may be associated with decreased mesocortical DA
activity.

Evidence for Subcortical Hyperfunction

Increased DA activity of the subcortical, striatal DA neurons

has been the basis of the original DA hypothesis. Although
unlikely to be the only, or even the main, dopaminergic
abnormality in schizophrenia, some evidence does suggest that
increased striatal or mesolimbic DA activity is related to some
schizophrenic symptoms. Increased activity in those areas is
suggested by anatomical and functional imaging studies and
more indirectly by measurement of pHVA.

Anatomical Imaging Studies

Only very recently have imaging studies been able to focus on

volumetric measurement of the subcortical structures with the
availability of high-resolution MRI scanners with section
thickness of 3 mm. Increased volume of the left caudate
nucleus has been described in a study comparing 44
schizophrenic patients with 29 healthy controls (40). This effect
may be medication-related, because it was not found in
neuroleptic-naive patients but, instead, appeared only after
patients had been receiving neuroleptic treatment.

Functional Imaging Studies

In vivo measurement of D2 receptor affinity in humans, using

PET, has provided conflicting results. An increase in D2
receptor numbers in striatum of 10 neuroleptic-naive
schizophrenic patients has been reported, using
[11C]methylspiperone as a D2 ligand (41). In contrast, D2
receptor density was not different in 15 (42) and 18 (43)
similarly drug-naive schizophrenic patients as compared to
normal controls when studied with [11C]raclopride. Similarly,
when [76Br]bromospiperone was used to compare D2 receptor
density in 12 schizophrenic patients (who were either drug-
naive or at least 1 year drug-free) with 12 controls, no group
differences in D2 receptor density were found (44).
Interestingly, the more acutely ill patients had higher D2
receptor density in the striatum than did the more chronically
ill patients and higher than the control subjects, suggesting
that DA2 receptor density may be state-dependent. Part of
these conflicting data may be due to the ligand used. For
instance, methylspiperone, but not raclopride, binds potently
to 5HT2 receptors. Moreover, the methods with which PET
data were analyzed varied across studies. In addition, as the
study using [76Br]bromospiperone suggests, differences in
patient population may partly explain the different D2 receptor
densities found in schizophrenic patients. Finally, the ligands
used occupied different populations of DA receptors, and they
may therefore point toward an increase in number in only the
receptors occupied by methylspiperone but not raclopride.

pHVA and the Mechanism of Action of Neuroleptics

The relationship between pHVA concentrations and
neuroleptic treatment response suggests an association between
the effects of neuroleptics on DA activity and treatment
outcome (Table 1). Neuroleptics initially increase (45) and
subsequently decrease pHVA concentrations (49!popup(ch113,
50, 51, 52, 53). Both the initial increase and the subsequent
decrease by neuroleptics are associated with clinical response.
Interestingly, increased pretreatment pHVA concentrations (49,
50, 52, 53), 54 but also see refs. 45) and 55) are predictive of
good treatment response to neuroleptics. Conversely, clinical
decompensation after discontinuation of neuroleptic is
associated with increases in pHVA levels (56, 57, 58). Thus,
pHVA studies suggest that neuroleptics initially increase and
subsequently decrease DA activity. This is consistent with
studies in rodents where, in the nigrostriatal (A9) and
mesolimbic (A10) DA systems, a single dose of a neuroleptic
increases DA neuron firing (59) while chronic (3–4 weeks)
neuroleptic administration decreases DA neuron firing in A9
and A10 below pretreatment levels. Interestingly, atypical
neuroleptics—that is, antipsychotics that do not induce
extrapyramidal side effects, such as, for instance, clozapine—
are anatomically more selective in their effect on DA neuronal
firing than typical neuroleptics in that they decrease DA
activity in A-10 only (59). On the basis of these data, it has been
proposed that decreased activity in A9 is responsible for
induction of extrapyramidal side effects, while in A10 it leads
to the antipsychotic effects of neuroleptics (59).

The effects of clozapine on pHVA are less clear-cut than those

of typical neuroleptics. Clozapine treatment decreased pHVA
concentrations with larger decrements associated with good
treatment response (60). However, in another study the effect
of clozapine on pHVA was less robust, although treatment
responders tended to show a decrement in pHVA while
nonresponders did not (57). A complicating factor in examining
clozapine's effect on pHVA concentrations is the fact that,
unlike typical neuroleptics such as haloperidol (Davidson,
unpublished results) and fluphenazine (60), it increases plasma
norepinephrine (NE) concentrations. Because about one-third
of NE is metabolized into HVA in the peripheral nervous
system (24), the clozapine-induced increase in plasma NE
(pNE), may partially overshadow a possible lowering effect of
clozapine on pHVA. Consequently, measurement of pHVA as a
reflection of clozapine's effect on (central) DA turnover may be
compromised by its concomitant opposite effect on NE
metabolism. Therefore, a relationship between symptom
improvement on clozapine and its effects on pHVA could be
obscured by this potent effect of clozapine on pNE.

pHVA and Positive Symptoms

Studies examining a relationship between steady-state pHVA

and schizophrenic symptoms have been less consistent than
studies examining the effect of neuroleptic treatment on pHVA
(Table 3). Four studies have found a positive correlation
between pHVA levels and clinical severity (27, 46, 61, 62), while
three studies did not (47, 53, 63). The most likely explanation
for the different results across studies is the number of pHVA
samples taken as a basis for the correlational studies. The
studies employing more than one sampling of pHVA found
significant positive correlations between pHVA and severity of
symptoms, whereas studies using one single measurement of
pHVA did not. The studies producing significant correlations
between pHVA and severity of schizophrenic symptoms
averaged two (27), three (46), four (61), or thirteen (62) pHVA
samples, whereas the studies that produced negative findings
assessed pHVA only once (47, 53, 63). Repeated pHVA
measurements in the same individual therefore appears to
increase the signal/noise ratio for pHVA by reducing the intra-
individual variance in pHVA concentrations (see also
Schizophrenia and Glutamate).

Postmortem Studies

Although HVA and DA concentrations in postmortem brains of

schizophrenic patients consistently show patient–control
differences, the localization of these differences are not
consistent. Increased HVA concentrations in schizophrenic
patients have been found in caudate and nucleus accumbens
(64) and cortex as compared to normal brains. The difference
in caudate was attributable to prior medication history, while
the finding in accumbens only applied in the medication-free
patients. Similarly, although DA was found to be increased in
nucleus accumbens in schizophrenic patients compared to
controls (65), another study found increased DA in the caudate
of schizophrenic patients, but not in nucleus accumbens (66).
Finally, increased DA has been found in the amygdala of
schizophrenic patients, mostly in the left hemisphere (67).
These inconsistencies may be due to differences in medication
status of the patients studied, varying analytical and statistical
methods used, and, finally, genuine variability in the location
of DA abnormalities in schizophrenia.

