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SCHIZOPHRENIA AND THE Dl RECEPTORzE:;: NEGATIVE
MINDA R. LYNCH Research and Development Serv., V.A. Medical Ctr., and Dept. Psychiatry, S.U.N.Y. Health Science Ctr. Syracuse, New York U.S.A. (Final form, January 1992) Contents 1.
2. 2.1. 2.2. 3. 4. 4.1. 4.2. 4.3. 5. 6. 6.1. 6.2. 6.3. 7. 7.1. 7.2. 8. 9.
Abstract Introduction Negative Symptoms of Schizophrenia Response to N.:uroleptics Organic Correlates Cortical Modv.i.ationof Subcortical DA Activity DA Receptor Coupling Central Dl and D2 Sites 6-hydroxydopamine Lesion Effects Receptor Coupling in Schizophrenia Dl and Negative Symptoms Modeling the Negative Profile NAS DA Hypoactivity The PFC and Behavioral Reactivity A Role for PFC Dl Receptors Mechanisms for Dl Regulation NE and Negative Symptoms 5-HT and Negative Symptoms DA Receptors and Schizophrenia: Future Challenges Conclusions Acknowledgements References
797 798 798 799 a00 802 804 a04 804 806 808 810 a10 812 812 814 a14 816 al7 819 a19 a20
Abstract Lynchr Minda R.: Schizophrenia and the Dl receptor: Focus on negatibe symptoms. Prog. Neuro-Psychopharmacol. G Biol. Psychiat. 1992, 16(6):797-832. 1.
Negative symptoms have been associated with structural impairment in the PFC, and hypothesized to arise from a central hypodopaminergic substrate.
M. R. Lynch
798
2.
Corticofugal PFC neurons, which are inhibited by VTA DA innervation, exert a tonic excitatory modulation on DA activity in the NAS. Lesions of ascending DA forebrain projections "uncouple" the functional link between Dl and D2 receptors, permitting independent activation of Dl sites in generating behavioral output. A previously identified absence of this Dl/D2 link in schizophrenic brain suggests that functional activation of PFC Dl receptors may induce hyperinhibition of descending corticofugal efferents to the NAS. Consequent hypoactivity of DA in the NAS is proposed to give rise to negative symptoms of schizophrenia, and low dose DA agonist treatments may mimic behavioral features of this symptom profile via direct PFC Dl stimulation. It follows that clozapine's efficacy for negative symptoms may be attributable, in part, to blockade of PFC Dl receptors, with subsequent enhancement of glutamate-facilitated NAS DA activity.
3.
4.
5.
6.
Keywords: clozapine, dopamine hypothesis, Dl receptor, hyperinhibition, negative symptoms, prefrontal cortex, receptor coupling, schizophrenia. Abbreviations: computed axial tomography (CAT), dihydroxyphenylacetic acid (DOPAC), dopamine (DA), homovanillic acid (WA), B-hydroxydopamine (6-OHDA), 5Lhydroxyindoleacetic acid (5-HIAA), magnetic _ resonance imaging (MRI), 3-methoxy-4-hydroxy-phenylglycol (MHPG), 3-methoxytyramine (3-MT), N-methyl-D-aspartate (NMDA), norepineph(NAS), positron emission tomography rine (NE), nucleus accumbens (PET), prefrontal cortex (PFC), serotonin (5-HT), tyrosine hydroxylase (TH), ventral tegmental area (VTA). 1. Introduction In the following
review,
observations
chemical
and neuropharmacological
clinical
data
to propose
the substrate gous
animal
a specific
for negative
model
symptoms
of this symptom
2. Negative The pathognomonic fied by both logical
category
for a negative Cannon which
closely
et al. 1990, include
a chronic
"defect
overlapping
Carpenter
affective
tor retardation,
of schizophrenia
mechanism
as originally
(19191,
with more
of this disease et al. 1985).
comprise
recent
Negative
anhedonia,
anergia
impairment
(see Table
syndrome"
which
1985,
symptoms,
flattening,
or "deficit
identia noso-
descriptions
(Andreasen
and neurocognitive state"
in
and a homolo-
of Schizophrenia
of schizophrenia,
profile
biowith
pathophysiological
(1950) and Kraepelin
symptom
behavioral,
are integrated
profile.
Symptoms
features
Bleuler
from animal
investigations
or psychomol), define
is a major
fac-
799
SchtiphreniaandtheDlreceptor Table Differentiating
Features
of Schizophrenic
Positive
symptoms
Characteristic
1 Symptom
profile
Profilesa
Negative
profile
Hallucinations Delusions Thought disorder
Amotivation Anhedonia Anergia Poverty of speech Blunted affect Intellectual impairment
Response to neuroleptics (DZ receptor antagonists)
Symptom
Poor response
DA agonist
No effect/worsening
Clinical
tCentra1
DA independent/ DA hypoactivity
Proposed
treatment
pathoetiology
Structural CAT NRI
pathology
alleviation
DA
improvement
Normal
Tissue injury/necrosis Ventricular enlargement Hypofrontality
CSF metabolites
Normal
+DA, 5-HT metabolites
Functional assessment Cerebral blood flow Neurologic signs PET
Normal
Impaired Hypofrontality Hypofrontality Mixed findings
aSee references
in text
tor in the schizophrenic's social
functioning
2.1. Response
(Meltzer
ease
tors
Bunney
1980),
tant
effects
(and/or
poor
(D2 receptor
1976).
deficit
The hypothesis
DA receptor Saller
state
drugs,
of central
which
has proven with
antagonists)
(Angrist
patient,
[Freeman 19851).
particularly
so-called
are
DA recep-
of neuroadaptations blockade
and Salama
pharmacotherapy
was
and be-
of the schizophrenic
via blockade
1987,
implicat-
of this dis-
electrophysiological
via the cascade
follow
Lane and Blaha
to traditional
leptics
and
of schizophrenia
that neuroleptic
for management
which
err the schizophrenic
and Stahl
biochemical,
therapeutic
DA systems 1987,
life
in the etiopathology
to indicate
efficacious
their
(Seeman
central
1973, Meltzer
observations
clinically induce
DA activity
by substantial
havioral
of
1989).
Zureick
the DA hypothesis
form,
central
(Matthysse
supported
and
quality
to Neuroleptics
In its original ed increased
diminished
'typical'
in and
Howevresisneuro-
et al. 1980, Johnstone
et
800
M.R Lynch al. 1978: but see also discussions by Breier et al. 1987 and Meltzer et al. 1986) that alleviate more florid positive symptoms of the disease (i.e., hallucinations, delusions and disordered cognition).
A modified DA hypothesis by Crow (1980) accounts for dif-
ferences in neuroleptic responsivity among patients with positive or negative symptom profiles.
Crow proposes that positive schizophren-
ic symptoms, representing a 'Type I' profile, can be linked to pathophysiologic disturbances of central DA transmission.
By con-
trast, features of the defect state, or 'Type II' schizophrenia, are proposed to arise from a non-dopaminergic substrate: in fact, negative symptoms may be attributable to tissue injury or necrosis in this underlying substrate (Hughlings-Jackson 1932).
It has subse-
quently been reported that negative schizophrenic symptoms improve with DA agonist treatment (e.g., amphetamine [Angrist et al. 19821 or L-DOPA [Alpert and Rush 1983, Gerlach and Luhdorf 19751) (versus postitive symptoms which show either no change or exacerbation following DA agonist administration [Angrist et al. 1974, Snyder 1973l). These latter observations prompted a further modification of the DA hypothesis to specifically implicate central DA -activity
in the
etiopathology of negative schizophrenic symptoms (MacKay 1980, Meltzer 1979).
Support for a hypodopaminergic hypothesis has come
from reports that global reductions of cerebral DA, in sub-human primates, induce social withdrawal, blunted affective responses and retarded motor activity (McKinney et al. 1980, Redmond et al. 19711, resembling symptoms which characterize the schizophrenic deficit syndrome. 2.2. Organic Correlates As contrasted with the positive symptoms of schizophrenia, an organic component to the pathophysiological substrate of the deficit syndrome has been suggested by both biochemical correlations and observations from neuroimaging. ble 1.
These findings are summarized in Ta-
For example, enlarged cerebral ventricles have been reported
from schizophrenics with negative symptoms (Andreasen et al. 1982, DeQuardo et al. 1989, Williams et al. 1985), poor response to antipsychotic treatment (Weinberger et al. 1980) and cognitive impairment (Golden et al. 1980, Johnstone et al. 1976). Other studies have shown a positive correlation between enlarged ventricular size, cortical atrophy, or poor prognosis with drug therapy, and reduced
SchizcphrentaandtheDlreceptor CSF concentrations Lindstrom gesting
that patients
deficiencies cular
with
Regional
veal a pattern schizophrenic
and recent decreased
studies
(Breier
et al. 1991).
between
neurological
from anecdotal
and case reports
damage
with
schizophrenic for a review): cognitive (i.e., 1979,
impairment
parallel
suggest
ality
vascular
on measures
features
Thus,
ces support
data
activity
glucose
PET scans
images
indices
damaged,
in remaining would
reported
of this
studies
re-
from schizohypo-
to be unrelated 1990,
to
Delisi
and blood
consistent
flow indi-
indices findings
for these
of PFC terminals neural
the summation systems,
and
in the PFC of chronic
or surviving
neural
cortex
Moreover,
(Buchsbaum
In accounting
represent
and compensating,
et al.
