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another showing no change

5

. Although the

majority of subsequent studies with PET or SPET
have found no significant difference in striatal D

2

receptor density between controls and patients
with schizophrenia, in a recent meta-analysis of
studies carried out between 1986 and 1997, a
small but significant elevation of D

2 

receptors was

noted in patients with schizophrenia

5

. However,

the variability of D

2 

receptor density is high both

in controls and patients with schizophrenia, and it
has been argued that the small magnitude of the
effect (approximately a 12% increase), and the
possibility that any change reflects alteration in
the baseline synaptic dopamine, means that there
are no real functional differences in the density of
striatal D

2 

receptors in schizophrenia (reviewed in

reference 5).

Despite these equivocal findings in drug-naive

patients, emission tomography has reinforced the
accepted theory that antipsychotic efficacy is
related to D

2

, with 65% blockade a putative

threshold for antipsychotic response

6

. Nonethe-

less, the situation appears very complex in that
non-responders to antipsychotics still show high
levels of striatal D

2 

blockade

7,8

. Furthermore, the

highly effective atypical antipsychotic clozapine
produces far less striatal D

2 

blockade than typical

antipsychotics

7–9

, often below the putative 65%

threshold (

Figure 4.2

). These findings have yet to

be fully explained.

Extrapyramidal side-effects (EPS) have also

been studied and a threshold of 80% D

2 

occup-

ancy has been repeatedly shown to be necessary to
produce EPS

6 

(

Figure 4.3

). It may be that high

levels of 5-HT

2A 

receptor blockade, as seen with

Healthy volunteer

High D

2 

receptor availability =

no occupancy

Clozapine treated 

patient with schizophrenia

Medium D

2 

receptor availability =

medium (~60%) occupancy

Typical antipsychotic-treated 

patient with schizophrenia

Low D

2 

receptor availability =

high (80%+) occupancy

[123I]

IBZM SPET SCANS OF STRIATAL D

2 

RECEPTOR OCCUPANCY

Figure 4.2 

Three single photon emission tomography (SPET), scans of striatal D

2 

and D

2

-like receptor availability at the level

of the basal ganglia. In the scan on the left from a healthy volunteer there is no receptor occupancy and therefore 100%
receptor availability for the binding of the D

2 

receptor tracer 

[123I]

IBZM. The scan on the right is from a patient with

schizophrenia receiving a typical antipsychotic. The bright areas from the left hand scan indicating high receptor density are
not evident on the right-hand scan as the antipsychotic is occupying the majority of the receptors and preventing the tracer
from binding. Unfortunately despite this high level of occupancy this patient has failed to respond to treatment. The central
scan is from a patient receiving clozapine, although the striatum are not as ‘bright’ as in the healthy volunteer they are visible.
This scan indicates intermediate occupancy of the receptors by clozapine. Importantly the patient with the intermediate
occupancy has responded to treatment. Studies such as this one, when performed in larger groups, indicate that the simple
dopamine hypothesis suggested by the data in 

Figure 4.1

 needed refining. Figure reproduced with permission from Pilowsky

LS, Costa DC, Ell PJ, 

et al.

Clozapine, single photon emission tomography, and the D

2 

dopamine receptor blockade

hypothesis of schizophrenia. 

Lancet

1992;340:199–202

©2002 CRC Press LLC

RELATIONSHIP BETWEEN D2 RECEPTOR

OCCUPANCY EPS AND RESPONSE

100%

50%

0

% Striatal D

2

 Receptor Occupancy

Dose of antipsychotic

No EPS

ineffective

potentially
effective &
No EPS

potentially
effective but
high EPS risk

Clinical effect

Figure 4.3

Illustration of the relationship between clinical effectiveness, extrapyramidal side-

effects (EPS) and D

2

receptor occupancy. With the exception of clozapine-induced D

2

occupancy,

below 60% striatal D

2

occupancy produced by an antipsychotic medication is likely to be

associated with treatment non-response, whilst occupancies above 80% are likely to be associated
with a high risk of EPS. Once a patient is receiving a dose of an antipsychotic likely to be
producing an occupancy between 60% and 80% there is little to be gained, in terms of treatment
response, by increasing the dose of the antipsychotic further as the patient will almost certainly
develop EPS. Figure after references 6, 7 and 51

Figure 4.4

The effect of amphetamine (0.3 mg/kg) on

[123I]

IBZM binding in healthy control subjects and

untreated patients with schizophrenia. 