Receptor affinity studies have found increases in D2, but not

D1, receptors in the striatum of schizophrenics (68, 69, 70, 71,
72; see Table 4). Although these results could have been a result
of prior medication use, most studies show that those patients
who were neuroleptic-free for at least 1 year prior to study or
were drug-naive still have increased striatal D2 receptors.
Moreover, a bimodal distribution of D2 receptor numbers in
brains of schizophrenic patients indicates that neuroleptics do
not uniformly increase D2 receptor numbers (68). That
neuroleptic treatment alone cannot explain the increased D2
receptor affinity in schizophrenia is also suggested by
postmortem studies in other patient groups treated with
neuroleptics: Patients with Alzheimer's disease and
Huntington's disease who had been treated with neuroleptics
prior to death showed increases in striatal DA receptors of only
25% as compared to controls, whereas schizophrenics had
greater than 100% increases (68). Thus, the available data
indicate that D2 (but not D1) receptor density is increased in
schizophrenia, and that this finding cannot be accounted for by
medication history alone.

D4 receptors have also been reported to be elevated in

postmortem schizophrenic brain in subcortical regions (73).
Because a selective D4 ligand was not used in this study,
subtraction of two different ligands was used to infer the D4
receptor number. The differences found between schizophrenic
and controls was quite robust, but awaits confirmation (see all
Cytochrome P450 Enzymes and Psychopharmacology).

Conclusion

Increased striatal DA activity has not been demonstrated

directly in schizophrenia. Postmortem and in vivo receptor
binding studies provide some, but not consistent, evidence that
striatal DA function is increased, while studies examining
pHVA prior to and after neuroleptic treatment only provide an
indirect suggestion that modulatory DA activity in
schizophrenia can alter symptomatology. pHVA appears to be a
useful indicator of central DA activity, and studies examining
pHVA justify the following conclusions: (a) Increased DA
turnover is related to good response to neuroleptic treatment,
and (b) neuroleptic treatment decreases DA turnover, and this
effect is related to treatment response.

Temporal Lobe Function and Dopamine

An increasing number of MRI studies indicate abnormalities in
the temporal lobes (more pronounced on the left side) in
schizophrenic patients. Decreases of 10% in total temporal lobe
volume (74) or 20% of temporal lobe gray matter have been
found, present at first episode (75). Interestingly, the
abnormalities of the temporal cortex in schizophrenia appears
to be associated with specific positive symptoms, such as
auditory hallucinations (76) and thought disorder (77).
Additional, indirect evidence that the temporal lobes are
associated with (positive) schizophrenic symptoms is the
discovery that stimulation of the superior temporal gyrus (left
and right) elicits auditory experiences (78) and that psychotic
symptoms in temporal lobe epilepsy patients appear related to
anatomical abnormalities in the medial temporal lobe
(established at postmortem examination) (79). Although
speculative, since increased D2 receptor binding has been
found in the temporal cortex of brains of schizophrenic
patients (80), the abnormalities found in the temporal cortices
of schizophrenic patients and its association with some of the
schizophrenic symptoms may be related to dysfunctional DA
systems in those areas. These findings are particularly
provocative in light of the fact that hippocampal lesions to rat
pups produces subcortical hyperdopaminergia and an
enhanced stress response at adulthood (81).

Frontal Cortical DA Function and Negative Symptoms

Negative Symptoms and Cortical Function

The negative or deficit symptoms—that is, decreased social

interaction, apathy and avolition—are considered to be core
symptoms of schizophrenia. Indeed, Bleuler proposed that
deficit state symptoms represent pathognomonic signs of
schizophrenia and are at the root of the poor social and work
function that characterize people with chronic schizophrenia.
Primate studies suggest that insufficient frontal cortical
functioning is responsible for poor social skills: Monkeys with
frontal lobe ablations not only have an inability to suppress
irrelevant stimuli, poor concentration, and impaired delayed
response testing, but also exhibit the poor social function that is
reminiscent of deficit state symptoms which characterize
schizophrenia (82).

Only a handful of studies have directly attempted to link

decreased activity of the PFC in schizophrenia with negative
symptoms. Decreased activation of the PFC as measured by
SPECT was only found in schizophrenic patients with
predominantly negative symptoms (31). Furthermore, negative
symptoms were associated with decreased frontal blood flow as
assessed by PET (33). Although preliminary, these data do
suggest a link between negative symptoms and impaired
cortical function in schizophrenia.

There are data indicating that frontal lobe dysfunction can be

associated with psychotic symptoms. Evidence of frontal lobe
damage leading to abnormal behaviors strikingly similar to
some of the more persistent symptoms observed in
schizophrenia can be found in anecdotal and case series
describing (a) patients with frontal lobe injury and (b)
primates with frontal lobe ablations (e.g., see ref. 83). Although
there is great individual variation in the severity and constancy
of the symptoms that emerge in patients even with severely
damaged frontal lobes, some of these bear a remarkable
resemblance to the deficit state symptoms in schizophrenia.
For example, orbitofrontal and anteromedial lesions can
produce flattened affect.

That negative symptoms are associated with decreased DA

function (in the mesocortical DA system) is suggested
indirectly. pHVA concentrations levels were lower in chronic,
treatment refractory schizophrenic patients than in normal
subjects (62). Treatment with the DA reuptake blocker,
mazindole (35), or with the DA agonist, SKF393939 (84),
appears to ameliorate negative symptoms in some
schizophrenic patients. Although indirect, these data imply that
decreased DA activity can modulate negative symptoms in
schizophrenia.