1986)
other
but functional
do not yield
that degeneration
activity
state
find hypofront-
cortex
1991).
atrophy
state:
ces,
metabolic
of frontal
neurologic
impairment.
pensatory
1986
flow measures
to damage
utilization,
has been
ing this structural it is possible
lobe
induces
in frontal
investigations
(Bachneff
of cerebral
in the defect
blood
and Weinberger
secondary
some
of schizophrenia
(PET scan)
primates
[Brozoski
aberrations
from structural,
a pattern
schizophrenics
while
controls
from PET scan
the clinical 1986).
between
normal
frontal
in the deficit
performance
(Berman
innervation
of cerebral
no difference versus
symptoms
However,
of
Descriptions
of the negative
in nonhuman
from cerebral
of structural
negative
region.
frontality
bral
reports
with
reduced
phrenics
response
and severity
Zec and Weinberger
reported
vol-
axons)
19841).
of hypofrontality
these
cortical
those
negative
and Nasrallah
correlation
sustaining
features
re-
of cortical
impairment
1987,
lobe damage
of delayed
with
Coffman
et al. 1990).
of patients
have
imaging
is a positive
(Merriam
diagnostic
paralleling
and see Goldman-Rakic
of patients
there
sug-
the ventri-
loss of myelinated
(Goldman-Rakic
and frontal
deficits
Observations
port
defining
profile
in association
of prefrontal
symptoms
CAT or MRI
this reduction
(i.e.,
In addition, signs
symptoms lining
et al. 1990,
attribute
matter
schizophrenic
overlap
also
(Andreasen
white
schizophrenic
employing
1974,
et al. 1986),
in structures
of hypofrontality
ume
(Bowers
van Kammen
negative
analyses
symptoms
1986)r
negative
et al. 1983,
of neurotransmission
system.
to
of DA and 5-HT metabolites
1985, Nyback
of cereparallel-
differen-
triggers
systems.
of activity
regional
patterns
com-
As in both of glu-
M.R Lynch
802 case utilization
may not reflect
3. Cortical Ascending
DA projections
corticolimbic ticolimbic region)
fibers
ly to PFC where
cal pyramidal
binding White
identified
to central
taneous
activity
in the PFC
inhibition
iontophoretic and Aghajanian
1976).
VTA DA projections
et al. 1988).
Corticofugal
glutamatergic
cortical
DA terminal
tie et al. 1985,
Glowinski
glutamate
ullon
release
veal
mesolimbic
nucleus
ing the enzyme cholamine presynaptic
effect
synthesis),
tally,
via NMDA
19861,
see Grace
circuitry
and
stimulates
1990)(i.e.,
(b) infusion DA release calcium
is depicted
(Nieo-
NMDA
recep-
studies
terminals terminals
anatomically
of
electri-
through
in the first
data
exert
DA release
TH-labeled
sub-
1980, Chris-
(a) ultrastructural
appose
of
inhibi-
increases
Thus,
may be mediated
1991 for a description
lesion
efferents
with
as
(Bunney
and neurochemical
subcortical
tyrosine
receptor-induced
(Carter
DA activity.
and are therefore
facilitation:
spon-
from the PFC innervate the NAS
and Pickel
oxidizes
neurochemical
DA activity,
since:
directly
(Sesack
which
into the NAS also
This
This
on DA terminals
the effect
stimulation-induced
Behavioral
in NAS enhancing
that PFC efferents
(Clark and
PFC glutamatergic
of the PFC stimulates
et al. 1978).
tors located
1981).
over subcortical
cal stimulation
inhibition
of the VTA inhibits
selective
including
that these
the
Ligand
via VTA DA projections,
projections
regions
from the rat suggest tonic modulation
mediated
to the PFC abolishes
(Thierry
provide
structures.
of DA to the PFC mimics
Conversely,
and corti-
et al. 1984) and this stimula-
(Ferron
appears
application
neural
stimulation
of in-
observa-
DA afferents
subcortical
(A-10
anterior-
and dendrites microscopic
between
induces
electrical
VTA
and more
et al. 1989) which
innervating
DA receptors
Thus,
tion-induced
tion
(Goldman-Rakic
pathway
1987).
synapses
electron
mesoMesocor-
in the midbrain
tuberculi,
cell bodies
Recent
DA Activity
into nigrostriatal,
from cell bodies
upon
terminals.
(Fuxe et al. 1985).
and olfactory
1991).
cells
efferent
systems
they synapse
have also
major
course
(Bachneff
of Subcortical
are organized
and hypophyseal
to the accumbens
terneurons tions
Modulation
a loss of cortical
re-
in this contain-
step of catepositioned
of glutamatergic
for
agonists
(Jones et al. 1987)(specifiinflux
[MacDermott
of this mechanism
in the schematic
diagram
et al. in NAS).
of Fig 1.
803
SchixophreniaandtheDlreceptor
/----------
7
l DEf?
Fig 1. Glutamatergic (Glut) modulation of NAS DA activity which gives rise to behavioral output via lower motor circuitry (i.e., NAS projections through ventral pallidum to the mesencephalic locomotor region [Mogenson 1987, Swerdlow et al. 19861). Note that PFC DAinduced hyperinhibition or disinhibition of glutamate to the NAS can affect the level of NAS DA-activated behavior.
Behavioral the opposite ity
(specifically,
in the rat) NAS
correlates effect
(Willins
(e.g., with
1987,
et al. 1991). 6-OHDA
pharmacologic
1976,
Pijnenburg
these glutamatergic amphetamine, phetamine these
infusion
observations
(NAS) regions, activity
relieve
suggest
glutamatergic
the locomotor
Conversely,
by PFC infusion
(Vezina
with NAS DA inducing
effects
activation (Costa11
inhibition
seen and of
by concurrent
et al. 1991).
dam-
Together,
and in subcortical
on DA-stimulated
hyperactivity
and Lyness
of the DA agonist,
induced
that DA in the PFC,
opposite
neurons
hyperactivity
of DA in the NAS
stimulation
into the
of corticofugal
(Leccese
resembles
locomotor
hypermotility
Disinhibition
a behavioral
into the NAS
exert
cortical
et al. 1976).
hyperactiv-
of DA in the PFC
NAS DA turnover
stimulation
demonstrate
antagonists
and induces
efferents
reduces
depletions
inhibition.
et al. 1980)
findings
of NAS DA-modulated
of glutamatergic
Severe
infusion)
mediated
et al. 1979) which
following Naylor
biochemical
of amphetamine-induced
infusion
to the NAS enhances
Pycock
(LeMoal
reductions
following
from DA-receptor projections
to these
- an attenuation
behavioral
and DA in the PFC pro-
M.RLynch
804 ducing
hypomotility
via decreased
A hypodopaminergic schizophrenia
hypothesis
to include
tivity,
specifically,
DA terminals discussion
would that
tion of these
release.
for the negative
et al. 1991, Weinberger
(Davis
modified
glutamate
a role
for corticofugal
wherein
result
mechanisms
follows,
cortical
which
perturbation
might
of
of NAS DA acof PFC
of NAS DA activity.
glutamate-containing consequent
NAS DA -activity),
profile
can be further
regulation
neuropathological
in aberrations
symptom
1987)
induce
pyramidal
In the
hyperinhibicells,
to PFC perturbation,
will
(hence,
be con-
sidered.
4. DA Receptor 4.1.
Central
Central subtypes
Dl and D2 Sites
DA receptors on the basis
tems, with
uncoupled,
clic AMP activity subtypes dense
with
closely VTA
overlap
Behavioral caine)
effects
the Dl receptor Arnt
19881,
for most
and Dl/D2
physiologically
an inhibitory
region
densities
influence both
on cy-
receptor
is especially of D2
(rarde et
for the Dl site projections
drugs
in PFC
from the
(e.g., amphetamine
to stimulation
'enabling'
(or facilitating)
behavioral
"coupling"
role
of both
effects
with
(see
sites
is
(White et al.
has been demonstrated
as well
or co-
at the D2 site,
In fact, co-activation
agonist-induced
in neostriatum,
and the
et al. 1978).
attributed
receptor
sys-
cyclase
Although
1979).
of afferent
Tassin
an
AMP effector
to adenylate
to the distribution
of DA agonist
serving
into Dl and D2 receptor
cyclic
this cortical
the pattern
1987 for a review).
required
having
Moreover,
et al. 1986,
are generally
coupled
as compared
1978). with
classified
link with
and Calne
in the PFC,
Dl sites, Hyttel
(Savasta
or else
(Kebabian
are found
al. 1987,
have been of their
the Dl site normally
D2 receptor
Coupling
as in the NAS
electro-
(Wachtel
et
al. 1989). 4.2. 6-OHDA Damage
Lesion
to DA terminals
for neuroadaptive pathological triggers
Effects in rat neostriatum
capabilities
conditions
a sequelae
of central
producing
of compensatory
neuronal
has served DA systems,
as a model in response
degeneration.
processes
as outlined
DA loss in
to
SchbzophreniaandtheDlreceptor Table 2 6-OHDA Lesion-Induced
+D2
Neuroadaptation
Max
Craese et al. 1977 Hu et al. 1990
+DAhigh conformation
Arnt
+Basal DA release
Robinson et al. 1990 Zigmond et al. 1990
tL-DOPA stimulated
DA release
Abercrombie
Functional Dl activation: Circling (unilateral lesion) Locomotion (bilateral lesion)
tDl-induced
neural
HU et al. 1990
conformations),
inhibition
Robertson
c-fos
alterations
at both post-
and conversion and pre-synaptic Partial
transmitter
from surviving
cellular
release
DA at control
are findings enhanced
to suggest
consequent
stimulates
from 6-OHDA
greater
activation
rat
[Molloy
OHDA
or reserpine
and
exception
that
is, circling
in intact
induce
inactive
of inducing
central
activation
is demonstrated
behavioral
For example,
in extracellular
than
However,
to uncouple
of D2 agonist-induced (b) "enhanced"
significant
by:
behavioral effects
in the unilaterally
L-
fluid)
striatum.
significant
but not in DA intact,
19841).
extra-
may be actually
perturbation.
