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Dopaminergic mechanisfl*in the pathogenesis of schizophrenia MENEK GOLDSTEIN’2 AND ARIEL 1.DEUTCHt
Dopaminergic
mechanisfl*in
the
pathogenesis
of
schizophrenia
MENEK
GOLDSTEIN’2
AND
ARIEL
1.DEUTCHt
‘Department
of Psychiatr#{231}New
York Uni4sity
School
of Medicine,
New
York,
New
York 10016,
USA;
and
tDepi
of Psychiatry,
Yale UnivereitySchool
of Medicine,
New
Haven,
Connecticut
06510,
USA,
and
tDepartment
of Veterans
Affairs
Medical
(rter,
West
Haven,
Connecticut
06516,
USA
ABSTRACT
The
dopamine
hypothesis
of
schizophre-
ogy,
biochemistry,
pharmacology,
anatomy,
and
systems
nia
has
been
the
dominant
theoretical
construction
guid-
neuroscience
have
led
to
a
greater
appreciation
of
the
com-
plexity
of
the
central
dopaminergic
systems,
their
interac-
ing
research
and
treatment
of the
schizophrenic
disorders
tions
with
other
defined
transmitter
systems
in
the
brain,
over
the
past
generation.
This
hypothesis,
in
its
simplest
and
their
role
in
complex
cognitive
processes.
guise,
posits
the
presence
of a functional
alteration
in
cen-
tral
dopaminergic
systems
in
the
brains
of
schizophrenic
patients.
Recent
findings
have
resulted
in
a greater
under-
standing
of
the
complexity
of
the
central
dopaminergic
DA
RECEPTORS
systems
and
have
led
to
revisions
of
the
hypothesis
of
a
If
the
dopamine
hypothesis
of
schizophrenia
is
correct,
it
simple
functional
hyperactivity
of
central
dopaminergic
should
be
possible
to
uncover
some
change
in
1)
DA
content
systems.
These
recent
data
suggest
that
there
may
be
regionally
restricted
changes
in
the
function
of
the
or turnover,
2)
DA
neuronal
responsiveness
to
perturbation,
mesotelencephalic
dopamine
system,
and
that
these
or
3) the density
or
affinity
of DA
receptor
sites
in
postmor-
tem
brain
samples
from
schizophrenic
patients.
This
task
has
changes
may
be
in
opposite
directions.
Such
changes
may
be
associated
with
dysfunctions
of
interactions
between
frequently
been
disappointing,
marked
by
several
instances
of
distinct
dopaminergic
terminal
field
regions,
and
may
be
promising
findings
languishing
after
attempts
at
independent
verification
have
failed.
subserved
by
functional
derangements
in
other
transmit-
This
is
perhaps
not
surprising:
the
ter
systems
or
reflect
regionally
restricted
changes
in
ex-
problems
encountered
in
working
with
postmortem
samples
pression
or
function
of
distinct
dopamine
receptors
or
(such
as agonal
state,
postmortem
interval,
and
regional
dis-
catecholamine
synthetic
enzymes.
A
recent
FASEB
sym-
section
differences),
as well
as
the
problems
inherent
in diag-
posium
reviewed
new
advances
in
molecular
biology,
bio-
nosis,
heterogeneity
of the
schizophrenias,
and
the
presence
or
history
of
APD
treatment,
are
well
known.
Nonetheless,
chemistry,
pharmacology,
anatomy,
and
systems
neuro-
the
lack
of consistent
changes
in
concentrations
of DA
or
its
science
as
they
relate
to
schizophrenia,
and
discussed
the
implications
of these
data
for
guiding
future
research
and
metabolites
has
led
some
investigators
to
suggest
that
the
defect
in
schizophrenia
is
not
of
DA
systems,
and
others
to
treatment
strategies.-
Goldstein,
M.;
Deutch,
A.
Y.
propose
that
the
alteration
in
central
DA
systems
is
more
Dopaminergic
mechanisms
in
the
pathogenesis
of
schizo-
phrenia.
FASEBJ.
6:
1992.
subtle
than
a simple
change
in levels
of DA
or
its metabolites.
2413-2421;
Some
reports
have
suggested
that
DA
receptor
density
may
be elevated
in schizophrenia
(see
ref
1). Changes
in
the
number
Key
Words:
dopamine
.
antipsychotic
drugs
.
cholecystokinin
of
D2 receptors
are
perhaps
the
most
consistent
alterations
cortex
excitatory
amino
acids
neurotensin
.
dopamine
receptors
reported
from
postmortem
tissue,
although
there
are
dissent-
ing
votes
as
well.
It
is possible
that
changes
in
receptor
den-
sity
are
not
constant
throughout
the
course
of the
disease
(1)
in
perhaps
its
or
that
the
changes
are
more
subtle
than
simple
differences
THE
DOPAMINE
HYPOTHESIS
OF
SCHIZOPHRENIA,
most
simple
form,
posits
the
existence
of a functional
altera-
tion
in
central
dopaminergic
systems
in
the
brain
of
schizo-
phrenic
patients.
This
hypothesis
is based
primarily
on
phar-
1From
the
symposium
Dopaminergic
Involvement
in Schizophrenia
and
macological
evidence.
All
the
known
clinically
effective
Other Mental
Disorders presented
by the
American
Society
for
Phar-
antipsychotic
drugs
(as
demonstrated
in
double-blind,
macology
and
Experimental
Therapeutics
at
the
74th
Annual
placebo-controlled
studies)
block
dopamine
D2
receptors.
Meeting
of the
Federation
of American
Societies
for Experimental
Although
actions
of these
agents
on
other
transmitter
recep-
Biology,
April
2,
1990,
Washington,
D.C.
Participants
included
tors
may
augment
or
modify
therapeutic
responsiveness,
the
A.
Barnett,
B.
S.
Bunney,
A.
Carlsson,
A.
Y.
Deutch,
K.
Fuxe,
fact
that
all
antipsychotic
drugs
(APD5)3
are
D2
antagonists
M.
Goldstein,
T
Hokfelt,
5. -0.
Ogren,
P.
Seeman,
C.
A.
Tam-
but
share
no
other
common
action
on
any
known
receptor
minga,
and
D.
R.
Weinberger.
Organized
by
M.
Goldstein
and
A.
Y. Deutch.
suggests
that
there
is a functional
derangement
(or
derange-
2To whom
correspondence
should
be addressed
at:
Neurochemis-
ments)
of
central
dopammne
(DA)
systems
in
schizophrenia.
try
Laboratories,
Room
H544,
NYU
Medical
Center,
560
First
This
conclusion
is buttressed
by
the
fact
that
chronic
admin-
Ave.,
New
York,
NY
10016,
USA.
istration
of indirect
DA
agonists,
such
as amphetamine,
may
3Abbreviations:
APDs,
antipsychotic
drugs;
PET,
positron
emis-
result
in
a psychotic
state
that
in
many
aspects
resembles
sion
tomography;
CCK,
cholecystokinin;
NT,
neurotensin;
EAA,
schizophrenia.