Negative Symptoms and Decreased Frontally Mediated

Cognitive Function

Schizophrenic patients perform poorly on cognitive tests that

are thought to depend on activation of the PFC, such as the
WCST (e.g., see ref. 32) and the "Tower of London" (31).
Animal studies suggest that some of these cognitive deficits
may be due to decreased mesocortical DA activity: (a) Surgical
ablation of the PFC or selective destruction of mesocortical DA
neurons in monkeys impaired performance of the spatial
delayed-response task, a test thought to depend on activation of
the frontal cortical areas in monkeys (85); (b) iontophoretically
applied DA in area 46 [corresponding to the dorsolateral
aspects of the PFC (DLPFC) in humans] improved
performance in the delayed-response task in monkeys (86); and
(c) administration of D1 antagonists dose-dependently
produced deficits in performance during the delayed response
task, while the selective D2 antagonist raclopride did not (86).
Because the terminals of the mesocortical DA system consists
of the D1 (and likely D5) receptor subtype (87), these findings
suggest that the mesocortical DA system is important for
memory and retrieval functions in high-order primates, and by
inference in humans as well. These data are consistent with the
notion that the decreased cognitive performance on frontally
mediated tasks in schizophrenia may be the result of decreased
activity of the mesocortical (D1/5) system. Indeed, single-dose
administration of DA agonists, such as apomorphine and
amphetamine, ameliorate cognitive performance on frontally
mediated tasks (36). Studies examining the effect of selective
D1/5 agonists on cognitive function in schizophrenia have yet
to be conducted.

Andreasen et al. (31) and Wolkin et al. (33) demonstrated that

these cognitive deficits occur predominantly in negative-
symptom schizophrenics. By inference, the cognitive deficits
and negative symptoms in schizophrenia may both be related
to decreased mesocortical DA function.

Therapeutic Implications

DA1 Agonists: Increasing DA Function in Cortex?

The persistent symptoms of schizophrenia appear to be the

deficit state symptoms rather than the positive symptoms and
appear to be related to decreased DA function in the cortex
rather than being related to increased DA activity in the
subcortical regions. Thus, it is not surprising that these
symptoms are resistant to treatment with DA antagonists.
Indeed, one would expect these symptoms to be amenable to
treatment with DA agonists with cortical selectivity. Because
mesocortical DA neurons are primarily of the D1 and D5 type,
it can be hypothesized that selective D1 or D5 agonists would
be particularly helpful for these symptoms. Moreover,
consistent with the finding by Jaskiw et al. (88) that increasing
prefrontal cortical DA activity reduces striatal DA activity, D1
or D5 agonists would be expected to decrease the hypothesized
increased DA activity in subcortical DA neurons and thus be
useful (in combination with traditional D2 antagonists) in the
treatment of acute psychoses as well. Preliminary data from
treatment of nonresponsive patients treated with mazindole or
SKF39393 are consistent with this notion (39, 84).
To treat both positive and negative symptoms of schizophrenia,
a balance between increasing DA activity at D1/5 receptors and
decreasing it at D2, D3, or D4 receptors may be needed. Studies
examining such combination treatments, using selective D1
agonists and D2, D3, or D4 antagonists, have yet to be
conducted, but promise to be scientifically and possibly
practically fruitful.

5HT2 and 5HT3 Antagonists: Roles in Regulating DA Function

It would be overly simplistic to hypothesize that the

pathophysiology of schizophrenia is only dopaminergic in
nature. Several authors have suggested that it may be
abnormalities in the interaction between monoaminergic
systems in general and between serotonin (5HT) and DA
systems in particular (38), rather than abnormalities in any
one system, that is relevant to the pathophysiology of
schizophrenia. Indeed, it is particularly difficult to discuss DA
without mentioning its interactions with 5HT. Both
neurotransmitter systems are highly intertwined, anatomically
and functionally, with 5HT having an inhibitory modulation on
DA function (89). Moreover, human studies consistently find
high correlations in CSF between the DA and 5HT metabolites
HVA and 5-hydroxyindolic acid (5HIAA), respectively (see ref.
90). This appears to be the result of a functional interaction,
with 5HIAA "controlling" HVA (90), and is not due to a shared
transport mechanism (91).

Blockade of 5HT receptors diminishes extrapyramidal side

effects induced by DA antagonists. Indeed, ritanserin, a
selective 5HT1c/2 antagonist, significantly reduced
extrapyramidal side effects when added to neuroleptic
treatment in schizophrenic patients in several placebo-
controlled, double-blind studies (92). Thus the addition of
5HT2 antagonism to DA2 receptor blockade may lead to
decreased extrapyramidal side-effect potential of DA receptor
blockade. Although more speculative, it has also been
suggested that blockade of 5HT2 (38) or 5HT1c (89) receptors
mediates, in part, the superior clinical efficacy of clozapine.

Another interesting relationship is the one between 5HT3

systems and DA function. For instance, 5HT3 antagonists fail
to alter basal DA activity, but they reverse the increase in DA
release that results from behavioral and biological stressors
(93, 94). This may have important implications for the
treatment of schizophrenia and schizophrenia spectrum
disorders. If 5HT3 antagonists prevent stress-induced increases
in DA activity, these drugs would be particularly useful in the
prevention of relapse in schizophrenic patients and may also
have a role in patients that are prone to display psychotic
decompensations, such as borderline personality disorders.

FUTURE DIRECTIONS

The explosion in knowledge concerning DA in general, and its

possible role in modulating the symptoms of schizophrenia in
particular, offers rich ground for drug development and for
further elucidating the biology of schizophrenia and its
symptomatology. The following seem to be particularly exciting
directions.

1. The development of drugs with selectivity for frontal cortical

regions could be a viable approach to the treatment of the
negative or deficit symptoms of schizophrenia. Dopamine D1
or D5 receptors would be most appropriate targets.

2. The development of specific D4 antagonists will be an

important test of the centrality of this DA receptor subtype in
alleviating the positive symptoms of schizophrenia, and it will
further our understanding of the relatively unique properties
of clozapine.

3. The role of the corticostriatal glutamatergic pathway and its

likely role in mediating the reciprocal relationship between
cortical and subcortical dopaminergic activity needs to become
a target for investigation both in antemortem and postmortem
protocols. With the generation of new antibodies for the
glutamatergic receptors, the latter may be a particularly
worthwhile pursuit.

4. The importance of stress in precipitating subcortical

hyperdopaminergia following lesions to the cortex has obvious
implications for understanding the initiation of schizophrenic
symptoms. Studies in schizophrenic patients that attempt to
rigorously document stressful events in a longitudinal context,
and correlate them with changes in dopaminergic parameters
as well as with symptom fluctuation, would be particularly
informative.

5. Some link must be sought between the morphometric

abnormalities that have been found in postmortem
examination of schizophrenic tissue and the bidirectionality of
dopaminergic systems.

With the inevitable conduct of the above investigations, real

advances in testing the validity of current conceptualizations
regarding DA and schizophrenia will finally be made.

Schizophrenia is a major therapeutic challenge of modern

medicine, and one of the last frontiers of brain research. The
illness is defined by delusions, hallucinations, disorganized
behavior, and cognitive difficulties such as memory loss. It
occurs in 1% of the world population and usually first appears
in early adulthood. Although antipsychotic medications have
dramatically improved the lives of patients with schizophrenia,
the causes of the illness remain unknown.