(e.g., SKF 38393)
(functional)
Uncoupling
ist blockade
lation:
appears
maintains
Even more
(measured
of DA
by increased
which
efficacy
are behaviorally
and Waddington
for independent
Dl receptor.
levels.
in the rat,
in DA depleted,
(with the possible
vior
1987);
DA release
receptor
in the process
are compensated
that transmitter
drugs
(e.g., Dl and D2 recep-
terminals,
(non-lesion)
Dl agonists
tal animals.
lesions
striatum
Dl agonist
Secondly, havioral
junctions
to a DA terminal
lesioned
et al. 1989
from low- to high-affinity
neurotransmission.
lowing
1984
Krueger et al. 1976 Mishra et al. 1974 Parenti et al. 1982 Rosenfeld et al. 1979 Tassin et al. 1982
2, including
sitive
Arnt and Hyttel Arnt 1985a
cyclic AMP
tor upregulation
DOPA
et al. 1990
iDl-induced
Dl-activated
Table
1987
be-
experimen-
in the normosengrooming
DA depletion
beha-
with
Dl and D2 sites, of behavior
6al-
via the
(a) loss of Dl antagoneffects
(see Arnt
from central lesioned,
DA stimu-
and locomo-
806
M.RLynch
tor activation 1985b]
rat,
ditional
in the bilaterally
following
evidence
is enhanced
selective
that efficacy
consequent
that Dl-induced
cyclic
lesioned
or reserpinized
[Arnt
Dl agonist
administration.
Ad-
of Dl-mediated
loss comes
AMP activation
is enhanced
striatum
and PFC,
following
terminal
nuclei.
Electrophysiological
6-OHDA
ical observations
in revealing
striatum
neural
enhances
tion of selective oncogenes ment
in 6-OHDA
sult
which
is significant
naling event
changes tions
kinase
induces
in synaptic
ble with
the notion
neuropathological
involve
neostriatum,
processes AMP
in Dl receptor
that Dl receptor
mechanisms
of genetic
which
maintain
re-
AMP sigmediated
long term
1990).
function
alterations
tran-
This
cyclic
mediating
(Sheng and Greenberg
changes
treat-
suggest-
interface.
is the DA receptor genes
proto-
Dl agonist
(not D2) triggered
- early
applica-
nuclear
by selective
production)
efficacy
in these biochem-
of DA in the neo-
importantly,
the Dl-cyclic
immediate
of lesion-induced
lesion
these
from microiontophoretic
Most
in that Dl-
(or protein which
that 6-OHDA
may
beyond
in accumbens,
support
but not non-lesioned
Dl efficacy
occur
transduction
from observations
to DA projections
data
are activated
lesioned,
ing that enhanced scription
damage
inhibition
Dl agonists. c-fos)
(i.e.,
signal
to DA terminal
Observaare compati-
are significant
chronic
conditions
for of
psychopathology. In conclusion, following pletion
given
6-OHDA
of PFC DA axons
interactions receptors
reviewed
in the following Coupling
an abundant
in animal tions,
which
and enhanced
Receptor
behavioral,
relatively
human
brain.
tions
in human
data
reveal
neural
enhanced
Dl/D2
receptor of Dl
or remaining
for this hypothesis,
derived
in central
efficacy
de-
activation
from surviving
disruptions
events
that partial
may uncouple
and/or
Dl receptor
Dl/D2
from
recep-
in schizophrenia,
are
section.
in Schizophrenia
experimental
literature
neurophysiological
few studies
Seeman
it follows
by DA released
Supporting
studies
tor coupling
While
independent
in this region,
post-mortem
of Dl-mediated
lesion,
in schizophrenia
and permit
PFC DA terminals.
4.3.
a facilitation
neurochemical
et al.
striatum
have probed
documents
receptor
(1989) recently
by incubating
the Dl/D2
and biochemical
tissue
associations
examined samples
Dl/D2 with
link
investigain
interacselective
807
SchizophreniaandtheDlreceptor radioligands or DAlow
affinity
antagonists therefore
state
for the endogenous
preferentially D2 agonists
occupation
at the DZhigh blockade
to normal
brain
and normal
could
history.
The authors
in some
schizophrenics.
the rat suggest and/or
though
binding
coupling
et al.
of the Dl site
D2 and
by Dl
in D2 antagonist
(1989) demonstrated in samples between
to previous
permit
that
from schizoschizophrenic neuroleptic
link may be "missing" lesion
independent
in schizophrenic
in schizophrenic
has not been made
effects
in
activation
brain.
(1987) report
Hess et al.
1987).
conformation
via noncompetitive
from 6-OHDA
would
a DAhigh
is evidenced
that the Dl/D2
Observations
determination
(Seeman
reductions
not be attributed
to Dl receptors
a similar
binding
that differences
concluded
port of this suggestion,
in either
ligand
was not present
that uncoupling
enhancement
tagonist
Dl/D2
Seeman
effect
and moreover,
tissue
antagonist
site.
tissue.
exist
to the low affinity
of agonist-induced
this Dl antagonist phrenic
bind
reduce
antagonist binding
Both sites
for the two sites.
In sup-
enhanced
Dl an-
neostriatum
(al-
for mesocorticolim-
bit regions). In addition, siveness
et al.
of adenylate
from chronic this enzyme ride.
Memo
cyclase
schizophrenics,
fluoride
ter recognition intracellular
enzymes
linked
Hess et al.
receptors
from schizophrenic
sodium
which
transduction
fluo-
activate (Bockaert
of second
in schizophrenia. a decrease
of
the transmit-
a modification
suggesting
functional
a similar
determination
of schizophrenic
brain
that structural
perturbation
and D2 receptor
sites,
for the neostriatum
inhibition tory
brain,
with
bypasses
to the Dl receptor
in striatum
stimulation
on G proteins
suggest
respon-
Fur-
in striatal
a compensatory
Dl
down-
activity
at the Dl-second
mes-
for cyclic
AMP activation
in PFC
junction.
Although
here
treated
(1987) have reported
to heightened
stimulation
for signal
findings
thermore,
regions
directly
an increased
maximal
AMP activation
responsible
these
systems
senger
NAS tissue
cyclic
messenger
regulation
to Dl receptor
site and acts
Therefore,
reported
and a greater
in schizophrenic
Sodium
1991).
(1983) have
of DA terminals
enhancing
Dl activity
and nucleus
of glutamatergic
influence
has not yet been
neurons
on DA terminals
in the manner Dl-induced
normally
in NAS would
it follows
in PFC may uncouple
accumbens. which
reported,
induce
exert
Dl
reported hyper-
an excita-
a hypodopaminer-
808
M.RLynch
gic state
at the subcortical
of schizophrenia tential
mechanisms
matergic
tion of cortical
might
include
Dl receptors corticofugal
of the Dl site to G-protein gand
binding
output,
events.
lesions
in the rat which
produce
region
induce
(Tassin
et al. 1982).
adenylate 1986).
Chronic
L-DOPA,
and apathy
through
similar
PFC regions,
a role
Pogluta-
in a popula-
a modulatory efficient
which
role
coupling
transduce
li-
of this hypothesis,
PFC
a 52% loss of DA in this cortical
chronic
symptoms,
also
cyclic
amphetamine,
remain
central
for enhanced
atten-
Dl-mediated
reverses
et al.
emotional
signal
et al. 1990).
transducAlthough
to be demonstrated
that DA agonists
schizophrenic
which
(Roberts-Lewis
attenuates
(Engber
drugs
AMP stimulation
down-regulates
partially
Dl receptors
by DA agonist
negative
more
of Dl-mediated
which
also desensitize
with
and/or
in rat neostriatum
the observation
for alleviating and L-DOPA)
serve
mechanisms
in schizophrenia,
striatal
effects
patible
activity
symptoms
on these
activation
In support
Moreover,
schizophrenic
cyclase
withdrawal tion
a sensitization
negative
at Dl sites
usually
effector
as negative
CSF DA metabolites.
functional
which
to cellular
uates
expressed
by reduced
for hyperinhibition
efferents
for DZ-mediated
level,
and reflected
which
symptoms
(i.e.,
Dl receptor
Dl stimulation
for
are efficacious amphetamine
function
is com-
in the schizophrenia
deficit'state.