Accordingly,
there
has
been
the
targeting
of
excitatory
amino
acid;
PCP,
phencyclidine;
LCGU,
local
cerebral
both
basic
and
clinical
science studies
of
schizophrenia
on
glucose
utilization;
PFC,
prefrontal
cortex;
EPS,
extrapyramidal
central
dopaminergic
systems.
Advances
in
molecular
biol-
side
effects;
DA,
dopamine.
O892-6638I92lO006-24l3l01.50.
© FASEB
74fl
in receptor number. Among studies supporting the latter the brain. Designation of these receptors as
in
receptor
number.
Among
studies
supporting
the
latter
the
brain.
Designation
of
these
receptors
as
falling
broadly
view
was
the
finding
that
there
is
a bimodal
distribution
of
within
a
D2
class
is
meant
simply
to
serve
as
a
convenient
D2 receptor
density,
and
that
only
in one
of these
modes
can
heuristic
for
the
moment;
the
molecular
biology
of
DA
re-
a
change
in
the
density
of
D2
receptors
be
discerned
(1).
ceptors
is
evolving
at
such
a
rapid
pace-and
the
corre-
Although
one
can
exclude
effects
due
to APD
pharmacother-
sponding
generation
of subtype-specific
ligands
is lagging
so
apy
through
statistical
means,
in
the
absence
of
tissue
from
far behind
-
that
a plateau
must
be
reached
before
some
con-
patients
never
treated
with
APDs
it
is
difficult
to establish
sensus
can
be
achieved.
conclusively
the
degree
to
which
an
increase
in
receptor
D1
receptors
have
also
recently
been
cloned
(see
ref
5).
number
is
iatrogenic
or
reflects
the
schizophrenic
process.
The
D1
receptors
cloned
so far
resemble
other
receors
that
result
in
adenyl
cyclase
stimulation,
with
a
relativ
‘1y
short
An
alternative
strategy
to
the
problem
of defining
changes
in receptor
density
or affinity
been
to
use in
vivo
imaging
third
cytoplasmic
loop.
The
first
D1 receptor
to
be
cloned
has
has
techniques.
Recent
attempts
have
used
positron
emission
now
been
joined
by
two
more
D1
receptors.
One
of
these
tomography
(PET)
to
assess
the
possibility
of changes
in
the
closely
resembles
the
original
D1;
the
other
D1
receptor
number
of striatal
D2 receptors
in schizophrenic
patients
not
cloned
has a significantly
higher
affinity
for
DA.
In
addition,
treated
with
APDs.
Unfortunately,
these
imaging
studies
still
another
D1
receptor,
with
slightly
different
pharmaco-
have
yielded
conflicting
results
(2,
3); this
may
be
attributable
logical
characteristics,
has
been
cloned;
this
receptor
has
to
the
different
ligands
used
in
the
studies
or
to
differences
been
designated
D5.
It
is
likely
that
other
D1 receptors
(for
in
patient
populations.
example,
a striatal
D1
receptor
coupled
to
phospholipase
C),
Difficulties
in
clearly
establishing
a change
in
central
DA
as
well
as additional
D2
receptors,
will
be cloned
in
the
fu-
ture.
This
is clearly
supported
by
observations
tht
certain
function
in schizophrenic
subjects
have
led
to the
hope
that
an
DA
receptors
in
the
brain,
such
as
the
D2
receptor
in
the
examination
of other
parameters
of DA
function,
particularly
those
made
possible
by
advances
in
molecular
biology,
will
prefrontal
cortex
of
the
rat,
have
pharmacological
profiles
enable
one
to determine
if there are indeed changes in central
that
differ
from
those
of the
DA
receptors
that
have
now
been
cloned
(see
ref
6).
nervous
system
(CNS)
DA
systems
in schizophrenic
psychoses.
Rapid
advances
in
the
cloning
of
DA
receptors
and
the
Molecular
biology
of
DA
receptors
availability
of specific
probes
with
which
to assess DA
recep-
tor
gene expression
have raised
the hope
that
it may
be possi-
Molecular
biological
strategies
have
resulted
in the
cloning
of
a
ble
to define
specific
alterations
in
the
gene expression
of var-
number
of DA
receptor
genes.
The
DA
receptors
are
G protein-
ious
DA
receptors
in
postmortem
tissue
and
to characterize
coupled
receptors
with
seven
transmembrane-spanning
do-
a linkage
with
the D2 receptor
region
in extended
families
of
mains.
The
sequence
homology
between
the
conserved
por-
schizophrenic
patients.
Current
studies
suggest
no
linkage
tions
of
the
protein,
particularly
the
membrane-spanning
between
the D2
DA
receptor
and
schizophrenia
(7).
However,
regions,
opened
the
possibility
of
using
probes
for
other
more
extensive
investigations
with
specific
DA
receptor
G
protein
family
receptors
to
screen
libraries
for
DA
recep-
probes
for
tightly
defined
regions
of
the
chromosome
may
tors.
This
strategy
was
rewarded
with
the
initial
cloning
of
prove
instructive.
a
D2
receptor
eDNA
(4);
subsequent
studies
revealed
that
It should
be
realized
that
a description
of a change
in
gene
this
gene
was
subject
to
alternative
splicing,
leading
to
two
expression
leaves
other
equally
important
to
be
D2
receptors
with
differences
in
the
third
cytoplasmic
loop
at
resolved:
Is
gene
transcription
specifically
questions
altered?
Is
the
or
near
the
G
protein-binding
domain.
More
recent
studies
mRNA
translated
appropriately?
Is
posttranslational
pro-
have
led
to
cloning
of
the
putative
D3
receptor,
which
in
cessing
altered?
What
is
the
normal
role
of
these
DA
recep-
terms
of binding
characteristics
appears
to
be
a
D2
isoform.
tors
in
behavior
and
in
psychopathological
conditions?
For-
Paradoxically,
binding
of
ligands
to
this
receptor
is
not
tunately,
the
investigation
of
these
questions
can
be guided
changed
in
the
presence
of
guanine
nucleotides,
suggesting
by
recent
developments
of the
biochemistry
and
pharmacol-
that
the
protein
is
not
G
protein
coupled;
further
work
will
ogy
of
central
DA
neurons.
be
required
to establish
the
biochemistry
of this
receptor
and
to determine
whether
the
D3 protein
represents
a functional
Biochemistry
and
pharmacology
of
DA
receptors
receptor.
Finally,
over
the
past
year
still
another
DA
receptor,
the
pharmacology
of which
generally
conforms
to
a D2-type
The
deduced
amino
acid
sequence
of the
cloned
DA
receptors
receptor,
has
been
cloned;
this
has
been
designated
the
allows
the
prediction
of the
size of the expressed
protein.
Re-
D4
receptor.
In
addition,
another
D2
type
receptor
has
been
sults
of biochemical
examinations
of partially
purified
receptor
cloned,
which
differs
from
the
others
by
virtue
of
gating
a
protein
have
deviated
from
these
predictions
to
a
certain
calcium
current.
degree.