Of the many contemporary theories of schizophrenia, the most

enduring has been the dopamine hypothesis. As originally put
by Van Rossum in 1967 (ref. 1, p. 321), "When the hypothesis
of dopamine blockade by neuroleptic agents can be further
substantiated, it may have fargoing consequences for the
pathophysiology of schizophrenia. Overstimulation of
dopamine receptors could be part of the aetiology ... [emphasis
added]." Indeed, this speculative sentence by Van Rossum
foreshadows the title of the important work by Abi-Dargham
et al. (2) in this issue of PNAS: "Increased baseline occupancy
of D2 receptors by dopamine in schizophrenia."

The discovery of the antipsychotic/dopamine receptor (3, 4),

now commonly known as the dopamine D2 receptor, led to
repeated confirmation that it is the primary site of action for
all antipsychotics (3-5), including clozapine and quetiapine (6).
All these drugs have different potencies at the receptor. The
potency depends on the drug's dissociation constant at D2,
which, in turn, relates to the rate of release of the drug from
the D2 receptor. For example, the dopamine D2 receptor
releases clozapine and quetiapine more rapidly than it does any
of the other antipsychotic drugs (7, 8).

Given the tight correlation between the clinical potency and

the D2-blocking action of the antipsychotic medications,
dopamine overactivity could be the common denominator in
the psychotic element of schizophrenia. This possibility has
been actively investigated. Dopamine overactivity can be
presynaptic (an excess of dopamine release from dopamine
nerve terminals) or postsynaptic (an increase in the density of
D2 receptors or an increase in postreceptor action). The
innovative report by Abi-Dargham et al. (2) sheds light on both
pre- and postsynaptic aspects by using an indirect method to
measure the levels of endogenous dopamine in patients and
controls.

Although numerous postmortem studies have consistently

revealed D2 receptors to be elevated in the striata of patients
with schizophrenia (9), the majority of the postmortem tissues
examined have come from patients who have been treated with
antipsychotics, raising the probability that the drugs
themselves contributed to the elevation of D2 receptors. To
measure the density of D2 receptors in never-medicated
patients with schizophrenia, D2-selective ligands have been
used with in vivo brain imaging methods (10-12). The results
have not been consistent. Data with [11C]methylspiperone
show elevated D2 receptors in schizophrenia (ref. 10, but see
also ref. 12), whereas data with [11C]raclopride do not show
such elevation (ref. 11 and discussed later in this paper). One
major reason for this discrepancy is the quantitatively different
effects of endogenous dopamine on [11C]methylspiperone and
[11C]raclopride (see references in ref. 7).

Hence, one way to resolve this discrepancy is to measure D2

receptors after partial depletion of endogenous dopamine in
patients. The work of Abi-Dargham et al. (2) provides this
resolution. Fig. 1 summarizes the principle used by Abi-
Dargham et al. Fig. 1 (Top) illustrates that the radiobenzamide
(S)-()-3-[123I]iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-
pyrrolidinyl)methyl]benzamide ([123I]IBZM) binds to the
same number of D2 receptors in control and schizophrenia
individuals. That is, the "binding potential" was the same in
both sets of subjects. However, after partial depletion of
endogenous dopamine by oral ingestion of -methylparatyrosine
over 2 days, the binding of [123I]IBZM rose by 19% in
schizophrenia but only by 9% in control subjects (Fig. 1,
Bottom). In fact, when Abi-Dargham et al. examined the
number of D2 receptors after partially removing the obscuring
effect of endogenous dopamine, the D2 receptors were
significantly elevated in schizophrenia patients as compared
with control subjects. When the authors examined the data by
subgroups, the results of increased receptors reached
significance for previously medicated patients, but exhibited
only a trend for patients who had never been medicated with
antipsychotic drugs. Despite this lack of statistical significance
in this latter group of patients, the empirical findings of Abi-
Dargham et al. indicate that an increase in dopamine D2
receptors must occur, because it is not possible for patients to
show a greater increase yet not have a higher number of D2
receptors. Thus, the paper by Abi-Dargham et al. provides
support for both an increase in the level of dopamine as well as
an increase in the number of D2 receptors in schizophrenia,
compared to control subjects.

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Fig. 1. Method and findings of Abi-Dargham et al. (2) to
reveal an increased occupancy of dopamine D2 receptors in
schizophrenia. (Top) The number of dopamine D2 receptors,
measured by the [123I]IBZM binding potential (green triangles
with I), were the same in the brain striata of control and
schizophrenia subjects. The levels of synaptic dopamine (pink
triangles with D), which is higher in patients compared to
control subjects, normally occupies most of the D2 receptors,
masking the difference between control and schizophrenia
individuals. (Bottom) After partial depletion of endogenous
brain dopamine by oral ingestion of -methylparatyrosine over
2 days, the binding of [123I]IBZM rose in both the control and
schizophrenia subjects, but that for the patients rose
significantly higher.

Schizophrenia, as compared with control subjects, also is

associated with an increased releasability of dopamine (13, 14).
A high release rate of dopamine reduces the binding of
radiobenzamides to tissues (15, 16), but enhances the binding
of radiospiperone (17, 18). Competition with endogenous
dopamine, as well as dopamine-induced internalization of the
D2 receptors, may account for the lessened binding of
radiobenzamides to the tissue (13, 14), because the benzamides
are generally water-soluble and have less ready access to
vesicle-associated receptors. Radiospiperone compounds, by
contrast, are highly lipid-soluble and readily permeate cell
membranes to reach internalized receptors.

In addition to the two schizophrenia-associated factors of

increased D2 receptors and increased dopamine release, there
is a third factor. Dopamine D2 receptors exist in monomer,
dimer, and oligomeric forms (19). The D2 monomer, but not
the D2 dimer, is selectively labeled by a photolabel of
radiospiperone (19). This finding is in contrast to a benzamide
photolabel (for nemonapride), which readily binds to both
monomers and dimers of D2 (19). This important distinction
between benzamides and butyrophenones may explain why
more D2 receptors are detected in schizophrenia (as compared
to controls) by radiospiperone, even without depletion of
endogenous dopamine. This finding is illustrated in Fig. 2,
where the control individual has three D2 receptors, two in the
dimer form and one in the monomer form. It is proposed that
in schizophrenia, under the influence of increased release of
endogenous dopamine, all three exist in the monomer form.
Thus, radioraclopride binding would show no difference, but
the binding of radiospiperone would be higher in the
schizophrenia brain (as compared to controls) because of an
increased number of monomers.