5. Dl and Negative Psychopharmacological role
for hyperinhibition
substrate 2.
observations
of negative
First,
psychotic would
be effective
the ability events
which
pharmacotherapy is relatively
ineffective
schizophrenia
(Angrist
typical'
neuroleptic,
(florid)
positive
1988,
Meltzer
1991,
would
drugs,
for treating
clozapine,
Meltzer
and Zureick
while
the chronic
is efficacious symptoms
a
activity
symptoms, neuronal
neuroleptics),
defect
state
et al. 19781,
the
for relieving
Unlike
and
traditional
of this disease 1989).
in Fig
that anti-
neural
('typical'
et al. 1980, Johnstone
and negative
predict
Dl-triggered
Additionally,
D2 antagonist
schematically
schizophrenic
to desensitize
with
in the pathophysiological
Dl-induced
negative
this prediction. with
herein
or attenuate
in treating
are compatible
are diagrammed
proposed
block
of DA agonists
supports
which
at PFC Dl sites,
symptoms,
the hypothesis drugs
Symptoms
in 'a-
both
(Kane et al.
typical
neuro-
809
Schizophrenia and the D 1 receptor
’ Behavioral output/ reactivity
Fig 2. Potential pharmacotherapeutic mechanisms for reversing hyperinhibition of glutamatergic (glut) corticofugals in the schizophrenic deficit state. leptic drugs, this dibenzodiazepine has weak D2 antagonist properties and shows greater binding to the Dl site -in vivo (Andersen et al. 1986, Farde et al. 1989, Fuxe et al. 1989). Moreover, it preferentially binds to the high-affinity, adenylate cyclase-coupled Dl state (Andersen and Braestrup 1986).
Clozapine's behavioral profile
is also unlike that of D2 blockers in that it does not induce catalepsy or antagonize agonist-induced stereotypy (Maj et al. 1974, Stille et al. 1971).
On both behavioral and neurochemical assay it
resembles the prototypical Dl antagonist, SCH 23390 (Murray and Waddington 1990, Wood and Altar 1988): It increases intraneuronal metabolites, DOPAC and HVA, without affecting extraneuronally produced 3-MT (which reflects transmitter release). Secondly, clozapine blocks stereotyped behavior induced with NMDA antagonist treatment, suggesting that part of this drug's neuropharmacologic profile may involve enhancement of central glutamatergic activity (Schmidt et al. 1991).
In the present model, an-
tagonism at Dl receptors in schizophrenic PFC would release these sensitized sites from hyperinhibition, enhancing glutamatergic activation of DA in the NAS and thereby reversing the mesolimbic DA hypoactivity which gives rise to negative symptoms.
k4EA. R Lynch
810
Lastly, the prototypical Dl antagonist, SCH 23390, antagonizes social isolation in the Java monkey (Ellenbroek et al. 1989).
As
this behavioral profile has been proposed as an animal model for negative symptoms of schizophrenia, its antagonism by central Dl receptor blockade provides additional evidence to implicate ligand activity at the Dl site in producing the schizophrenic deficit state. 6. Modeling the Negative Profile 6.1. NAS DA Hypoactivity Increases of DA in the NAS induce behavioral hyperactivity in the rat (Costa11 and Naylor 1975, Pijnenburg et al. 1976) and are also believed to be the critical substrate for euphoragenic properties of reinforcing drugs (Koob and Goeders 1989, Wise and Rompre 1989).
On
the other hand, reductions of NAS DA induce hypoactivity on measures of spontaneous locomotion (Joyce and Iversen 1978, Koob et al. 1978).
Low doses of direct DA receptor agonists (e.g., the mixed
Dl/D2 agonist, apomorphine) decrease DA turnover and DA cell firing in subcortical DA regions (Aghajanian and Bunney 1973, Bannon and Roth 1983) and also induce hypomotility, which resembles the locomotor suppression observed after DA depletion of the NAS (DiChiara et al. 1976).
Moreover, low dose DA agonist treatment in-
duces a behavioral profile characterized by anhedonia and cognitive deficiency in operant behavior paradigms
(carnoy et al. 1986a, 198613). This low dose agonist-induced profile has been suggested as
an isomorphic model for the negative symptoms of schizophrenia (Carnoy et al. 1986b). Traditionally, low dose DA agonist effects have been attributed to DA inhibition from selective stimulation of central DA autoreceptors which have a greater affinity for the endogenous ligand than do postsynaptic sites (Seeman 1980).
However, recent studies point in-
stead, to a particularly agonist-sensitive population of post-synaptic DA receptors as the substrate for low dose DA agonist effects (Lynch 1991, Stahle and Ungerstedt 1987, 1989). Post-synaptic DA receptors in the PFC have been proposed to exist primarily in a DAhigh state, since this region has a low DA "tonus" (i.e., sparse innervation, compared to other forebrain DA terminal regions)(Ere-
811
SchizophreniaandtheDlreceptor shefsky
the neurocircuitry bury
et al. 1984)
the rat
for low dose and also
As VTA terminals ceptors
(Bannon
high-affinity effects
may be found
matergic
projections
population
proposed
PFC-NAS
DA agonist
receptors
induce
in
directly
et al. 1984).
suggests
mediating
in
(Brad-
yawning
infusion
(Bradbury
this observation
in the PFC.
circuitry,
hypoactivity
to PFC lack synthesis-regulating
regulating
would
as a component
agonist-induced
suppression
et al. 1987),
post-synaptic
agonist-induced
In fact,
locomotor
projecting
implicated
for low dose
(Hitri et al. 1989).
into the PFC induces
ceptor
The PFC has been
et al. 1990).
autore-
that the
low dose
DA agonist
Furthermore,
if located
on gluta-
NAS DA activity,
agonism
at this re-
hypoactivity
as diagrammed
of subcortical in the shematic
DA.
This
of Fig 3,
Hypomotility/ yawning
Fig 3. Schematic of hypothesized post-synaptic DAhigh receptor substrate mediating peripherally administered, or PFC infused, low dose DA agonist behavioral effects which arise from hypodopaminergic activity in the NAS: (abbreviations as in Fig 2).
can account
for observations
for low dose the notion ioral
DA agonist
that hypoactivity
suppression
implicating
behavioral
in the rat.
PFC in the neurosubstrate
effects
and is compatible
in NAS DA systems
gives
with
rise to behav-
M. R Lynch
812 6.2. The PFC and Behavioral Several involved
previous with
of symptom
severity
symptoms,
in the rat induces crombie tory
influence
increased mate
a selective Thierry
in the NAS,
(e.g., greater
etc.).
Recently,
suggest
that
PFC DA, hances
Rosin
cortical
menter-induced
inducing
et al.
stress.
(hence,
disinhibition
concentration
is assessed
glutamatergic
system
with
hyperinhibition
hypo-
DA would latory
induce
hypoactivity tween
tions
release in the NAS
of glutamate
state,
opposite
(as in the Rosin
stress-induced
comparing
to removal
increases
genetically
bred
respectively.
that
in PFC moduis, DA
in investiga-
versus
In these
studies,
increase
of PFC DA to experimenter-induced
only hypo-emotional
be-
and behavioral
experimentally
significant
6.3. A Role
this
An association
for hypo-
en-
producing
increases
tionality.
olucci-D'Angio
Thus,
of corticofugal
of PFC DA activity
of
"in check",
release
et al. 1992 study):
has been demonstrated animals
depletion
(where DOPAC
behavior,
stress-induced
which
by experi-
in the NAS),
responsivity
in NAS DA-mediated
deficit
withdrawal,
findings
as an index of DA activity).
in the NAS and b-responsivity.
hypo-responsivity
of behavioral
severe
increases
or disinhibition
an effect
influences
reported
herein,
over gluta-
social
of glutamate
may keep behavioral
or hyper-reactivity
In the schizophrenic
exacerbation proposed
of NAS DA is influenced investigations,
(Aber-
increased
diminution
of speech,
(1992) have
DOPAC
stress
the modula-
hyperinhibition
a further
In their
footshock-induced
the model
In the
as increas-
Considering
stress-induced
poverty
modulation
manifest
of DA in the PFC
with
enhance
anergia,
1986).
on NAS DA activity,
underlying
would
is an exacerbation
Experimenter-induced
activation
In accordance
PFC DA activity
would
is especially
reactivity.
(Weinberger
et al. 1976).
of PFC corticofugals
symptoms.
release
output
to stress
decompensation
PFC DA may be the mechanism of negative
and behavioral
and amotivation.
et al. 1989b,
that PFC DA
in schizophrenia
in response
withdrawal
suggest
responses
'decompensation'
case of negative ed social
investigations
emotional
Stress-induced
Reactivity
animals
hyper-emoshow a
stress
(Bert-
et al. 1990).
for PFC Dl Receptors
The PFC has a higher (Farde et al. 1987,
density
Hyttel
of Dl receptor
1978)
and central
subtypes
than of D2
Dl receptor
sites
have
813
SchizophreniaandtheDlreceptor a ten-fold (Seeman
greater
1987).
are induced
affinity
Accordingly,
by agonism
1990)
can be visualized
onist
administration),
and Robertson
for endogenous
overlap
al. 1986,
Tassin
proto-oncogenes
at central
in untreated
Given
with
PFC
ascending
behavioral
prior
(Dragunow
(Savasta
Supporting Table
DA agonist
treat-
at this Dl release
in
NAS DA activity.
observations
For example,
3.
et
that the high affinity
of low dose
is the PFC -Dl receptor. Hence, DA agonist binding ment cortical site might be the event that inhibits glutamate the NAS, decreasing
Dl ag-
of PFC Dl receptors, from VTA
it is possible
which
et al.
neostriatum
DA terminals
effects
(Graybiel
(i.e., without
this high density
et al. 1978),
DA site mediating
(such as c-fos)
Dl receptors
but not in untreated
1988).
and their
DA than the D2 receptor
for this hypothesis
peripheral
are summarized
administration
in
of selective
Dl
Table 3
Consequences of Central Dl Activation peripheral
SCH 23390
t locomotor + yawning
PFC SCH 23390 infusion
4 amphetamine-induced
PFC a-flupentixol
t NAS DOPAC
Dl
infusion
agonism
6-OHDA induced Dl/D2 uncoupling
(e.g., SCH 23390)
antagonists dose
DA agonist
et al. 1990)
al. 1991).