[123I]

IBZM is a

tracer for D

2 

receptors which allows 

in vivo

measurement of D

2

receptor availability (or binding

potential) in humans using single photon emission
tomography (SPET). The y-axis shows the percentage
decrease in 

[123I]

IBZM binding potential induced by

amphetamine, which is a measure of the increased
occupancy of D

2

receptors by dopamine following the

challenge. Thus, these results indicate that, when
challenged with amphetamine, patients with
schizophrenia release more dopamine than do healthy
controls. Figure reproduced with permission from
Laruelle M, Abi-Dargham A, Gil R, 

et al.

Increased

dopamine transmission in schizophrenia: relationship
to illness phases [Review]. 

Biol Psychiatry

1999;

46:56–72

50

0

10

20

30

40

[123

1]IBZM displacement by  

amphetamine (% baseline)

p < 0.001

Controls Schizophrenics

DOPAMINE RELEASE BY AMPHETAMINE

most of the newer antipsychotics, may be
protective against EPS by altering this threshold
(reviewed in reference 10).

Recent neurochemical imaging studies have

indicated that people with schizophrenia have an
increased sensitivity of their dopaminergic
neurones to amphetamine challenge

11 

(

Figure

4.4

). Thus, it may be that in response to ‘stress’

such people will over-release dopamine and this
may drive psychosis.

There are currently five types of dopamine

receptors identified in the human nervous system:
D

1 

to D

5

. D

1 

and D

5 

receptors are similar in that

they both stimulate the formation of cAMP by
activation of a stimulatory G-coupled protein. D

2

to D

4 

receptors act by activating an inhibitory G-

protein, thereby inhibiting the formation of
cAMP. D

2 

receptors are more ubiquitous than D

3

or D

4

receptors. D

3

receptors are differentially

situated in the nucleus accumbens (one of the
septal nuclei in the limbic system) and D

4

receptors are especially concentrated in the frontal
cortex (

Figure 4.5

). There are a number of

different dopaminergic pathways or tracts (

Figure

4.6

). The nigrostriatal tract projects from the

substantia nigra in the midbrain to the corpus
striatum. This tract primarily has a role in motor
control, although the ventral striatum has a role in
reward- and goal-directed behaviors. Degeneration
of the cells in the substantia nigra leads to
idiopathic Parkinson’s disease, and it is by blocking
the dopamine receptor at the termination of this
pathway that the parkinsonian side-effects of
classical antipsychotics arise. The mesolimbic/
mesocortical tract has its cell bodies in the ventral
tegmental area adjacent to the substantia nigra.
This tract projects to the limbic system and
neocortex in addition to the striatum. This

Figure 4.5 

There are currently five types of dopamine receptor identified in the human nervous system, D

1

to D

5

.

D

1

and D

5

receptors are similar in that they both stimulate the formation of cAMP by activation of a stimulatory

G-coupled protein. D

1

and D

5

are therefore known as D

1

-like receptors. D

2

to D

4

receptors activate an inhibitory

G-protein, thereby inhibiting the formation of cAMP. They are collectively known as D