Differences
between
the
predicted
and
actual
masses
The
nomenclature
for
the
recently
cloned
DA
receptors
is
of the
receptors
are
thought
to
be
attributable
to posttransla-
still
a matter
of debate.
Extended
discussion
will
no
doubt
be
tional
modifications
of
the
protein,
including
glycosylation.
required
before
a consensus
regarding
the
defining
charac-
The
D2 receptor
has
been
examined
by photoaffinity
label-
teristics
(for
example,
molecular
vs.
pharmacological)
will
be
ing
of receptor
preparations
with
[‘25]N3-NAPS,
followed
by
reached.
On
the
basis
of
the
pharmacology
of the
expressed
SDS
gel
electrophoresis
and
treatment
with
endo-
and
exo-
protein,
we
will
refer
to
all
of the
above-mentioned
receptors
glycosidases
(8).
Such
studies
have
revealed
that
the
D2
as
D2
isoforms,
and
specifically
designate
the
alternative
receptor
consists
of a protein
core
with
an estimated
molecu-
splice
products
of the
original
D2
receptor
clone
as
D2A
and
lar
mass
of
approximately
44
kDa,
consistent
with
the
value
D28,
and
the
more
recently
cloned
members
as
D3
and
D4
derived
from
the
amino
acid
sequence
of
the
cloned
D2
(see
ref
5).
Although
these
receptors
can
be
broadly
classified
receptor
(4).
as
D2
isoforms
on
the
basis
of
general
pharmacological
Other
glycosylated
species are also present and show several
characteristics,
distribution
of
the
mRNAs
for
the
various
protein
bands
on
SDS
gels,
with
masses
ranging
from
34-
to
forms
differ
somewhat,
leaving
open
the
possibility
that
140
kDa
(9).
The
34-kDa
photolabeled
band
is
an
N-linked
differences
in
the
action
of APDs
may,
in part,
be
attributable
glycoprotein,
which
upon
digestion
with
glycopeptidase
F
to
the
heterogeneous
distribution
of
specific
D2 isoforms
in
yields
a protein
with
an
apparent
molecular
mass
of
23 kDa.
2414 Vol.
6
April
1992
The
FASEB Journal
GOLDSTEIN
AND
DEUTCH
These studies suggest that the D2 receptor may consist of two cused on the D2
These
studies
suggest
that
the
D2 receptor
may
consist
of two
cused
on
the D2 receptor;
toward elucidation
additional
attention
will
have
to
be
common
binding
units
of
approximately
44
and
23
kDa.
directed
of
regulatory
mechanisms
of
However,
Goldstein
and
colleagues
(10)
noted
that
[‘25]N3-
other
DA
receptor
isoforms
in
the
future.
NAPS
photoaffinity
labeling
of the
purified
D2 receptor
ob-
tained
from
the
prolactin-secreting
7315a
adenohypophyseal
Interactions
between
DA
receptor
subtypes
tumor,
or
from
the
tumor-derived
cell
line
MMQ,
labels
a
major
protein
of 32-34
kDa.
Northern
blot
analysis
of the
D2
There
has
been
remarkable
growth
in
our
understanding
of
receptor
mRNA
isolated
from
the
solid
tumor
and
MMQ
the
significance
of
interactions
between
DA
receptor
sub-
cells
reveals
mRNA
of
the
same
size
as
the
rat
striatum
types.
Barnett
and
associates
(15)
have
reviewed
pharmaco-
(J. Y. Lew
there
and
M.
Goldstein,
unpublished
results).
Although
logical
and
behavioral
studies
detailing
the
function
of
Dl
receptors.
are
difficulties
in
resolving
on
gels
different
mRNA
In
many
cases,
D1
receptor
stimulation
potentiates
the
expression
of D2 receptor
function
(16).
Such
interactions
species
of similar
size,
these
data
suggest
that
the
D2 binding
units
of 34-140
kDa
may
be
derived
from
the
same
gene,
and
may
have
important
implications
for
the
treatment
of
that
differences
in
the
mass
of these
receptor
proteins
are
due
schizophrenia
with
antipsychotic
drugs.
Accordingly,
con-
to
posttranslational
modifications.
The
molecular
relation
siderable
attention
has
been
devoted
to
elucidating
the
between
these
units,
as
well
as
their
role
in
mediating
neu-
mechanisms
through
which
D2
and
D1
receptor
subtypes
ronal
events,
has
not
yet
been
established.
may
interact.
The
ability
to
localize
the
mRNAs
for
the
various
DA
Studies
of
the
mechanisms
through
which
the
DA
recep-
tors
are
regulated,
and
examination
of
the
mechanisms
receptor
subtypes
has
revealed
that
interactions
between
D1
and
D2
isoforms
may
occur
in
at
least
two
distinct
ways:
one
through
which
DA
receptors
in
turn
regulate
DA
synthesis,
involving
interactions
between
different
neurons,
the
other
may
offer
important
clues
into
treatment
strategies
for
via
D2-D1
interactions
operative
in
the
same
cell.
In
situ
schizophrenia.
Several
recent
developments
have
furthered
our
understanding
of
the
regulation
of
DA
receptors.
hybridization
studies
have
revealed
D2
mRNA
in
approxi-
DA
receptors,
by
virtue
of
changes
in
receptor
density
or
mately
half
of the
striatal
medium
spiny
neurons
(17);
the
D1
affinity,
become
more
or
less
responsive
(supersensitivity
and
mRNA
has
similarly
been
localized
to
approximately
half
of
desensitization)
to
stimulation
after
changes
in
exposure
to
the
striatal
medium
spiny
neurons
(18).
receptor
ligands.
The
DA
hypothesis
of
schizophrenia
sug-
Interactions
between
D2
and
D1
receptors
may
be
under-
gests
that
DA
receptors
might
be
supersensitive.
Although
stood
in
terms
of the
presence
of these
two
receptor
types
in
the
development
of denervation
and
drug-induced
supersen-
different
striatal
neurons.
The
D2
receptor
appears
to
be
sitivity
of
DA
receptors
has
been
relatively
well
character-
localized
to
the
striatal
neurons
expression
GABA
and
ized,
less
well
understood
are
the
means
through
which
enkephalin
(i.e.,
the
striatopallidal
neurons);
the
D1
receptor
desensitization
is
manifested.
These
processes
have
been
is predominantly
localized
to striatal
projection
neurons
con-
the
focus
of
recent
investigations
of
and
13-adrenergic
taining
GABA
and
substance
P (striatonigral
neurons)
(19).
In
-
receptors,
which
have
demonstrated
that
desensitization
addition
to
the
separate
localization
of DA
receptor
genes
to
involves
phosphorylation
of
the
receptor
(11).
Phospho-
different
striatal
cells,
both
D2 and
D1 mRNAs
are
present
in
rylation
of
the
DA
receptors
has
not
been
extensively
the
same
neuron
in a smaller
percentage
of striatal
cells
(20).
investigated.