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Fig. 2. Possible model to account for the increased
number of dopamine D2 receptors in schizophrenia seen with
[11C]methylspiperone but not with [11C]raclopride. It is
known that the photolabel of spiperone
([125I]azidophenethylspiperone) primarily or selectively labels
monomers of D2 receptors, whereas the benzamide photolabel
([125I]azido-iodo-nemonapride) unselectively labels
monomers, dimers, and oligomers of D2 receptors (see text).
These findings suggest that even if there is no increase in the
total population of D2 receptors in schizophrenia, an increase
in the proportion of monomers caused by the increased level of
dopamine in schizophrenia (see Fig. 1) would result in an
increase in the binding of [11C]methylspiperone (red triangle
with S) in schizophrenia but not with [11C]raclopride (white
triangle with R).

The dopamine hypothesis has been much criticized. For

instance, although therapeutic doses of most antipsychotics
occupy 60% to 80% of the D2 receptors in patients, clozapine
and quetiapine have been apparent exceptions, exhibiting
clinical efficacy with only 10% to 45% occupation of D2
receptors (see references in ref. 7). It therefore has been
suggested that the dopamine hypothesis of schizophrenia be
extended into a serotonin-dopamine hypothesis. However,
recent work on imaging both D2 and serotonin-2 receptors in
patients taking antipsychotics fails to find evidence for a
contribution from the occupation of serotonin receptors (20).
For example, the threshold for clinical antipsychotic action
remains at 65% occupation of D2 receptors in first-episode
patients, whether one uses haloperidol, which has no serotonin-
receptor blocking action, or risperidone or olanzapine, which
block all serotonin-2 receptors but at doses far below those
needed for clinical efficacy. Similarly, the threshold for
extrapyramidal signs, which is 80% D2 occupancy, remains
unaltered despite the presence of 100% block of serotonin-2
receptors for risperidone or olanzapine. It should also be noted
that therapeutic doses of clozapine and quetiapine transiently
occupy high levels of D2 receptors in patients, but the effect
lasts for only the first few hours (6). Thus, the D2-occupying
properties of clozapine and quetiapine are remarkable only for
their short duration of action; they otherwise support the
dopamine hypothesis of schizophrenia, as originally outlined
by Van Rossum (1).

There is more to schizophrenia than psychosis. The

psychological abnormalities and cognitive difficulties in
schizophrenia precede and outlive the psychosis. The
hypothesis of dopamine dysregulation is the best explanation
for the psychotic episode in schizophrenia; the pathophysiology
of other psychological and cognitive abnormalities in
schizophrenia remains unclear. A combination of susceptibility
genes (21) and other factors contributes to schizophrenia, and
the net result dysregulates the dopamine neurotransmission
system, leading to high release of dopamine, more D2
receptors, and an apparent predominance of monomer forms
of D2. This dopamine dysregulation leads to the psychotic
episode. Further research needs to uncover underlying
mechanisms that predispose the brain to the dysregulation of
the dopamine system (22). Until then, the dopamine hypothesis
remains the main path to the origin and treatment of clinical
signs and symptoms of psychosis in schizophrenia.

Schizophrenia

First, let's discuss what schizophrenia is not. People who have

schizophrenia do NOT have multiple personalities. In 1911,
Eugen Bleuler, first used the word "schizophrenia." Although
the word schizophrenia does come from the Greek words
meaning "split" and "mind," people with schizophrenia do not
have split personalities. This misunderstanding has caused
many people to misuse the term schizophrenia. The "split
mind" refers to the way that people with schizophrenia are
split off from reality; they cannot tell what is real and what is
not real. Contents of this Page
Who has schizophrenia?
Symptoms
Causes
Treatment
References

Who has schizophrenia?

Schizophrenia is one of the most common mental illnesses.
About 1 of every 100 people (1% of the population) is affected
by schizophrenia. This disorder is found throughout the world
and in all races and cultures. Schizophrenia affects men and
women in equal numbers, although on average, men appear to
develop schizophrenia earlier than women. Generally, men
show the first signs of schizophrenia in their mid 20s and
women show the first signs in their late 20s. Schizophrenia has
a tremendous cost to society, estimated at $32.5 billion per year
in the US (statistic from Brain Facts, Society for Neuroscience,
2002).
What are the symptoms of schizophrenia?
The behavior of people with schizophrenia is often very strange
and shocking. This change in behavior, when people cannot tell
the difference between what is real and what is not, is called
"psychosis" or a "psychotic episode." The American
Psychiatric Association has published guidelines that are used
to classify people with mental disorders. The most recent
guidelines are contained in a book called the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition (known
as DSM-IV for short). The DSM-IV describes several
symptoms that a person MUST have before he or she is
classified as having schizophrenia. These symptoms include
two or more of the following behaviors for a duration of at
least one month:
Delusions - bizarre, false beliefs
These beliefs seem real to the person with schizophrenia, but
they are not real. For example, a person may believe that aliens
or spies are controlling his or her behavior, mind and thoughts.
Sometimes these delusions can be paranoid in nature. People
with paranoia have an unreal fear or suspicion that someone is
"out to get them." Delusions may also be of grandiosity. In
these cases, people believe that they are someone important,
such as a president, king or prime minister.

Hallucinations - bizarre, unreal perceptions of the environment

These hallucinations can be:
Auditory (hearing voices) - sometimes the "voices" tell a
person to do something
Visual (seeing lights, objects or faces)
Olfactory (smelling things)
Tactile (for example, feelings that bugs are crawling on or
under the skin)
Disorganized Thinking/Speech
Abnormal thoughts are usually measured by disorganized
speech. People with schizophrenia speak very little; others
have speech that is disjointed. Sometimes the person will
change the topic midway through a sentence.

Negative Symptoms - the absence of normal behavior

Delusions, hallucinations and abnormal speech indicate the
presence of abnormal behavior. Negative symptoms include
social withdrawal, absence of emotion and expression, reduced
energy, motivation and activity. Sometimes people with
schizophrenia have poor hygiene and grooming habits.

Catatonia - immobility and "waxy flexibility"

Catatonia is a negative symptom where people become fixed in
a single position for a long period of time. "Waxy flexibility"
describes how a person's arms will remain frozen in a
particular position if they are moved by someone else.

When people show any of these five symptoms, they are

considered to be in the "active phase" of the disorder. Often
people with schizophrenia have milder symptoms before and
after the active phase.