2

-like receptors. D

2

receptors are more ubiquitous than D

3

or D

4

receptors. D

3

receptors are differentially situated in the nucleus

accumbens (one of the septal nuclei in the limbic system) and D

4

receptors are especially concentrated in the

frontal cortex

CLASSIFICATION OF DOPAMINE RECEPTORS

Caudate-

putamen

N. accumbens

Olfactory
tubercule

Hippocampus

Hypothalamus

Olfactory
tubercule

Hypothalamus

N. accumbens

Cerebellum

Frontal

cortex

Medulla

Midbrain

Caudate-

putamen

N. accumbens

Olfactory
tubercule

Dopamine

D

1 

receptor

family

D

1 

D2 D3 D4

D

5

D

2 

receptor

family

©2002 CRC Press LLC

dopaminergic innervation supplies fibers to the
medial surface of the frontal lobes and to the
parahippocampus and cingulate cortex, the latter
two being part of the limbic system. Because of
this anatomic representation it is thought that this
tract is where antipsychotic medication exerts its
beneficial effect. The third major pathway is
termed the tuberoinfundibular tract. The cell

62

Figure 4.6 

Representation of the primary dopamine-containing tracts in the human brain. The nigrostriatal tract is

primarily involved in motor control, but also in reward- and goal-directed behavior. Blockade of D

2

receptors here

produces some of the antipsychotic effects of antipsychotics, but high levels of blockade (> 80%) produce
parkinsonian side-effects. Blockade of D

2

receptors in the tuberoinfundibular pathway increases plasma prolactin.

It is thought that it is the blockade of D

2

and D

2

-like receptors in the mesolimbic and mesocortical tracts that

underlies the primary antipsychotic effects of all currently available antipsychotics

THE DOPAMINERGIC PATHWAYS

A Substantia nigra

B Ventral tegmental area

C To amygdala

D Tuberoinfundibular DA system

E Nucleus accumbens
 (ventral striatum)

F To the striatum (caudate nucleus, 

 putamen and globus pallidus) 

G Frontal cortex

E

F

D

A

G

B

C

bodies for this tract reside in the arcuate nucleus
and periventricular area of the hypothalamus.
They project to the infundibulum and the anterior
pituitary. Dopamine acts within this tract to
inhibit the release of prolactin. The blockade of
these receptors by antipsychotics removes the
inhibitory drive from prolactin release and leads
to prolactinemia.

Figure 4.7 

Dopamine is synthesized in

a common pathway with
norepinephrine. In the pathway shown,
tyrosine hydroxylase is the rate-limiting
enzyme. Dopamine 

β

-hydroxylase is

only found in noradrenaline neurons in
the CNS

Phenylalanine

Tyrosine

tyrosine

hydroxylase

(pterin cofactor)

Dopa

decarboxylase

(pyridoxal cofactor)

Dopamine

ȋ

-hydroxylase

(copper containing enzyme)

Ascorbate and O

2 

required

Dopa

Dopamine

Norepinephrine

Rate
limiting
step

H

H

C CH

COOH

NH

2

H

H

C CH

COOH

NH

2

H

H

C CH

HO

HO

HO COOH

NH

2

H

H

C CH

2

HO

HO

NH

2

OH

H

C CH

2

HO

HO

NH

2

DOPAMINE SYNTHESIS

©2002 CRC Press LLC

Figure 4.8 

Dopamine is

metabolized by two enzymes.
One, monoamine oxidase type B
(MAO-B), is intraneuronal, and the
other, catechol-

O

-methyl

transferase (COMT), is extraneur-
onal. The primary metabolite of
dopamine is homovanillic acid 

Dopamine

Catechol-O-methyl 
transferase (COMT)

Monoamine oxidase  
type B (MAO-B)

Intraneural

Homovanillic acid

(HVA)

DOPAMINE METABOLISM

Extraneural

Dopamine is synthesized as part of the com-

mon pathway for catecholamines (

Figure 4.7

).

Dopamine is metabolized by two enzymes; one,
monoamine oxidase type B (MAO-B), is
intraneuronal, and the other, catechol-O-methyl
transferase (COMT), is extraneuronal. The prim-
ary metabolite of dopamine is homovanillic acid
(HVA; 

Figure 4.8

).

Serotonin

The serotonergic hypothesis of schizophrenia
predates the dopaminergic hypothesis and stems
from the finding by Woolley and Shaw in 1954

12

that the hallucinogen LSD acted via serotonin.