The
use
of
synthetic
peptides
to
specific
Little
is known
of
the
precise
neuronal
localization
of
other
amino
acid
sequences
of
the
D2
receptor
has
allowed
initial
DA
receptors
that
have
been
cloned,
including
the
putative
studies
of the
phosphorylation
of DA
receptors.
Lee
and
col-
D3
receptor
(which
has
been
reported
to
be
present
in
the
leagues
(12)
have
recently
generated
peptides
corresponding
ventral
but
not
dorsal
striatum)
and
D4
and
D5
receptors.
to
amino
acids
221-235
(designated
D2-3)
and
332-343
It
remains
to be determined
if D2
and
D1
receptors
func-
(D2-5);
these
peptides
are
phosphorylated
in
the
presence
of
tion interactively
in
the
population
of neurons
that
expresses
the
catalytic
subunit
of
protein
kinase
A.
The
Km
of
the
both
DA
receptor
subtypes.
The
key
to understanding
whether
peptides
is approximately
132
and
200
jM
(D2-3
and
D2-5,
these
receptors
function
in
a
cooperative
or
antagonistic
respectively),
with
Vmax
of
0.28
and
0.98
tM
. min’
. mg’
fashion
will
be
a thorough
understanding
of the
signal
trans-
(12).
As
the
Km
values
for
restricted
peptide
sequences
are
duction
pathways
through
which
the
different
DA
receptors
usually
higher
than
those
for the
haloprotein,
it is conceivable
operate.
DA
receptors
have
generally
been
classified
on
the
that
the
Km
for
phosphorylation
of
the
D2
receptor
by
pro-
basis
of
their
effects
on adenyl
cyclase
activity:
D1
receptors
tein
kinase
A
is
in
the
range
of
the
physiological
concentra-
stimulate
whereas
D2
receptors
inhibit
or
have
no
effect
on
tion
of
the
receptor
protein.
Several
other
peptides
cor-
adenyl
cyclase.
Thus,
one
could
explain
antagonistic
interac-
responding
to
other
segments
of
the
D2 receptor
have
also
tions.
However,
synergistic
interactions
between
the
two
been
tested
as
substrates
for
kinase-induced
phosphoryla-
receptor
subtypes
presumably
could
not
operate.
However,
tion.
A
peptide
corresponding
to
amino
acids
144-152
has
recent
studies
have
indicated
that
D1
receptors
may
work
proved
to
be
a
substrate
for
protein
kinase
C,
whereas
through
more
than
one
transduction
system:
D1
receptors
another
peptide
sequence
(AA
220-233)
is
a
substrate
for
that
regulate
phosphoinositol
turnover
in the kidney
and
stri-
both
protein
kinases
A
and
C (J. Grebb,
P. Greengard,
and
atum
have been
uncovered.
Thus,
the
second-messenger
sys-
M.
Goldstein,
unpublished
data).
tems
through
which
ligand-receptor
interactions
affect
intra-
Phosphorylation
of
solubilized
and
semi-purified
D2
cellular
mechanisms
may
be
coordinately
regulated
in
the
receptor
(13)
has
also
been
examined.
Several
phosphopro-
case of
D2-D1
interactions.
teins
can
be
seen
after
protein
kinase
A-induced
phosphoryl-
Seeman
and
colleagues
(21)
recently
examined
the
interac-
ation
of the
receptor;
one of these
corresponds
to
the
molecu-
tions
between
D2 and
D1 receptors,
and
reported
the absence
lar
mass
(92-94
kDa)
of
a
D2
binding
unit
(12).
Other
recent
of
a
D2-D1
link
in
a large
percentage
of
postmortem
striatal
reports
also
examined
the
regulation
of purified
D2
receptor,
samples
from
schizophrenic
subjects.
D2
agonists
reduce
and
indicate
that
protein
A-induced
phosphorylation
of
the
binding
of
[3H]raclopride
to
D2
receptors
in
striatal
and
D2
protein
reduces
affinity
of
the
receptor
for
DA
agonists
pituitary
membrane
preparation;
these
data
are
consistent
but
not
antagonists
(14).
Studies
of the
mechanisms
through
with
the
proposal
that
raclopride
binding
to
the
D2
receptor
which
DA
receptors
are
regulated
have
predominantly
fo-
is
subject
to
displacement
by
endogenous
DA
(22).
The
D1
1 c
flflflA
k A.h.Irnr,r
k ACrLJ
A kIICI.AC
KI
CrLlI7flOI_JOEKII
A
antagonist SCH 23390 prevented the DA agonist-induced Fuxe (26) hypothesizes that through such
antagonist
SCH
23390
prevented
the
DA
agonist-induced
Fuxe
(26)
hypothesizes
that
through
such
receptor-receptor
reduction
in
[3H]raclopride
binding
to
D2
sites
in
the
striatum
interactions
the
“set
point
of synaptic
transmission
can
be
al-
but
not
adenohypophysis
(which
lacks
D1 receptors).
Converse-
tered
without
interfering
with
synaptic
homeostasis?’
The
ly, DA
agonist-induced
decreases
in
the
binding
of
[3H]SCH
receptor-receptor
interactions
appear
to
operate
more
effi-
23390
to
D1
receptors
was
prevented
by
the
D2
antagonist
ciently
when
the
DA
receptor
site
is supersensitive.
A
direct
eticlopride
(21).
The
ability
of the
D1
antagonist
to block
an
examination
of
the
degree
to
which
receptor-receptor
inter-
agonist-elicited
decrease
in
D2
receptor
binding
is similar
to
actions
are
operative
in
both
schizophrenic
and
control
that
produced
by guanine
nucleotides;
this
form
of D2-D1
in-
human
brain
remains
to
be
determined.
The
presence
of
teraction
therefore
may
be linked
to
G
protein
mechanisms.
such
heterostatic
interactions
would
predict
that
basal
This
D2-D1
link
was absent
in
more
than
half
of
the
striatal
release
characteristics
of
DA
would
be
normal,
but
the
samples
from
schizophrenic
subjects.
However,
there
was
response
characteristics
of
DA
release
to
various
perturba-
also
a defect
in
receptor
interaction
in
striatal
samples
from
tions
might
be
exaggerated.
Such
a
scenario
might
explain
patients with Huntington’s
disease,
but
not
in
patients
with
the
lack
of consensus
on
changes
in basal
DA
concentrations
Alzheimer’s
or
Parkinson’s
disease
or
in
normal
controls.
in
schizophrenia.
The
linkage
of
DA
receptors
to effect
G
proteins
allows
a
The
extrapolation
of basic
science
findings
from
the
rodent
means
whereby
interactions
between
receptor
subtypes
can
to
the
human
is always
fraught
with
difficulty.
For
example,
occur
in
the
same
neurons.
Moreover,
recent
data
indicate
NT-DA
coexistence
in
AlO
DA
neurons
and
in
axons
in-
that
in
human
tissue
multiple
forms
of
both
D2
and
D1
nervating
the
medial
prefrontal
cortex
of the
rat
is well
estab-
receptors
can
be
differentiated
on
the
basis
of
guanine
lished
(28).