There are three basic types of schizophrenia. All people who

have schizophrenia have lost touch with reality. The three main
types of schizophrenia are:

Disorganized Schizophrenia (previously called "hebephrenic

schizophrenia") - lack of emotion, disorganized speech
Catatonic Schizophrenia - waxy flexibility, reduced movement,
rigid posture, sometimes too much movement
Paranoid Schizophrenia - strong delusions or hallucinations
What occurs in the brain?
A common finding in the brains of people with schizophrenia is
larger than normal lateral ventricles. The lateral ventricles are
part of the ventricular system that contains cerebrospinal fluid.
The picture below shows magnetic resonance image (MRI)
brain scans of a pair of twins: one with schizophrenia, one
without schizophrenia. Notice that the ventricles (red arrows)
are larger in the twin with schizophrenia. (Image courtesy of
NIMH Clinical Brain Disorders Branch.)

A reduced size of the hippocampus, increased size of the basal

ganglia, and abnormalities in the prefrontal cortex are seen in
some people with schizophrenia. However, these changes are
not seen in all people with schizophrenia and they may occur in
people without this disorder.

What are the causes of schizophenia?

There are probably multiple causes for schizophrenia and
scientists do not know all of the factors that produce this
mental disorder.
Genetics
Schizophrenia does "run in the family." In other words,
schizophrenia has an important genetic component. Evidence
for a genetic component comes from twin studies. Monozygotic
twins (identical twins) are those with exactly the same genetic
makeup; dizygotic twins (fraternal twins) are those who share
only half of their genetic makeup. If genetics was the ONLY
factor in developing schizophrenia, then both monozygotic
twins should always develop this illness.
Twin Studies
Twin studies have shown that the tendency for both
monozygotic (identical) twins to develop schizophrenia is
between 30-50%. The tendency for dizygotic (fraternal) twins
to develop schizophrenia is about 15%. The tendency for
siblings who are not twins (such as brothers of different ages) is
also about 15%. Remember, schizophrenia is found in the
general population at a rate of about 1%. Therefore, because
the tendency for monozygotic twins is NOT 100%, genetics
cannot be the only factor. However, because the tendency for
monozygotic twins to have schizophrenia is much greater than
the tendency for dizygotic twins, genetics DOES play a role.

Adoption Studies
Some studies have looked at the family background of people
who were adopted at an early age and who later developed
schizophrenia. One study (Kety et al., 1968) found that 13% of
the biological relatives of the adoptees with schizophrenia also
had schizophrenia, but only 2% of the relatives of "normal"
adoptees had schizophrenia. These studies support the role of
genetics in schizophrenia.

To learn more about the role of genetics in schizophrenia, see

the Genetics and Mental Disorders page at the National
Institute of Mental Health.

Environment
Nongenetic factors that may influence the development of
schizophrenia include: family stress, poor social interactions,
infections or viruses at an early age, or trauma at an early age.
Somehow the genetic makeup of individuals combines with
nongenetic (environmental) factors to cause schizophrenia.

Neurotransmitters
Many studies have investigated the possible role of brain
neurotransmitters in the development of schizophrenia. Most
of these studies have focused on the neurotransmitter called
dopamine. The "dopamine theory of schizophrenia" states that
schizophrenia is caused by an overactive dopamine system in
the brain. There is strong evidence that supports the dopamine
theory, but there are also some data that do not support it:

Evidence FOR the Dopamine Theory of Schizophrenia:

Drugs that block dopamine reduce schizophrenic symptoms.

Drugs that block dopamine have side effects similar to
Parkinson's disease. Parkinson's disease is caused by a lack of
dopamine in a parts of the brain called the basal ganglia.
The best drugs to treat schizophrenia resemble dopamine and
completely block dopamine receptors.
High doses of amphetamines cause schizophrenic-like
symptoms in a disorder called "amphetamine psychosis."
Amphetamine psychosis is a model for schizophrenia because
drugs that block amphetamine psychosis also reduce
schizophrenic symptoms. Amphetamines also make the
symptoms of schizophrenia worse.
Children at risk for schizophrenia may have brain wave
patterns similar to adults with schizophrenia. These abnormal
brain wave patterns in children can be reduced by drugs that
block dopamine receptors.

Evidence AGAINST the Dopamine Theory of Schizophrenia:

Amphetamines do more than increase dopamine levels. They

also alter other neurotransmitter levels.
Drugs that block dopamine receptors act on receptors quickly.
However, these drugs sometimes take many days to change the
behavior of people with schizophrenia.
The effects of dopamine blockers may be indirect. These drugs
may influence other systems that have more impact on the
schizophrenic symptoms.
New drugs for schizophrenia, for example, clozapine, block
receptors for both serotonin and dopamine.

Treatment of Schizophrenia
Medication
Drugs to treat schizophrenia are called antipsychotic
medications. This type of drug was first developed in the 1950s.
They have proved to be highly successful in treating the
symptoms of schizophrenia. The different types of
antipsychotics work best on different symptoms of the
disorders and are not addictive. The drugs are not a cure for
the disease, but they do reduce the symptoms.
Antipsychotic Drugs
Generic Name Trade Name Comments
Aripiprazole Abilify New antipsychotic medication that
may work on dopamine and serotonin systems.
Chlorpromazine Thorazine The first antipsychotic
medication developed
Chlorprothixene Taractan
Clozapine Clozaril Does not have "tardive dyskinesia" (see
below, side effects) as a side effect, but there is a 1-2% chance
of developing a low white blood cell count
Fluphenazine Prolixin A phenothiazine type drug
Haloperidol Haldol
Loxapine Loxantane NOT a phenothiazine type drug
Mesoridazine Serentil
Molindone Moban
Olanzapine Zyprexa Blocks serotonin and dopamine
receptors
Perphenazine Trilafon
Quetiapine Seroquel Blocks some serotonin and
dopamine receptors; Introduced in 1997
Risperidone Risperdal Blocks some serotonin and
dopamine receptors
Thioridazine Mellaril Also used as a tranquilizer
Thiothixene Navane
Trifluoperazine Stelazine Also used to control anxiety and
nausea

Possible Side Effects of Antipsychotic Drugs

Parkinson's disease-like symptoms - tremor, muscle rigidity,
loss of facial expression
Dystonia - contraction of muscles
Restlessness
Tardive dyskinesia - involuntary, abnormal movements of the
face, mouth, and/or body. This includes lip smacking and
chewing movements. About 25-40% of patients who take
antipsychotic mediations for several years develop these side
effects.
Weight gain
Skin problems
Counseling
Antipsychotic medications often do not reduce all of the
symptoms of schizophrenia. Also, because people with
schizophrenia may have become ill during the time when they
should have developed technical skills and a career, they may
not have the ability to become useful members of society.
Therefore, psychological therapy, family therapy and
occupational training may be used along with antipsychotic
medication to help these people get back into the community.
ScienceDaily (Apr. 25, 2007) — New research helps bridge an
important gap in understanding schizophrenia, providing the
best evidence to date that defects in the brain's white matter
are a key contributor to the disease, which affects about 1
percent of people worldwide. The findings, to be published
online by the Proceedings of the National Academy of Sciences
during the week of April 23, also demonstrate how two of the
dozen or more genes previously linked with schizophrenia may
contribute to the disease.