Similarly,
NAS D2-stimulated behavioral the NAS
[Vezina
voltammetric substrate
locomotor
efferents
findings
also
affinity
t apomorphine-induced
yawning yawning
the opposite spontaneous
yawning
amphetamine
suggesting
for the Dl site,
of
DA.
which
re-
may be the
Louilot
extracellular
in into
In vivo --
inhibition.
NAS
et
increases infusion
that this antagonist
of a-flupentixol, increases
activity
(Hietala
that PFC Dl receptors
modulation
that PFC infusion
of low
in PFC enhances
(i.e., greater
from Dl-mediated indicate
effect
locomotor
in the rat
of Dl receptors
concurrent
et al. 1991]),
locomotion
4 apomorphine-induced
activation
with
for glutamatergic
(1989) report high
and reduced antagonism
hyperactivity
glutamate
induces
- increased
treatment
(Maldonado
leases
activity
et al.
exhibits DOPAC
a
in the
814
M.
NAS
(versus
which
infusion
had no effect
central
apomorphine
DA with
allowing induces
(Longoni
a higher
controls
(Morelli
mental
findings
implicate
in low dose whereas
DA agonist
antagonism
hyperactivity
frequency
agonism
effects
from
fibers
from raphe
1987).
Both ascending
regulating
locomotor
tral NE and central volved
systems below
projection
5-HT activity
of schizophrenia. in modulating
and depicted
Forebrain
noradrenergic
(Oades
enhanced
nist treatment
[Tassin
ly to mesocorticolimbic However,
ing NE terminals that
systems
and 5-HT projecand Loughlin
have been
implicated
have been
Moreover,
hypothesized giving
both
in cen-
to be in-
rise
to negative
role of these
transmitter
is described
in the discussion
in Fig 4.
to PFC
these NE terminals
to frontal
Moreover,
the sensitivity
as 6-OHDA
nuclei
midbrain
(in addition must
of
sparing
infusion
in order
to Dl ago-
electrolytic
send axons
anterior-
ascending
destroys
to DA projections),
be intact
lesion
in response
which
while
innervation
Dl supersensitivity
Significantly,
DA cell bodies
activity
in this re-
but not 6-OHDA,
AMP production
terminal
have been
noradrenergic
to PFC develop
et al. 19821).
cortex
behavioral
of Dl receptors
electrolytic,
cyclic
of the VTA destroy
projections.
behavioral
(Fallon
for NAS DA-mediated
projections
(specificaliy,
lesions
and hypolocomotion,
coeruleus,
mechanisms
et al. 1986).
sustaining
tegmental
experi-
PFC) Dl sites
(or facilitates)
the PFC
projections
in the rat
to the PFC may modulate
ventral
(possibly
Symptoms
in the substrate
as animals
in normosen-
these
NAS DA.
PFC DA activity
implicated
gion
than
Collectively
The potential
schematically
7.1. NE and Negative
receptor
of yawning
from DA in the NAS.
in the pathophysiological
symptoms
Dl/D2
apode-
for Dl Regulation
innervate
output
in animals
to
of the Dl site),
induces
from the locus
nuclei,
and
"uncouples"
at central
increased
binding
facilitates
activation
such as yawning
at this site
arising
Noradrenergic
(which
et al. 1986).
7. Mechanisms
tions
et al. 1987),
reserpine
sulperide,
ligand
at the Dl site)
for independent
sitive
D2 antagonist,
Furthermore,
(i.e., agonism
yawning
of brain
interactions,
the selective
on NAS DOPAC).
Dl receptors
morphine-induced pleted
with
R. Lynch
NE
ascend-
it appears
for Dl upregulation
815
SchizophreniaandtheDlreceptor
J Behavioral output
Fig 4. Potential transmitter interactions in the pathophysiological substrate of negative schizophrenic symptoms. (tPFC Dl denotes enhanced efficacy or independent activation as a result of Dl/D2 uncoupling.);(abbreviations as in Fig 2).
to develop
(Tassin
van Kammen lation
the severity
of both
CSF NE remained apy with
activity
receptors
(Grossman
Considering
with
Dl sites
the modulatory
Dl receptors,
activity
in the negative
tates
with
ligand
region.
alphal,
and Schumann
cortical
agreement
who relapsed
1982,
of these
clozapine
et al. 1977, Perry
noradrenergic
(Goldman-Rakic
of increased
model)
profile
elevated
at PFC Dl sites
central
might
receptor
et al. 1990). of
noradrenergic
suggest
that
PFC NE activity
following
therhas
and beta-adrenergic
Peroutha
in PFC
symptom
the present
binding
alpha2
and
MHPG.
role of PFC NE in sensitization
reports
corre-
symptoms
from neuroleptic
Moreover,
haloperidol.
at central
a high positive
schizophrenic
CSF NE and the NE metabolite
and the distribution
overlaps
reported
of negative
in patients
the D2 antagonist,
et al. 1983),
recently
(drug-free)
high
antagonist
subtypes
(1990)
et al.
between
elevations
et al. 1986).
terminal
(in facili-
loss
in this
818
M.R.Lynch
7.2. 5-HT and Negative Forebrain logical
5-HT systems
disturbances
schizophrenic wherein
have also been
of central
symptomatology.
greater
and greater
DA activity
Indirect
citing
decreased (Bennett
compensatory
density
et al. 1979, Mita
adaptation
5-HT2
tant
even greater effective
schizophrenia
Evidence
antagonist
(Bersani
DA by ascending
tors may be located (DeBelleroche afferents
to PFC may differ
cortex
cortex may
gestion
facilitate
5-HT agonist
(Rasmusson 5-HT/DA comotor
lesion
posed should
two transmitter of NAS and
In fact,
forebrain modulation
raphe 5-m
structures
regula-
decreases
DA in
5-HT projections
and in agreement increases
sys-
recep-
of DA by 5-HT
of inhibitory
raphe
Hence,
administration
interactions
are also
cortex
disinhibiting
model, reduce
induce
suggests
that reductions
generating
involved
from DA in the NAS.
to frontal
herein)
thereby cuitry
of the median
DA activity,
et al. 1989) which
posed
these
from the midbrain
from this pattern
are also
et al. 1990).
inhibition
in these
et al. 1981).
site)
(which
with
to the
this sug-
DA turnover
in the PFC
et al. 1990).
activity
nervation beek
(Herve
Mizuki
However,
et
in treatment-resis-
et al. 1979).
1982).
(Altar
and mianserin
between
a
for negative
at the 5-HT2
terminals
on DA terminals
may represent
of clozapine
for tonic
Nicolaou
(Meltzer
from two reports
5-HT systems.
efficacy
symptoms
connection
and Gardiner
as electrolytic
frontal
potency defect
a role 5-HT
(Herve et al. 1979,
profile
in schizophrenic
risperidone
et al. 1990,
for a functional
in the rat favors
striatal
tion,
as both
for reducing
profile,
comes
properties
to
proposed
of central
in this drug's
rise
symptom
et al. 1986) which
blocking
of schizophrenia,
systems
tem
receptor
give
has been
a positive
to overactivity
may be important
possess
balance
of PFC 5-HT receptors
al. 1986)
markedly
in NAS),
in pathophysiowhich
a negative
for this hypothesis
Moreover,
symptoms
predicts
(e.g.,
evidence
implicated
neurotransmission A 5-HT/DA
5-HT activity
1989).
brain
Symptoms
the opposite DA activity
the regulation
behavioral
(in agreement
innervation
behavior.
hyperactivity with
effect
- increased
at the level
upon
in-
(Kals-
the model cortical
of the NAS
Based
of lo-
of serotonergic
of PFC 5-HT decrease
efferent
locomotor
with
Reductions
pro-
DA tone,
DA neurocir-
the currently
PFC 5-HT activity
of the NAS and give
rise
proto
SchizophrentaandtheDlreceptor
817
negative symptoms seen in the defect state of schizophrenia. In summary, evidence from animal experimentation suggests that cortical 5-HT modulates PFC
DA activity in a facilitatory manner. Increased central 5-HT activity, which has been previously implicat-
ed in the pathophysiological substrate for the negative schizophrenic profile, would enhance activity in remaining PFC DA terminals. In conjunction with increased efficacy of cortical Dl sites on glutamatergic efferents to NAS, 5-HT facilitation of PFC DA activity could enhance
NAS
DA
hypoactivity and therefore the expression
of negative schizophrenic symptoms. 8. DA Receptors and Schizophrenia: Future Challenges Although a great deal is known about the way in which brain Dl and D2 receptor types interact to influence behavior, these interactions have been characterized in striatal, and less often, accumbens, substrates.