However,
recent
immunohistochemical
studies
nucleotide
effects
on
agonist
binding,
and
that
these
different
suggest
that
such
coexistence
may
not
be
present
in
primate
forms
of receptor
subtypes
(which
may
or may
not
correspond
species,
including
humans
(see
refs
29,
30).
Caution
must
be
to more
recently
cloned
D2
and
D1
isoforms)
are
(at
least
in
exercised
before
reaching
a conclusion
concerning
the
exis-
part)
localized
to different
neuronal
populations
(23,
24).
tence
(or
lack
thereof)
of both
NT
and
DA
in
the
same
mid-
Thus,
there
may
be multiple
mechanisms
through
which
DA
brain
neurons.
receptor
subtypes
interact.
The
opportunities
afforded
by
the
use
of
in
situ
hybridiza-
tion
histochemistry
to
localize
specific
mRNAs
may
help
to
resolve
this
issue.
It
is difficult
to demonstrate
unequivocally
DA
INTERACTIONS
WITH
OTHER
TRANSMITTER
a
lack
of
coexistence
in
primate
species,
as
a
variety
of
SYSTEMS
manipulations
(such
as
colchicine
pretreatment)
must
be
made
to
ensure
that
the
intraneuronal
stores
of
the
peptide
The
regulation
of dopaminergic
function
in
the
brain
occurs
are
sufficiently
high
to
allow
detection
using
immunohisto-
through
processes
intrinsic
to
DA
neurons
and
via
interac-
chemistry.
However,
it
is
exceedingly
difficult
to
perform
tions
with
other
neurons.
In
light
of
the
inability
to define
such
manipulations
in
nonhuman
primate
species.
The
ap-
conclusively
an
alteration
in DA
concentrations
or
DA
recep-
plication
of molecular
approaches
to
the
study
of
the
human
tor
density
in
the
brain
of
schizophrenic
subjects,
some
in-
neurotensin
gene
may
clarify
the
status
of
NT-DA
coexis-
vestigators
have
suggested
that
the
involvement
of
DA
in
tence
in
the
primate.
schizophrenia
is
in
response
to
a
primary
defect
in
some
Applying
in
situ
hybridization
histochemistry
to
the
ques-
other
neurotransmitter.
In
this
model,
the
change
in
DA
tion
of CCK-DA
coexistence
in
primate
species,
H#{246}kfeltand
function
represents
a compensatory
homeostatic
response
in
Schalling
and
colleagues
(31) have
made
an
intriguing
observa-
neurons
either
downstream
or
anteceding
the
primary
neu-
tion
in
postmortem
schizophrenic
material.
The
presence
of
ronal
defect.
Whether
or
not
this
hypothesis
is correct,
it
is
CCK
in midbrain
DA
neurons
in
the
rat
has
been
well
charac-
clear that
the
many
aspects
of
DA
neuronal
function
can
be
terized
(29).
However,
Palacios
et
al.
(32)
reported
that
CCK
regulated
by
other
defined
transmitter
systems.
Such
inter-
and
TH
mRNAs
are
not
colocalized
in
neurons
in
the
pars
actions
may
involve
either
classical
transmitters
(such
as ex-
compacta
of
the
human
substantia
nigra.
Subsequently,
citatory
amino
acids)
or
peptide
transmitters.
H#{246}kfeltand
associates
(31)
reported
a relatively
high
degree
of
CCK
gene
expression
in nigral
DA
neurons
in
the
midbrain
Interactions
between
dopamine
and
neuropeptides
from
schizophrenic
patients
(31).
A
comparison
between
The
discovery
of
the
coexistence
of different
neurotransmit-
schizophrenic
and
normal
control
postmortem
material
re-
ters
in
single
neurons
has
altered
our
basic
concepts
of
the
vealed
that
a
relatively
high
number
of
CCK
transcripts
nature
of
information
processing
in
the
CNS.
The
ventral
could
be detected
in
neurons
of human
substantia
nigra
ob-
mesencephalic
DA
neurons
have
been
among
the
most
inten-
tained
from
schizophrenic
subjects;
in
contrast,
very
few
of
sively
studied
of
the
coexistent
neuronal
populations.
These
the
normal
control
subjects
had
detectable
CCK
mRNA.
neurons
express
DA
and
cholecystokinin
(CCK),
and
DA
However,
the
tissue
examined
came
from
schizophrenic
sub-
and
neurotensin
(NT);
frequently,
all
three
transmitters
are
jects
with
a history
of
antipsychotic
drug
treatment.
To
de-
present
in
the
same
cell
(25).
termine
if APD
treatment
could
modify
CCK
gene
expres-
Fuxe
(26)
has
developed
the
concept
of heterostatic
regula-
sion
in
the
midbrain,
chronic
administration
of antipsychotic
tion
by
following
the
regulation
of
D2
binding
and
its
drug
treatment
to a variety
of nonprimate
species
was
under-
modification
by
peptides
such
as
NT
and
CCK;
the
original
taken;
in
no
case
did
APD
treatment
induce
or
enhance
in
vitro
studies
have
been
recently
extended
with
in
vivo
CCK
gene
expression
in
the
substantia
nigra
(31).
Additional
analyses
(27).
Neurotensin
reduces
the
affinity
of
DA
D2
studies
will
be
required
to determine
the
rate
at
which
CCK
agonist
(3H-N-n-propylnorapomorphine)
binding
sites
without
gene
transcription
occurs
in
schizophrenic
and
normal
con-
affecting
the
characteristics
of
antagonist
binding;
although
trol
subjects,
and
if transcription
is modified
by
APD
treat-
the
magnitude
of the
change
in
receptor
affinity
is small,
the
ment.
These
intriguing
findings
of differential
expression
of
effect
is consistent.
This
type
of receptor-receptor
interaction
the
CCK
gene
in
DA
neurons
of schizophrenic
patients
may
is not
due
to displacement
at
the
receptor
site,
but
represents
accelerate
novel
approaches
to
the
treatment
of
schizophre-
an
interaction
at
the
level
of
the
peptide
and
dopamine
re-
nia,
including
the
development
of drugs
that
modify
peptide
ceptors
themselves.
transmission
yet
gain
relatively
free
access
to
the
CNS.
naiL
! 1O0
TI,
eAcco
SI_I
S
A
(fSI
rICTrIkI
AkirI
rICI
rrfL.I
Dopamine-glutamate interactions gests that interactions between the two transmitters may play a crucial role
Dopamine-glutamate
interactions
gests that
interactions
between
the
two
transmitters
may
play
a
crucial
role
in
the
pathogenesis
of
schizophrenia.
Over
the
past
several
years
increasing
attention
has
focused
on
the
possible
regulation
of
dopaminergic
function
by
ex-
citatory
amino
acids,
particularly
glutamate.