Prior genetic studies had linked schizophrenia to the genes for

neuregulin 1 (NRG1), a growth factor involved in brain
development, and erbB4, a receptor on brain cells through
which NRG1 exerts its action. But until now it hadn't been
shown that alterations in these genes lead to psychiatric
disorders. Working in a mouse model, researchers led by
Gabriel Corfas, PhD, Kristine Roy, PhD, and Joshua Murtie,
PhD, in the Children's Hospital Boston Neurobiology Program
now demonstrate, for the first time, that alterations in NRG1-
erbB signaling induce pathologic changes in the brain's white
matter. They further show that these changes lead to
alterations in biochemical signaling and to behaviors
suggestive of mental illness.
"We show that causing a defect in white matter is sufficient to
cause biochemical and behavioral changes resembling those
seen in neuropsychiatric disorders," says Corfas, the study's
senior author. "I think this will provide a new way of thinking
about the causes of, and possibly, therapies for schizophrenia."

The findings could also have implications for bipolar disorder,

which has also been linked with NRG1 and also involves white
matter defects, he adds.

Working with mice, the researchers blocked NRG1-erbB

signaling in oligodendrocytes --the cells that form the fatty
sheath, known as myelin, which insulates nerve fibers. These
myelinated nerve fibers make up the brain's white matter.
When NRG1-erbB signaling was blocked, the mice had more
oligodendrocytes than normal mice, but these cells had fewer
branches and formed a significantly thinner myelin sheath
around nerve fibers. As a result, the nerve fibers conducted
electrical impulses more slowly, the researchers found.

The mice also had changes in the nerve cells that make and use
dopamine, a key chemical in the brain that transmits messages
from one nerve cell to another. The dopamine system has long
been known to be altered in schizophrenia, and is the target of
many antipsychotic drugs.

"Changing the white matter in the brain apparently

unbalanced the dopamine system, something that also occurs
in patients with neuropsychiatric disorders," says Corfas.

Finally, mice whose NRG1-erbB signaling was blocked showed

behavioral changes that appeared to be consistent with mental
illness. They explored their environment less than normal mice
and had reduced social interaction, thought to be a
manifestation of so-called "negative" schizophrenic symptoms
such as decreased initiative and social withdrawal. The mice
also showed behaviors suggestive of anxiety, a symptom seen in
patients with schizophrenia and bipolar disorder, and
increased sensitivity to amphetamine, also seen in many
schizophrenia patients.

Is it possible to modify NRB1-erbB signaling with drugs, or

otherwise protect oligodendrocytes (and white matter) as a way
of treating or preventing schizophrenia?

"This is something that should be investigated," says Corfas.

"People are thinking about ways to repair white matter as a
treatment for multiple sclerosis, which is also a disease of white
matter. That research could now be used in thinking about
neuropsychiatric disorders."

Schizophrenia is typically diagnosed in late adolescence or

early adulthood, but it is almost always preceded by subtle
affective, cognitive or motor problems, Corfas adds. "We need
to investigate whether the white-matter defects emerge early,
before psychotic symptoms are evident," he says. "If they do,
that raises the possibility of early diagnosis and preventive
treatment."

The idea of schizophrenia arising from white-matter defects

may also help explain the timing of its emergence, Corfas
notes. Recent evidence suggests that myelination of the
prefrontal cortex (a brain area that has been implicated in
schizophrenia) occurs not only during infancy and
toddlerhood, but also during late adolescence or early
adulthood -- just when schizophrenia strikes.

"We now need to go back to patients with schizophrenia and

see whether those with variants of the NRG1 and erbB4 genes
have differences in their white matter," Corfas says. "It may be
that there are different kinds of schizophrenia, arising from
alterations in different genes, and that directed treatments
could be developed for the different forms."

Corfas and colleagues also plan to investigate other genes

linked with schizophrenia, studying whether they interact with
NRG1-erbB signaling and how they may alter brain function.

The research was funded by the National Institute of

Neurological Disorders and Stroke (NINDS), the National
Multiple Sclerosis Society, the National Institute of Mental
Health (NIMH), NARSAD: The Mental Health Research
Association, and an NIH Development Disability Research
Center Grant.

Adapted from materials provided by Children's Hospital

Boston, via EurekAlert!, a service of AAAS.
Need to cite this story in your essay, paper, or report? Use one
of the following formats:
APA

MLA
Children's Hospital Boston (2007, April 25). Understanding
Schizophrenia: How Genetics, White-matter Defects,
Dopamine Abnormalities And Disease Symptoms Are
Associated. ScienceDaily. Retrieved February 9, 2008, from
http://www.sciencedaily.com/releases/2007/04/070423185615.ht
m

When NRG1-erbB signaling was blocked, oligodendrocytes

from the brain's frontal cortex had a less complex structure
than normal, forming fewer branches. Shown are three-
dimensional reconstructions of oligodendrocytes from a normal
mouse (left) and a mutant mouse (right). (Credit: Image
courtesy Joshua Murtie, Ph.D., Children's Hospital Boston.)
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Progress in Dopamine Research in Schizophrenia: A Guide for
Physicians
Edited by Arvid Carlsson, M.D., Ph.D., and Yves Lecrubier,
M.D., Ph.D. Abingdon, Oxfordshire, U.K., Taylor & Francis
Group, 2004, 128 pp., $29.95 (paper).
RAJIV TANDON, M.D.
Tallahassee, Fla.