The profile of DA activity in PFC is quite different from
these more posteriorly located terminal regions (Bannon and Roth 1983, Bannon et al.
19871, and some of these differences have been
discussed (see also, Table 4 below).
As the cortex receives a more
Table 4 Differentiating Characteristics of the PFC DA systema tfiringrate
Bannonet al. 1987
4DA turnover
Bannonand Roth 1983
DA release independent of neural activity
Chrapusta et al. 1991
Lack of impulse-regulatingand synthesis-modulatingreceptors
Wolf and Roth 1987
xeceptors in DAhigh conformation
Ereshefsky et al. 1990
Dl
> 02
density
Farde et al. 1987, Hyttel 1978
basal c-fos activation
Dragunow and Robertson 1988
acompared to more subcortically located DA terminal regions (i.e., NAS and dorsal striatumf
sparse innervation of DA terminals, firing rate of PFC neurons is greater and DA turnover is enhanced.
DA in the PFC is released in-
dependently of neuronal activity t whereas striatal DA release is impulse flow dependent.
\ITA cells projecting to PFC, unlike those in-
818
M.R.Lynch
nervating
mesolimbic
modulating tively.
This
the nature striatum
profile
clude
case,
this,
for low dose agonist
at a neurochemical this region. substrates for these
hypotheses studies
have
of hypotheses minations control ceptor
further might
effects
included
presented
in the present density
PFC, and an examination substrate
following
ever,
in post-mortem
investigations
treatment.
density
An additional
changes
enhanced
reported
neuromechanisms for hypo-
ity to the behavioral of changes
al. 1985,
Hjorth
analysis.
review
with
atypical
deter-
symptoms.
there
is a problem
which
represent
to
in this re-
neuroleptic
negative
concern
await
Tests
as compared
alterations
attributable
in functional
Dl-stimulated
drugs How-
differentiat-
etiopathological
to previous
pharma-
for both -in vivo and -in in density do not nec-
effects
assays
adenylate
of altered
et al. 1983, Tassin
dependent
in their
is that alterations
in the absence
1986, Murugaiah
and
into
of PFC DA receptor
critical
these
from those
assessment
parallel
For example, been
of receptor
of the disease
essarily
of Dl and
infusion
in schizophrenic,
treatment
for treating
receptor
a
symptomatology.
for possible
are efficacious
cologic
ligand
may be relevant
PFC regions
which
vitro
through
in vivo or -in vitro binding, or func-(e.g., measures of cyclic AMP activation), of Dl
for Dl receptor
features
which
in-
in the high af-
significance
by analyzing
of schizophrenic
dif-
might
both behaviorally
investigation
proceed
regions
employing
seldom
ing aberraGons
selective
in
in the neurosubstrate
functional
following
Moreover,
assessment
receptors
level
low dose agonist
Likewise,
The
in neoeven
for sparse
regulation
(as is proposed
that
post-synaptic
existing
in PFC can be dissected
for behavior
dopaminergic
Thus,
behavioral
effects).
activation
identified
innervated
of DA receptors
respec-
processes,
to adjust
region.
densely
and perhaps
of PFC Dl receptors
D2 receptor
tional
and more
and synthesisregions,
in PFC suggests
from that
may be up-regulated
proportion
conformation,
population
activity
may be different
of DA to this terminal
between
a greater
finity
impulse-regulating soma and terminal
and that pre- and post-synaptic
the normosensitive innervation
lack
on their
of dopaminergic
of coupling
or NAS,
ferences
regions,
autoreceptors
cyclase
D1 density
et al. 1982),
of Dl stimulation
in Bmax or affinity
et al. 1988).
of neural
Therefore,
activity.
activity
has
(Hess et al. and supersensitiv-
can be induced
for the Dl site functional
in-
(Breese
measures
et
of Dl
819
SchizophreniaandtheDlreceptor sensitivity substrate
ioral
likely
to reflect
changes
of the underlying
in psychopathology.
Lastly,
drug
may be more
results
from biochemical,
investigations treatments
Veaugh-Geiss
in the rat suggest
vary with
1984,
electrophysiological
schedule
Csernansky
that effects
may show regional
specificity
of neuropharmacological
neostriatal
substrates
Chiodo
and Bunney
may also differ strate Grace
1983,
(Abercrombie 1989).
This
latter
from normosensitive
cautions
may not yield
effects
by neuropathologic
effects
and Wang
of these
1991,
19831)
and
sub-
Hollerman
and
that data derived
information drugs
(e.g.,
1987,
in the underlying
Bean and Roth
observation
animals
lels neuropharmacologic compromised
of integrity
et al. 1989ar
et al. 19861,
[Blaha and Lane
Drew et al. 1990, White
as a function
(Carey and De-
Kashihara
mesolimbic
versus
of neuroleptic
of administration
et al. 1990,
and behav-
which
in a neural
paralsystem
perturbation.
9. Conclusions Sensitization to result
of Dl receptor
from perturbation
leased
from surviving
tergic
efferents
ity.
treatments features
which
for this symptom
ture
for this drug's hand,
L-DOPA)
chronic
the functional effector
reducing
effects
profile, although
Hence,
is furof schiz-
low dose agonist
clozapine
by blocking
antagonism
treatments
critical
negative
ligand
these
symptoms.
(e.g., amphetamine
Dl receptors, receptors
may be
of modulatory
NE) may also be a significant
in treating
between
DA activ-
symptoms
with
DA re-
in the rat paralleling
in part,
efficacy
junction
mesolimbic
of the accumbens
state.
DA agonist
may desensitize
of glutama-
in the negative
defect
5-HT and/or
(e.g.,
with
at the level
behavioral
at this PFC Dl site;
transmitters
other
produce
DA projections, hyperinhibition
by PFC Dl agonism
of the schizophrenic
efficacious activity
state
expression
and may be induced
ophrenia,
inducing
to NAS DA and thereby
to gain
in the PFC is hypothesized
of ascending
terminals
A hypodopaminergic
ther suggested
activity
possibly
feaOn the or
by altering
and their
cyclic
system.
Acknowledgements The author
would
like to acknowledge
funding
from the Department
AMP
820
M.R.Lynch of Veterans ments
Affairs
of Drs. Ernest
versions
Medical
Research
Damianopoulos
Service
and Helena
and the thoughtful
com-
I. Ryer on earlier
of this manuscript.
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Inquiries
and reprint
Dr. Minda R. Lynch Research Service V. A. Medical Ctr. 800 Irving Ave. Syracuse, NY 13210
requests
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be addressed
to:
SCHIZOPHRENIA AND THE Dl RECEPTORzE:;: NEGATIVE
MINDA R. LYNCH Research and Development Serv., V.A. Medical Ctr., and Dept. Psychiatry, S.U.N.Y. Health Science Ctr. Syracuse, New York U.S.A. (Final form, January 1992) Contents 1.
2. 2.1. 2.2. 3. 4. 4.1. 4.2. 4.3. 5. 6. 6.1. 6.2. 6.3. 7. 7.1. 7.2. 8. 9.
Abstract Introduction Negative Symptoms of Schizophrenia Response to N.:uroleptics Organic Correlates Cortical Modv.i.ationof Subcortical DA Activity DA Receptor Coupling Central Dl and D2 Sites 6-hydroxydopamine Lesion Effects Receptor Coupling in Schizophrenia Dl and Negative Symptoms Modeling the Negative Profile NAS DA Hypoactivity The PFC and Behavioral Reactivity A Role for PFC Dl Receptors Mechanisms for Dl Regulation NE and Negative Symptoms 5-HT and Negative Symptoms DA Receptors and Schizophrenia: Future Challenges Conclusions Acknowledgements References
797 798 798 799 a00 802 804 a04 804 806 808 810 a10 812 812 814 a14 816 al7 819 a19 a20
Abstract Lynchr Minda R.: Schizophrenia and the Dl receptor: Focus on negatibe symptoms. Prog. Neuro-Psychopharmacol. G Biol. Psychiat. 1992, 16(6):797-832. 1.
Negative symptoms have been associated with structural impairment in the PFC, and hypothesized to arise from a central hypodopaminergic substrate.
M. R. Lynch
798
2.
Corticofugal PFC neurons, which are inhibited by VTA DA innervation, exert a tonic excitatory modulation on DA activity in the NAS. Lesions of ascending DA forebrain projections "uncouple" the functional link between Dl and D2 receptors, permitting independent activation of Dl sites in generating behavioral output. A previously identified absence of this Dl/D2 link in schizophrenic brain suggests that functional activation of PFC Dl receptors may induce hyperinhibition of descending corticofugal efferents to the NAS. Consequent hypoactivity of DA in the NAS is proposed to give rise to negative symptoms of schizophrenia, and low dose DA agonist treatments may mimic behavioral features of this symptom profile via direct PFC Dl stimulation. It follows that clozapine's efficacy for negative symptoms may be attributable, in part, to blockade of PFC Dl receptors, with subsequent enhancement of glutamate-facilitated NAS DA activity.
3.
4.
5.
6.