A major
impe-
tus
for
this
focus
is
the
fact
that
the
output
of
the
cortex
CORTICAL FUNCTION, DOPAMINERGIC
MECHANISMS, AND SCHIZOPHRENIA
occurs-with
the
exception
of
a
few
peptidergic
neurons-
Attempts
to
localize
specific
sites
in
the
brain
that
are
dys-
almost
exclusively
via
neurons
containing
an
excitatory
functional
in schizophrenia
have been
undertaken
by
pathol-
amino
acid
(EAA),
such
as glutamate,
aspartate,
or
N-acetyl-
ogists
since
the last century
(see ref 42);
some
have suggested
aspartylglutamate.
This
fact,
coupled
with
the
belief
that
that
this
area
of endeavor
represents
the
graveyard
of neuro-
schizophrenia
(in
which
formal
thought
disorder
is
promi-
pathologists.
Efforts
of
investigators
to
describe
specific
nent)
has
some
cortical
abnormality,
has
led
to
an
increasing
pathological
foci
in
schizophrenia
have
traversed
the
same
awareness
of
the
means
whereby
cortical
mechanisms
may
path
as that
subsequently
followed
by biochemists
in
a search
influence
subcortical
dopaminergic
mechanisms
(see
below).
for
changes
in
DA
concentration:
initial
reports
followed
by
Cognitive
function
is thought
in large
part
to
be
cortical
in
counterclaims
and
a general
inability
to
replicate.
However,
nature.
However,
subcortical
sites,
including
those
in
the
the
advent
of
modern
anatomical
methods,
including
im-
striatum,
also
appear
to
be
involved
in cognitive
function
(see
munohistochemistry,
in
situ
hybridization
histochemistry,
ref 33);
such
involvement
may
reflect
corticostriatal
function
quantitative
morphometry,
and
in
vivo
imaging
techniques,
or,
alternatively,
may
be
manifested
by
striatal
influences
on
suggests
that
the
graveyard
of
pathologists
may
turn
into
a
other
downstream
targets.
Carlsson
and
Carisson
(34)
have
treasure
trove
(43).
hypothesized
that
the
cortex
can
control
sensory
input
and
Attempts
to
localize
dopaminergic
dysfunction
in
schizo-
thus
arousal
(which
may
be disturbed
in
schizophrenia;
see
phrenia
initially
focused
on
the
neostriatum,
the
area
in
the
ref
35)
via
the
striatum,
thalamus,
and
midbrain
reticular
brain
with
the
greatest
DA
concentration,
and
the
ventral
core;
this
regulation
of
cortical
sensory
input
and
arousal
mesencephalic
tegmentum,
source
of
DA
projections
to
the
presumably
involves
a number
of
functionally
distinct
cir-
forebrain.
These
attempts
arose
after
the
initial
statement
of
cuits
organized
as
parallel
cortico-striato-pallido-cortical
the
DA
hypothesis.
The
discovery
of
a
dopaminergic
in-
loops,
each
loop
having
a distinct
spatial
localization
within
nervation
of
cortical
regions
shifted
attention
to
the
defini-
each
of
the
relay
stations.
The
basic
proposition
in
this
tion
of
biochemical
and
anatomical
abnormalities
in
the
model
is
that
dopaminergic
inputs
to
the
striatal
complex
mesocortical
DA
system,
and
particularly
within
the
pre-
dampen
the
inhibitory
influence
of
striatofugal
neurons
on
frontal
cortex.
Although
many
studies
have described
changes
thalamo-reticular
projections
that
govern
arousal
in
the
cor-
in
the
cortex
of schizophrenics,
documented
changes
are
the
tex.
Thus,
if
striatal
dopaminergic
tone
is
elevated
(as
the
cell
density
in
the
cortex
rather
than
the
DA
innervation.
dopamine
hypothesis
of schizophrenia
holds),
there
is
an
in-
Such
changes
are
consistent
with
the
presence
of
enlarged
creased
sensory
input
and
arousal
that
can
lead
to
disor-
ventricles
in
(certain)
schizophrenic
subjects.
The
ability
to
ganized
thought
processes.
The
key regulatory
step
by
which
visualize
brain
anatomy
in
the
living
patient
has
revealed
striatal
dopaminergic
tone
is posited
to occur
is
via
cortico-
that
many
schizophrenic
patients
have
enlarged
ventricles
striatal
glutamatergic
projections
that
inhibit
DA
release.
(44,
45).
Because
enlarged
ventricles
usually
occur
at
the
ex-
Phencyclidine
(PCP),
an
N-methyl-D-aspartate
type
EAA
pense
of the
cortex
(leading
to cortical
thinning),
it
is not
un-
receptor
antagonist,
has
been
suggested
to
induce
certain
reasonable
to
assume
that
there
is
an
intrinsic
cortical
defect
schizophrenic
symptoms
in
some
persons.
The
ability
of
in
schizophrenia.
PCP
to
induce
catecholamine
release
is
well
documented.
Accordingly,
it is suggested
that
a decrease
in corticostriatal
Local
cerebral
glucose
utilization
in
schizophrenia
glutamatergic
transmission
would
enhance
subcortical
DA
release,
as does
NMDA
receptor
blockade
by
PCP.
Support-
In
vivo
imaging
methods
have
been
used
in
studies
of schizo-
ing
this
idea
is the
observation
that
in
the
virtually
complete
phrenic
subjects
to
delineate
structural,
pharmacological,
absence
of
dopamine
an
NMDA
antagonist
can
enhance
and
physiological
changes.
Although
the
spatial
resolution
of
locomotion
(36).
such
methods
is clearly
limited,
the
ability
to
define
changes
Unfortunately,
the
precise
interrelationships
between
stri-
within
certain
regions
of
the
brain
and
indeed
delineate
in-
atal
DA
release
and
glutamate
are
not
clear.
Wachtel
and
teractive
circuits
in
patients
offers
a
unique
oportunity.
Turski
(37)
have
noted
three
hypotheses
to
account
for
the
Tamminga
and
co-workers
(46,
47)
have
examined
local
ability
of
PCP
to
induce
a psychotic
state
and
enhance
DA
cerebral
glucose
utilization
(LCGU)
in
actively
psychotic
release.
However,
many
studies
in
which
striatal
glutamate
schizophrenic
subjects
not
on
APD
treatment
at
the
time
of the
levels
were
directly
manipulated
(rather
than
via
systemic
scan.
Overall,
schizophrenic
subjects
showed
reduced
LCGU
administration
influencing
glutamatergic
systems globally)
in
several
limbic
regions,
but
not
in neocortical
or
extrapyra-
suggest
that
corticostriatal
glutamate
may
actually
serve
to
midal
areas;
in particular,
a decrease
in
LCGU
was
observed
enhance
DA
release
(38-40),
and
have
led
to
the
suggestion
in
the
hippocampal
region
and
anterior
cingulate
cortex.
that
increased
(rather
than
decreased)
glutamate
influence
Tamminga
(47)
subsequently
divided
schizophrenic
pa-
over
the
striatum
may
underlie
the
positive
symptoms
of
tients
into
those
with
a
deficit
or
nondeficit
state.