For the past half-century, the dopamine hypothesis has

dominated thinking about the neuropharmacological
underpinnings of schizophrenia and antipsychotic action.
Despite the absence of any definitive evidence of specific
dopaminergic abnormalities in schizophrenia and only indirect
support for a specific role of dopamine antagonism in its
treatment, discussions about the pathophysiology and
treatment of schizophrenia continue to focus on dopamine.
There is, in fact, no single dopamine hypothesis of
schizophrenia and antipsychotic action. Ideas about the
pathophysiology of schizophrenia have evolved from too much
dopamine somewhere in the brain (1960s–1970s) to increased
activity at the D2 dopamine receptor (1970s–1980s) to the
current concepts of too much dopamine somewhere (the
"emotional" mesolimbic circuit) and too little dopamine
elsewhere (the "thinking" mesocortical circuit), or too much
dopamine sometime (stimulated "phasic" increase) and too
little dopamine most of the time (tonic deficiency). In the
context of an abundance of often confusing findings from
numerous areas of research, what is the current state of our
understanding of the role of dopamine in the pathophysiology
and treatment of schizophrenia?

This superbly edited pocketbook clearly describes the current

status of dopamine research in schizophrenia and antipsychotic
action. The relationship of cognitive dysfunction in
schizophrenia to dopamine susceptibility genes and prefrontal
dopamine signaling is described in the light of recent findings,
and information about the role of genetic variation in
predicting individual antipsychotic treatment response is
considered. The role of dopamine in different brain circuits is
summarized in the context of interactions with other
neurotransmitters (particularly glutamate and serotonin) and
the functions that these circuits subserve. The specific role of
dopaminergic neurotransmission in normal information
processing, reward-reinforcement, and attribution of salience
is described. How observed dopaminergic abnormalities in
schizophrenia can explain its complex psychopathology is then
considered: pathologically increased stimulated phasic
dopamine activity can explain the positive symptoms of
schizophrenia (paranoia, delusions, and hallucinations), and
decreased tonic dopamine activity can explain negative and
cognitive symptoms of the illness along with the greater
occurrence of substance abuse. The first half of this handbook
succinctly connects current research about the role of
dopaminergic abnormalities in the etiology and
pathophysiology of schizophrenia to the psychopathology of
the illness in a logical and coherent manner.

The second half of the book elucidates current thinking about

how specific antidopaminergic actions of medications are
relevant to their antipsychotic effects and what
pharmacological attributes might explain differences between
typical and atypical antipsychotics with regard to their
spectrum of efficacy in the treatment of schizophrenia and
their propensity to cause neurological and endocrine adverse
effects. There is a detailed consideration of amisulpride, which
is described as a "distinctive atypical antipsychotic agent
because of its uniquely high selectivity for dopamine
receptors." This chapter should be of particular interest to
American readers who are unfamiliar with amisulpride
because of its lack of availability. The final chapter considers
current challenges in the treatment of schizophrenia and
possible future strategies to meet these challenges.

I highly recommend this 100-page pocketbook to anyone with

an interest in understanding the current state of dopamine
research in schizophrenia and antipsychotic action without
wading through volumes. Adapted and abridged from the
proceedings of a recent symposium in which many
international experts in dopamine research in schizophrenia
participated, this concise handbook contains simple yet
nonbanal explanations of complex topics and combines brevity
with relatively comprehensive coverage of an important topic
in an easy-to-read format.

Schizophrenia
Aetiology

As schizophrenia is a complex brain disorder, it likely results

from the interplay of genetic, behavioural, developmental and
other factors. The exact cause of this group of illnesses is not
known but stress, trauma and viral infection at an early age
are factors thought to be involved.

Schizophrenia can run in families and it is likely that the

disease has a genetic component – if one twin of an identical
pair has schizophrenia, there is a 46% chance that the other
twin will also suffer from a schizophrenic disorder. It is not
known how many genes are involved or how the genetic
predisposition is transmitted. In addition, recent evidence
suggests that schizophrenia may result when neurons in the
brain form inappropriate connections during foetal
development. It may be that an intrauterine starvation or
infection causes such inappropriate connections to form and
these may lie dormant until puberty when substantial neuron
reorganisation occurs in the brain. Identification of specific
genes involved in the development of schizophrenia will
provide important clues as to what goes wrong in the brains of
people with the disease and this will guide the development of
improved treatments.

Stress imposed by life events or family circumstances appears

to be an important external event associated with
schizophrenia. The onset of illness is often associated with a
distressful period in life and it may be that stress can trigger
the onset of illness in those people with a genetic predisposition
to the disease.

An imbalance in the concentrations of dopaminergic and

glutamatergic systems in the brain is also thought to play a role
in the development of schizophrenia. The dopamine hypothesis
states that the behavioural patterns typical of schizophrenia
are a result of overactivity of dopamine in certain regions of
the brain. Serotonin is also important in schizophrenia and it
may be that the serotonin system interacts with the dopamine
system to modify the way in which it operates. The serotonin
receptors which are important in the treatment of
schizophrenia are 5-HT1, 5-HT2 and 5-HT3.
What Happens in the Brain?

The areas of the brain implicated in schizophrenia are the

forebrain , hindbrain and limbic system .

It is thought that schizophrenia may be caused by a disruption

in some of the functional circuits in the brain, rather than a
single abnormality in one part of the brain. Although the brain
areas involved in this circuit have not been defined, the frontal
lobe, temporal lobe, limbic system,(specifically the cingulate
gyrus , the amygdala and the hippocampus ) and the thalamus
are thought to be involved. The cerebellum , which forms part
of the hindbrain, also appears to be affected in people with
schizophrenia.

neurotransmitters are implicated in the development of

schizophrenia. The dopamine hypothesis of schizophrenia
postulates that schizophrenia is caused by an overactive
dopamine system in the brain; excessive dopamine and
reduced striatal activity can disrupt all aspects of motor,
cognitive and emotional functioning and can result in an acute
schizophrenic psychosis. An excessive dopamine concentration
in the brain of people with a schizophrenic disorder was
originally thought to be associated with increased activity of
the D2 class of dopamine receptors in the prefrontal cortex .
Recent studies indicate that reduced numbers of the D1 class of
dopamine receptors may contribute to the rise in dopamine
concentration. Other neurotransmitters, including serotonin,
glutamate, gamma aminobutyric acid and acetylcholine may
also be involved in the pathogenesis of schizophrenia. It may be
that due to the careful orchestration between neurotransmitter
systems, an imbalance in one neurotransmitter affects others
which are not causally involved in the pathogenesis of disease.

Several structural changes are found in the brains of people

with schizophrenia, most of which occur in the forebrain.
Reductions in the volume of grey matter in the frontal lobe,
and decreased brain volume and activity, have been repeatedly
noted among people with a schizophrenic disorder. The
ventricles are commonly found to be larger than normal, as
are the basal nuclei , while the hippocampus and amygdala are
often smaller. The disease is also associated with alterations in
blood flow to certain areas of the brain.