Dopamine Study

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CURE FOR SCHIZOPHRENIA

A JOURNEY

CAN BIOLOGICAL CONTROL

SYSTEMS BE THE ANSWER TO

CHEMICAL REGULATION?

DOPAMINE AND ITS ROLE

Mushahid M


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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 somepoint 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 temporallobe 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 positronemission 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.


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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 toshow 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, whichalternate 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, havebeen 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


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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 morefluorodopa. 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. Thesefunctions 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. Thisphenomena 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.


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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 areinvolved 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 receptoractivates 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


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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.


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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.)


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IDENTIFICATION OF MULTIPLE DA RECEPTORSUBTYPES

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 toadenylate 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


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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 antipsychoticcompounds.

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


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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 activityincreases 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 focusfrom 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


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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 alsoSchizophrenia 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


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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 beengenerated: 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


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(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 tofrontal 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 inschizophrenia 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


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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,


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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 certainlyencourage 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 DAactivity.

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 theavailability 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


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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 thereceptors occupied by methylspiperone but not raclopride.

pHVA and the Mechanism of Action of Neuroleptics


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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 andsubsequently 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 (34 weeks)

neuroleptic administration decreases DA neuron firing in A9

and A10 below pretreatment levels. Interestingly, atypical

neurolepticsthat 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 pHVAconcentrations 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


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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 nervoussystem (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) pHVAsamples, 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-


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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 patientcontrol

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-freepatients. 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


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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 hadgreater 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


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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, theabnormalities 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 toanatomical 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 symptomsthat is, decreased socialinteraction, apathy and avolitionare 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.


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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 isreminiscent 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, negativesymptoms 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 canproduce 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,


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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 thatdecreased 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 theWCST (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 byinference 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


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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 beuseful (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).


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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 theprevention 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 thenegative 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


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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 itslikely 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 subcorticalhyperdopaminergia 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


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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 ... [emphasisadded]." 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 andthe 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


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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 andcontrols.

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. Tomeasure 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


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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 weresignificantly 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 D2receptors 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.

View larger version (45K):

[in this window]

[in a new window]

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 (pinktriangles 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


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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 ofradiobenzamides 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 ofendogenous 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.


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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-episodepatients, 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 transientlyoccupy 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 D2receptors, 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


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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 "hebephrenicschizophrenia") - lack of emotion, disorganized speech

Catatonic Schizophrenia - waxy flexibility, reduced movement,

rigid posture, sometimes too much movement

Paranoid Schizophrenia - strong delusions or hallucinations


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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 shareonly 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


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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) isalso 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 StudiesSome 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 withnongenetic (environmental) factors to cause schizophrenia.

Neurotransmitters

Many studies have investigated the possible role of brain

neurotransmitters in the development of schizophrenia. Most


40/54

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 andcompletely 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.


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New drugs for schizophrenia, for example, clozapine, block

receptors for both serotonin and dopamine.

Treatment of SchizophreniaMedication

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 ThorazineThe 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

receptorsPerphenazine Trilafon

Quetiapine Seroquel Blocks some serotonin and

dopamine receptors; Introduced in 1997

Risperidone Risperdal Blocks some serotonin and

dopamine receptors


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Thioridazine Mellaril Also used as a tranquilizer

Thiothixene Navane

TrifluoperazineStelazine 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 andchewing 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.


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44/54

"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 thinkingabout 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 fattysheath, 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


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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 manyschizophrenia 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 atreatment 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 andtoddlerhood, 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


46/54

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 ResearchAssociation, 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


47/54

mouse (left) and a mutant mouse (right). (Credit: Image

courtesy Joshua Murtie, Ph.D., Children's Hospital Boston.)

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reduced significantly in people with schizophrenia, a study by

scientists at UC Irvine, Weill Cornell Medical College and

Rockefeller University ... > read more


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Changes In Brain Density Can Help Predict Schizophrenia

(Dec. 11, 2006) Changes in brain density could be used to

predict whether an individual who is at risk for schizophrenia

is likely to develop the condition or not. A study published

today in the open access journal ... > read moreFirst Mouse Model Of Schizophrenia Developed (Jul. 31, 2007)

Researchers have genetically engineered the first mouse that

models both the anatomical and behavioral defects of

schizophrenia, a complex and debilitating brain disorder that

affects over 2 million ... > read more

Innovative, Multicenter Study Of Schizophrenia Will Follow

Disease Traits In Hunt For Genetic Causes (Jun. 3, 2003)

Specific information processing abnormalities and brain-related circuit dysfunction in schizophrenia patients may be

the keys to finding the genetic basis of this puzzling,

devastating mental illness ... > read more

U Of T Researcher Links Schizophrenia, Gene Mutations (Feb.

21, 2005) The supersensitivity to dopamine that is

characteristic of schizophrenia can be caused by mutations to a

wide variety of genes, rather than alterations to just two or

three specific genes, says a ... > read more

Abnormalities Of The Mouth Associated With Schizophrenia

(Mar. 14, 2007) Recent research quantifies, for the first

time, how schizophrenia is apparently associated with a

broader hard palate and abnormalities in the teeth. This

knowledge may lead to improved early ... > read more

New Dopamine Brain Target Discovered; Potential

Breakthrough For Schizophrenia Treatment (Jan. 23, 2007)

A team of Canadian researchers, lead by Dr. Susan George and

Dr. Brian O'Dowd at the Center for Addiction and Mentalhealth, discovered a Gq/11-coupled signalling unit that triggers

a calcium signal. ... > read more


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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 indirectsupport 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


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pathophysiology of schizophrenia have evolved from too much

dopamine somewhere in the brain (1960s1970s) to increased

activity at the D2 dopamine receptor (1970s1980s) to the

current concepts of too much dopamine somewhere (the

"emotional" mesolimbic circuit) and too little dopamineelsewhere (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 ofschizophrenia (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


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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 abouthow 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 agentbecause 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


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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 dopaminesystem 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 acuteschizophrenic 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


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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 neurotransmittersystems, 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. Theventricles 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.

Documents

Dopamine Study