In
the
schizophrenia
by
evoking
DA
release
in
the
ventral
striatum
deficit
patients,
LCGU
was
decreased
in
the
thalamus
and
(41).
Indeed,
direct
infusion
of 2-amino-5-phosphopentanoic
frontal
and
parietal
cortices;
these
areas
exhibited
normal
acid,
an NMDA
antagonist,
to
the
striatum
via
in vivo
dialy-
metabolic
status
in
the
nondeficit
group
of
patients.
Both
sis
probes
blocks
glutamate-evoked
DA
release.
The
involve-
deficit
and
nondeficit
patients
exhibits
hippocampal
and
an-
ment
of
different
EAA
receptor
subtypes
(NMDA
vs.
non-
terior
cingulate
hypometabolism.
Physiological
dysfunction
NMDA
[e.g.,
AMPA
family]
receptors)
remains
unclear.
is
therefore
present
in
different
neuronal
circuits
in
deficit
Although
the
precise
nature
of
the
interactions
between
and
nondeficit
state
schizophrenics,
but
there
is
a
core
glutamate
and
dopamine
remains
to
be
resolved,
the
appar-
change
in metabolism
in
the
anterior
cingulate
area
and
hip-
ent
involvement
of certain
cortical
sites in schizophrenia
sug-
pocampal
region
of
all
patients.
DOPAMINERGIC
MECHANISMS
IN
SCHIZOPHRENIA
2417
LCGU measures are thought to predominantly reflect Although it appears that functional or structural defects
LCGU
measures
are
thought
to
predominantly
reflect
Although
it appears
that
functional
or
structural
defects
in
metabolism
of
nerve
terminals,
and
thus
LCGU
is usually
the
dopaminergic
innervation
of
cortical
sites
may
be
mani-
interpreted
to
indicate
that
changes
in
a particular
structure
fested
by
increasing
subcortical
dopaminergic
tone,
recent
are
a
reflection
of
the
functional
status
of
afferents
to
the
postmortem
studies
and
in
vivo
imaging
studies
suggest
that
region.
As
such,
one
might
expect
that
LCGU
measures
there
may
be
cortical
tissue
loss
in
schizophrenia.
How
can
would
give
somewhat
different
results
from
other
in
vivo
im-
one
correlate
such
a structural
deficit
with
increased
subcor-
aging
techniques.
For
example,
Tamminga
(47)
described
tical
DA
tone?
The
loss of cortical
thickness
can
result
from
how
the
overall
group
of schizophrenic
patients
she examined
deafferentation
or,
alternatively,
from
decreases
in
the
num-
had
no change
in neocortical
sites;
neocortical
hypometabolism
ber
of cortical
neurons.
In
the
latter
case, it is difficult
to
en-
vision
how
such
a decrease
in
corticofugal
neurons
could
be
became
apparent
only
when
the
deficit
state
patients
were
examined.
However,
there
could
be
deviations
from
normal
translated
into
increased
glutamatergic
release subcortically,
in
the
function
of
key
neocortical
sites
which
project
to
the
thereby
increasing
DA
tone.
One
possibility
is
that
the
loss
anterior
cingulate/hippocampal
regions.
in
neurons
in
the
cortex
is restricted
to
interneurons
rather
than
projection
neurons
(57).
Alternatively,
if some
glutamate-
The
dorsolateral
prefrontal
cortex
in
schizophrenia
containing
neurons
of
the
cortex
that
project
to
the
striatal
complex
are lost,
it
is conceivable
that
residual
neurons
are
Studies
using
a different
method
for
the
in vivo
assessment
of
hyperactive;
coupled
with
a decreased
reuptake
mechanism
changes
in energy
metabolism
in schizophrenia
clearly
suggest
for
the
amino
acid,
a relative
hyperglutamatergic
state
might
a functional
impairment
in
the
prefrontal
cortex
(PFC).
Thus,
be
present.
Obviously,
these
are
speculative
notions,
and
Weinberger,
Berman,
and
associates
(see
ref
48)
have
future
work
will
be
needed
to
resolve
the
nature
of
gluta-
described
how
cerebral
blood
flow
in
the
dorsolateral
PFC
is
matergic-dopaminergic
interactions
in
both
the
normal
augmented
in normal
subjects
under
the
conditions
of
a task
brain
and
in
schizophrenic
brain.
thought
to
specifically
reflect
prefrontal
cortical
function
(the
Wisconsin
Card
Sort
Task);
the
normal
increase
in
blood
flow
is dampened
in
schizophrenic
subjects.
These
data
may
MECHANISMS
OF
ACTION
OF
ANTIPSYCHOTIC
be
reconciled
with
those
of
Tamminga
et
al.
(47)
on
the
DRUGS
grounds
of
examination
of
different
dependent
measures
(cerebral
blood
flow
vs.
LCGU)
and
the
task-dependent
na-
ture
of
the
changes
described
by
Weinberger
and
Berman
One
cornerstone
of the
DA
hypothesis
of schizophrenia
is the
(48).
In
addition,
studies
by
Tamminga
(47)
clearly
indicate
observation
that
all
known
clinically
effective
antipsychotic
the
importance
of
defining
patient
characteristics.
drugs
are antagonists
at the
D2 DA
receptor
(see refs
58,
59).
Based
in
part
on
the
task-specific
changes
in
PFC
blood
Although
this
does
not
exclude
actions
at
other
receptors
flow
in
these
data,
Weinberger
(49)
has
elaborated
a
neuro-
from
modifying
the
actions
of
APDs,
it
would
appear
that
developmental
theory
of
schizophrenia.
This
theory
posits
a
antagonism
at
some
D2
receptor
isoform
is
necessary
for
functional
decrease
in
DA
in
the
PFC,
noting
that
cognitive
antipsychotic
action.
Moreover,
because
drugs
such
as sul-
deficits
are
seen
after
lesions
of
the
PFC
DA
innervation
in
piride
and
raclopride
are
thought
to be selective
D2 agents,
primates
(50).
Negative
symptoms
are
specifically
suggested
action
at
a
D2
site
may
be
both
necessary
and
sufficient
for
to arise
because
of the
cortical
DA
“lesion:’
whereas
florid
posi-
antipsychotic
activity,
and
indeed
for
atypical
antipsychotic
tive
symptornatology
(which
can
be
treated
with
relative
suc-
drug
action
(58).
This
does
not
mean
that
interactions
with
cess
by
conventional
antipsychotic
drugs)
occurs
because
of
other
receptors
(such
as the
5-HT2
receptor;
see
ref
59)
can-
excess
dopaminergic
tone
in
subcortical
sites,
including
the
not
modify
the
nature
of
the
clinical
actions
of
APDs,
ren-
nucleus
accumbens.
The
increase
in
DA
tone
in
subcortical
dering
them
more
(or
less)
effective
for
certain
symptom
con-
sites
is suggested
to occur
as
a result
decrease
stellations
or
changing
their
side-effect
profiles.