Keywords: clozapine, dopamine hypothesis, Dl receptor, hyperinhibition, negative symptoms, prefrontal cortex, receptor coupling, schizophrenia. Abbreviations: computed axial tomography (CAT), dihydroxyphenylacetic acid (DOPAC), dopamine (DA), homovanillic acid (WA), B-hydroxydopamine (6-OHDA), 5Lhydroxyindoleacetic acid (5-HIAA), magnetic _ resonance imaging (MRI), 3-methoxy-4-hydroxy-phenylglycol (MHPG), 3-methoxytyramine (3-MT), N-methyl-D-aspartate (NMDA), norepineph(NAS), positron emission tomography rine (NE), nucleus accumbens (PET), prefrontal cortex (PFC), serotonin (5-HT), tyrosine hydroxylase (TH), ventral tegmental area (VTA). 1. Introduction In the following
review,
observations
chemical
and neuropharmacological
clinical
data
to propose
the substrate gous
animal
a specific
for negative
model
symptoms
of this symptom
2. Negative The pathognomonic fied by both logical
category
for a negative Cannon which
closely
et al. 1990, include
a chronic
"defect
overlapping
Carpenter
affective
tor retardation,
of schizophrenia
mechanism
as originally
(19191,
with more
of this disease et al. 1985).
comprise
recent
Negative
anhedonia,
anergia
impairment
(see Table
syndrome"
which
1985,
symptoms,
flattening,
or "deficit
identia noso-
descriptions
(Andreasen
and neurocognitive state"
in
and a homolo-
of Schizophrenia
of schizophrenia,
profile
biowith
pathophysiological
(1950) and Kraepelin
symptom
behavioral,
are integrated
profile.
Symptoms
features
Bleuler
from animal
investigations
or psychomol), define
is a major
fac-
799
SchtiphreniaandtheDlreceptor Table Differentiating
Features
of Schizophrenic
Positive
symptoms
Characteristic
1 Symptom
profile
Profilesa
Negative
profile
Hallucinations Delusions Thought disorder
Amotivation Anhedonia Anergia Poverty of speech Blunted affect Intellectual impairment
Response to neuroleptics (DZ receptor antagonists)
Symptom
Poor response
DA agonist
No effect/worsening
Clinical
tCentra1
DA independent/ DA hypoactivity
Proposed
treatment
pathoetiology
Structural CAT NRI
pathology
alleviation
DA
improvement
Normal
Tissue injury/necrosis Ventricular enlargement Hypofrontality
CSF metabolites
Normal
+DA, 5-HT metabolites
Functional assessment Cerebral blood flow Neurologic signs PET
Normal
Impaired Hypofrontality Hypofrontality Mixed findings
aSee references
in text
tor in the schizophrenic's social
functioning
2.1. Response
(Meltzer
ease
tors
Bunney
1980),
tant
effects
(and/or
poor
(D2 receptor
1976).
deficit
The hypothesis
DA receptor Saller
state
drugs,
of central
which
has proven with
antagonists)
(Angrist
patient,
[Freeman 19851).
particularly
so-called
are
DA recep-
of neuroadaptations blockade
and Salama
pharmacotherapy
was
and be-
of the schizophrenic
via blockade
1987,
implicat-
of this dis-
electrophysiological
via the cascade
follow
Lane and Blaha
to traditional
leptics
and
of schizophrenia
that neuroleptic
for management
which
err the schizophrenic
and Stahl
biochemical,
therapeutic
DA systems 1987,
life
in the etiopathology
to indicate
efficacious
their
(Seeman
central
1973, Meltzer
observations
clinically induce
DA activity
by substantial
havioral
of
1989).
Zureick
the DA hypothesis
form,
central
(Matthysse
supported
and
quality
to Neuroleptics
In its original ed increased
diminished
'typical'
in and
Howevresisneuro-
et al. 1980, Johnstone
et
800
M.R Lynch al. 1978: but see also discussions by Breier et al. 1987 and Meltzer et al. 1986) that alleviate more florid positive symptoms of the disease (i.e., hallucinations, delusions and disordered cognition).
A modified DA hypothesis by Crow (1980) accounts for dif-
ferences in neuroleptic responsivity among patients with positive or negative symptom profiles.
Crow proposes that positive schizophren-
ic symptoms, representing a 'Type I' profile, can be linked to pathophysiologic disturbances of central DA transmission.
By con-
trast, features of the defect state, or 'Type II' schizophrenia, are proposed to arise from a non-dopaminergic substrate: in fact, negative symptoms may be attributable to tissue injury or necrosis in this underlying substrate (Hughlings-Jackson 1932).
It has subse-
quently been reported that negative schizophrenic symptoms improve with DA agonist treatment (e.g., amphetamine [Angrist et al. 19821 or L-DOPA [Alpert and Rush 1983, Gerlach and Luhdorf 19751) (versus postitive symptoms which show either no change or exacerbation following DA agonist administration [Angrist et al. 1974, Snyder 1973l). These latter observations prompted a further modification of the DA hypothesis to specifically implicate central DA -activity
in the
etiopathology of negative schizophrenic symptoms (MacKay 1980, Meltzer 1979).
Support for a hypodopaminergic hypothesis has come
from reports that global reductions of cerebral DA, in sub-human primates, induce social withdrawal, blunted affective responses and retarded motor activity (McKinney et al. 1980, Redmond et al. 19711, resembling symptoms which characterize the schizophrenic deficit syndrome. 2.2. Organic Correlates As contrasted with the positive symptoms of schizophrenia, an organic component to the pathophysiological substrate of the deficit syndrome has been suggested by both biochemical correlations and observations from neuroimaging. ble 1.
These findings are summarized in Ta-
For example, enlarged cerebral ventricles have been reported
from schizophrenics with negative symptoms (Andreasen et al. 1982, DeQuardo et al. 1989, Williams et al. 1985), poor response to antipsychotic treatment (Weinberger et al. 1980) and cognitive impairment (Golden et al. 1980, Johnstone et al. 1976). Other studies have shown a positive correlation between enlarged ventricular size, cortical atrophy, or poor prognosis with drug therapy, and reduced
SchizcphrentaandtheDlreceptor CSF concentrations Lindstrom gesting
that patients
deficiencies cular
with
Regional
veal a pattern schizophrenic
and recent decreased
studies
(Breier
et al. 1991).
between
neurological
from anecdotal
and case reports
damage
with
schizophrenic for a review): cognitive (i.e., 1979,
impairment
parallel
suggest
ality
vascular
on measures
features
Thus,
ces support
data
activity
glucose
PET scans
images
indices
damaged,
in remaining would
reported
of this
studies
re-
from schizohypo-
to be unrelated 1990,
to
Delisi
and blood
consistent
flow indi-
indices findings
for these
of PFC terminals neural
the summation systems,
and
in the PFC of chronic
or surviving
neural
cortex
Moreover,
(Buchsbaum
In accounting
represent
and compensating,
et al.
1986)
other
but functional
do not yield
that degeneration
activity
state
find hypofront-
cortex
1991).
atrophy
state:
ces,
metabolic
of frontal
neurologic
impairment.
pensatory
1986
flow measures
to damage
utilization,
has been
ing this structural it is possible
lobe
induces
in frontal
investigations
(Bachneff
of cerebral
in the defect
blood
and Weinberger
secondary
some
of schizophrenia
(PET scan)
primates
[Brozoski
aberrations
from structural,
a pattern
schizophrenics
while
controls
from PET scan
the clinical 1986).
between
normal
frontal
in the deficit
performance
(Berman
innervation
of cerebral
no difference versus
symptoms
However,
of
Descriptions
of the negative
in nonhuman
from cerebral
of structural
negative
region.
frontality
bral
reports
with
reduced
phrenics
response
and severity
Zec and Weinberger
reported
vol-
axons)
19841).
of hypofrontality
these
cortical
those
negative
and Nasrallah
correlation
sustaining
features
re-
of cortical
impairment
1987,
lobe damage
of delayed
with
Coffman
et al. 1990).
of patients
have
imaging
is a positive
(Merriam
diagnostic
paralleling
and see Goldman-Rakic
of patients
there
sug-
the ventri-
loss of myelinated
(Goldman-Rakic
and frontal
deficits
Observations
port
defining
profile
in association
of prefrontal
symptoms
CAT or MRI
this reduction
(i.e.,
In addition, signs
symptoms lining
et al. 1990,
attribute
matter
schizophrenic
overlap
also
(Andreasen
white
schizophrenic
employing
1974,
et al. 1986),
in structures
of hypofrontality
ume
(Bowers
van Kammen
negative
analyses
symptoms
1986)r
negative
et al. 1983,
of neurotransmission
system.
to
of DA and 5-HT metabolites
1985, Nyback
of cereparallel-
differen-
triggers
systems.
of activity
regional
patterns
com-
As in both of glu-
M.R Lynch
802 case utilization
may not reflect
3. Cortical Ascending
DA projections
corticolimbic ticolimbic region)
fibers
ly to PFC where
cal pyramidal
binding White
identified
to central
taneous
activity
in the PFC
inhibition
iontophoretic and Aghajanian
1976).
VTA DA projections
et al. 1988).