Indeed,
in
DA
in
the
PFC,
thereby
removing
of a functional
corticofugal
inhibition
glutama-
there
may
be
more
than
one
way
to
achieve
an
atypical
APD
tergic
neurons
from
tonic
DA-mediated
(6,
51).
profile
(58).
Recent
data
suggest
that
DA
depletion
in
the
PFC
can
in-
Elucidation
of
the
mechanisms
subserving
the
atypical
deed
remove
corticostriatal
glutamate
neurons
from
inhibition,
APD
profile
(clinical
efficacy
and
very
low
or
absent
extra-
and
thereby
evoke
a transsynaptic
increase
in DA
release
in
the
pyramidal
side
effects
[EPS;
see
ref
58])
have
been
a
major
ventral
striatum.
Deutch
and
associates
(41,
52,
53) have
shown
focus
of
study
over
the
past
several
years.
This
has
been
that
although
PFC
DA
lesions
do
not
appear
to increase
basal
prompted
in
large
part
by
the
introduction
of
clozapine,
DA
release
in
subcortical
sites,
they
do
enhance
responsiveness
which
is effective
in schizophrenic
patients
refractory
to con-
of
the
mesolimbic
DA
innervation
to
both
environmental
ventional
neuroleptics,
and
also
appears
to
be
of
consider-
perturbations
(mild
stress)
and
pharmacological
challenge.
able
use
in
the
treatment
of
negative
symptoms.
Unfortu-
The
PFC
has
been
the
most
extensively
studied
of the
cor-
nately,
clozapine
is
also
marked
by
a
relatively
high
tical
areas
in
terms
of
regulation
of
subcortical
function.
incidence
(1-2%)
of
agranulocytosis.
However,
recent
data
have
emphasized
a structural
defect
in
Ogren
and
colleagues
(60,
61)
have
been
instrumental
temporal
lobe
sites,
including
the
hippocampus
and
entorhi-
in
the
characterization
of
novel
APDs
with
low
or
ab-
nal
cortex
(54,
55).
These
data
are
also
consistent
with
the
sent
EPS
liability.
A
useful
notion
that
has
emerged
LCGU
findings
(47):
the
entorhinal
cortex
provides
the
major
from
their
behavioral
studies
is
that
atypical
APDS
have
input
to
the
hippocampus.
As
these
temporal
lobe
areas
also
a
very
wide
separation
between
the
ED50
required
to
project
to
the
ventral
striatum,
decreases
in
DA
in
these
lim-
reverse
apomorphine-induced
locomotion
and
the
ED50
for
bic
cortical
areas
might
also
be
expected
to
increase
accum-
eliciting
catalepsy;
in
contrast,
the
doses
of
typical
APDs
bal
DA
responsiveness.
Such
a change
may
be
manifested
in
(neuroleptics)
effective
for
the
two
behavioral
endpoints
are
discrete
parts
of the
accumbens,
such
as
the
shell
region
(56).
much
closer.
Using
these
behavioral
measures,
one
can
dis-
The
entire
cortical
mantle
projects
onto
the
striatum
in
a
sociate
known
and
potential
atypical
APDs
(clozapine,
rem-
topographically
defined
manner;
changes
in cortical
function
oxipride)
from
neuroleptics
(haloperidol).
These
animal
be-
should
therefore
result
in
transsynpatic
alterations
in
striatal
havior
screens
have
proved
useful
in
predicting
the
ultimate
function,
but
within
discrete
defined
striatal
sectors.
clinical
outcome
of
putative
APDs.
41R
/,sI
1.
Ar.,iI
100)
Tb
FAcFR
Ie,tirn.,iI
C.OI
1)STFtNJ
AN.Jfl
nFl
ITCH
Analysis of the receptor mechanisms of drugs that have a actions of typical and atypical
Analysis
of the
receptor
mechanisms
of drugs
that
have
a
actions
of typical
and
atypical
APDs
on
different
DA
systems
wide
separation
between
the
ED50s
for
reversal
of
agonist-
within
a “single”
structure,
such
as
the
striatum.
The
islandic
induced
locomotion
and
catalepsy
suggest
that
interadion
at
and
diffuse
DA
innervations
of
the
caudatoputamen
can
be
some
D2
isoform
may
be
the
key
mechanism
for
an
atypical
differentiated
on
the
basis
of
ontogenetic
characteristics,
profile.
Thus,
Ogren
et
al.
(62)
have
shown
that
the
actions
morphology,
responses
to
a certain
ergolene
derivatives,
and
of
substituted
benzamides
such
as
remoxipride,
an
atypical
spatial
relationships
with
the
patch
(striosomal)
and
matrix
APD,
cannot
be
accounted
for
on
the
basis
of
blockade
of
compartments
of the
striatum
as defined
on
the
basis
of other
5-HT2,
muscarinic,
or
adrenergic
receptors.
histochemical
markers.
Fuxe
and
Ogren
(66)
recently
ob-
If
an
atypical
APD
profile
can
be
achieved
by
action
at
D2
served
that
the
atypical
APD
remoxipride
exerts
selective
receptors,
such
a hypothesis
must
explain
the
typical
neuro-
effects
on
DA
release
in
the
diffuse
DA
innervation
of
the
leptic
profile
of the
selective
D2 antagonist
sulpiride.
Two
re-
medial
striatum;
distinct
compartmental
effects
of remoxipride
cent
findings
may
resolve
this
apparent
discrepancy.
The
first
on
striatal
c-fos expression
have
also
been
seen
(67).
These
is
the
cloning
of multiple
D2-type
isoforms:
typical
and
atyp-
data
may
suggest
that
different
DA
D2
receptor
forms
are
ical
APDs
may
interact
with
different
isoforms
of the
DA
D2
present
not
only
in
different
brain
regions,
but
also
within
receptor.
It
is
not
clear
to
what
degree
such
isoforms
may
different
classes
of
neurons
within
a
given
area.
correspond
to
the
currently
known
D2
forms,
such
as
the
so-
called
D4
receptor.
However,
examination
of
the
receptor
binding
profile
of
an
expressed
D4 suggests
that
the
pharma-
CONCLUSIONS
cology
cannot
explain
all
atypical
APDs.
The
second
expla-
nation
may
lie in atypical
APDs
interacting
with
different
D2
The
DA
hypothesis
of
schizophrenia
remains
a
hypothesis.
isoforms
that
are
heterogeneously
distributed
in
the
brain;
The
most
compelling
data
marshalled
in
support
of
the
recent
data
suggest
that
the
alternative
splice
products
of the
hypothesis
are
still
in
relationship
between
APDs
and
D2
original
D2
receptor
clone
(4)
may
be
expressed
to
different
receptors,
and
the
existence
of psychostimulant-induced
psy-
degrees
in
different
brain
regions,
as
are
other
cloned
D2-
choses.
It
has
been
difficult
to
determine
to
what
degree
the
type
receptors.
Accordingly,
it
might
be
possible
to
discern
DA
hypothesis
is
one
of schizophrenia,
as
opposed
to
one
of
reginally
specific
changes
in
DA
release
or
metabolism
that
psychosis.