Corticofugal
glutamatergic
cortical
DA terminal
tie et al. 1985,
Glowinski
glutamate
ullon
release
veal
mesolimbic
nucleus
ing the enzyme cholamine presynaptic
effect
synthesis),
tally,
via NMDA
19861,
see Grace
circuitry
and
stimulates
1990)(i.e.,
(b) infusion DA release calcium
is depicted
(Nieo-
NMDA
recep-
studies
terminals terminals
anatomically
of
electri-
through
in the first
data
exert
DA release
TH-labeled
sub-
1980, Chris-
(a) ultrastructural
appose
of
inhibi-
increases
Thus,
may be mediated
1991 for a description
lesion
efferents
with
as
(Bunney
and neurochemical
subcortical
tyrosine
receptor-induced
(Carter
DA activity.
and are therefore
facilitation:
spon-
from the PFC innervate the NAS
and Pickel
oxidizes
neurochemical
DA activity,
since:
directly
(Sesack
which
into the NAS also
This
This
on DA terminals
the effect
stimulation-induced
Behavioral
in NAS enhancing
that PFC efferents
(Clark and
PFC glutamatergic
of the PFC stimulates
et al. 1978).
tors located
1981).
over subcortical
cal stimulation
inhibition
of the VTA inhibits
selective
including
that these
the
Ligand
via VTA DA projections,
projections
regions
from the rat suggest tonic modulation
mediated
to the PFC abolishes
(Thierry
provide
structures.
of DA to the PFC mimics
Conversely,
and corti-
et al. 1984) and this stimula-
(Ferron
appears
application
neural
stimulation
of in-
observa-
DA afferents
subcortical
(A-10
anterior-
and dendrites microscopic
between
induces
electrical
VTA
and more
et al. 1989) which
innervating
DA receptors
Thus,
tion-induced
tion
(Goldman-Rakic
pathway
1987).
synapses
electron
mesoMesocor-
in the midbrain
tuberculi,
cell bodies
Recent
DA Activity
into nigrostriatal,
from cell bodies
upon
terminals.
(Fuxe et al. 1985).
and olfactory
1991).
cells
efferent
systems
they synapse
have also
major
course
(Bachneff
of Subcortical
are organized
and hypophyseal
to the accumbens
terneurons tions
Modulation
a loss of cortical
re-
in this contain-
step of catepositioned
of glutamatergic
for
agonists
(Jones et al. 1987)(specifiinflux
[MacDermott
of this mechanism
in the schematic
diagram
et al. in NAS).
of Fig 1.
803
SchixophreniaandtheDlreceptor
/----------
7
l DEf?
Fig 1. Glutamatergic (Glut) modulation of NAS DA activity which gives rise to behavioral output via lower motor circuitry (i.e., NAS projections through ventral pallidum to the mesencephalic locomotor region [Mogenson 1987, Swerdlow et al. 19861). Note that PFC DAinduced hyperinhibition or disinhibition of glutamate to the NAS can affect the level of NAS DA-activated behavior.
Behavioral the opposite ity
(specifically,
in the rat) NAS
correlates effect
(Willins
(e.g., with
1987,
et al. 1991). 6-OHDA
pharmacologic
1976,
Pijnenburg
these glutamatergic amphetamine, phetamine these
infusion
observations
(NAS) regions, activity
relieve
suggest
glutamatergic
the locomotor
Conversely,
by PFC infusion
(Vezina
with NAS DA inducing
effects
activation (Costa11
inhibition
seen and of
by concurrent
et al. 1991).
dam-
Together,
and in subcortical
on DA-stimulated
hyperactivity
and Lyness
of the DA agonist,
induced
that DA in the PFC,
opposite
neurons
hyperactivity
of DA in the NAS
stimulation
into the
of corticofugal
(Leccese
resembles
locomotor
hypermotility
Disinhibition
a behavioral
into the NAS
exert
cortical
et al. 1976).
hyperactiv-
of DA in the PFC
NAS DA turnover
stimulation
demonstrate
antagonists
and induces
efferents
reduces
depletions
inhibition.
et al. 1980)
findings
of NAS DA-modulated
of glutamatergic
Severe
infusion)
mediated
et al. 1979) which
following Naylor
biochemical
of amphetamine-induced
infusion
to the NAS enhances
Pycock
(LeMoal
reductions
following
from DA-receptor projections
to these
- an attenuation
behavioral
and DA in the PFC pro-
M.RLynch
804 ducing
hypomotility
via decreased
A hypodopaminergic schizophrenia
hypothesis
to include
tivity,
specifically,
DA terminals discussion
would that
tion of these
release.
for the negative
et al. 1991, Weinberger
(Davis
modified
glutamate
a role
for corticofugal
wherein
result
mechanisms
follows,
cortical
which
perturbation
might
of
of NAS DA acof PFC
of NAS DA activity.
glutamate-containing consequent
NAS DA -activity),
profile
can be further
regulation
neuropathological
in aberrations
symptom
1987)
induce
pyramidal
In the
hyperinhibicells,
to PFC perturbation,
will
(hence,
be con-
sidered.
4. DA Receptor 4.1.
Central
Central subtypes
Dl and D2 Sites
DA receptors on the basis
tems, with
uncoupled,
clic AMP activity subtypes dense
with
closely VTA
overlap
Behavioral caine)
effects
the Dl receptor Arnt
19881,
for most
and Dl/D2
physiologically
an inhibitory
region
densities
influence both
on cy-
receptor
is especially of D2
(rarde et
for the Dl site projections
drugs
in PFC
from the
(e.g., amphetamine
to stimulation
'enabling'
(or facilitating)
behavioral
"coupling"
role
of both
effects
with
(see
sites
is
(White et al.
has been demonstrated
as well
or co-
at the D2 site,
In fact, co-activation
agonist-induced
in neostriatum,
and the
et al. 1978).
attributed
receptor
sys-
cyclase
Although
1979).
of afferent
Tassin
an
AMP effector
to adenylate
to the distribution
of DA agonist
serving
into Dl and D2 receptor
cyclic
this cortical
the pattern
1987 for a review).
required
having
Moreover,
et al. 1986,
are generally
coupled
as compared
1978). with
classified
link with
and Calne
in the PFC,
Dl sites, Hyttel
(Savasta
or else
(Kebabian
are found
al. 1987,
have been of their
the Dl site normally
D2 receptor
Coupling
as in the NAS
electro-
(Wachtel
et
al. 1989). 4.2. 6-OHDA Damage
Lesion
to DA terminals
for neuroadaptive pathological triggers
Effects in rat neostriatum
capabilities
conditions
a sequelae
of central
producing
of compensatory
neuronal
has served DA systems,
as a model in response
degeneration.
processes
as outlined
DA loss in
to
SchbzophreniaandtheDlreceptor Table 2 6-OHDA Lesion-Induced
+D2
Neuroadaptation
Max
Craese et al. 1977 Hu et al. 1990
+DAhigh conformation
Arnt
+Basal DA release
Robinson et al. 1990 Zigmond et al. 1990
tL-DOPA stimulated
DA release
Abercrombie
Functional Dl activation: Circling (unilateral lesion) Locomotion (bilateral lesion)
tDl-induced
neural
HU et al. 1990
conformations),
inhibition
Robertson
c-fos
alterations
at both post-
and conversion and pre-synaptic Partial
transmitter
from surviving
cellular
release
DA at control
are findings enhanced
to suggest
consequent
stimulates
from 6-OHDA
greater
activation
rat
[Molloy
OHDA
or reserpine
and
exception
that
is, circling
in intact
induce
inactive
of inducing
central
activation
is demonstrated
behavioral
For example,
in extracellular
than
However,
to uncouple
of D2 agonist-induced (b) "enhanced"
significant
by:
behavioral effects
in the unilaterally
L-
fluid)
striatum.
significant
but not in DA intact,
19841).
extra-
may be actually
perturbation.
(e.g., SKF 38393)
(functional)
Uncoupling
ist blockade
lation:
appears
maintains
Even more
(measured
of DA
by increased
which
efficacy
are behaviorally
and Waddington
for independent
Dl receptor.
levels.
in the rat,
in DA depleted,
(with the possible
vior
1987);
DA release
receptor
in the process
are compensated
that transmitter
drugs
(e.g., Dl and D2 recep-
terminals,
(non-lesion)
Dl agonists
tal animals.
lesions
striatum
Dl agonist
Secondly, havioral
junctions
to a DA terminal
lesioned
et al. 1989
from low- to high-affinity
neurotransmission.
lowing
1984
Krueger et al. 1976 Mishra et al. 1974 Parenti et al. 1982 Rosenfeld et al. 1979 Tassin et al. 1982
2, including
sitive
Arnt and Hyttel Arnt 1985a
cyclic AMP
tor upregulation
DOPA
et al. 1990
iDl-induced
Dl-activated
Table
1987
be-
experimen-
in the normosengrooming
DA depletion
beha-
with
Dl and D2 sites, of behavior
6al-
via the
(a) loss of Dl antagoneffects
(see Arnt
from central lesioned,
DA stimu-
and locomo-
806
M.RLynch
tor activation 1985b]
rat,
ditional
in the bilaterally
following
evidence
is enhanced
selective
that efficacy
consequent
that Dl-induced
cyclic
lesioned
or reserpinized
[Arnt
Dl agonist
administration.
Ad-
of Dl-mediated
loss comes
AMP activation
is enhanced
striatum
and PFC,
following
terminal
nuclei.
Electrophysiological
6-OHDA
ical observations
in revealing
striatum
neural
enhances
tion of selective oncogenes ment
in 6-OHDA
sult
which
is significant
naling event
changes tions
kinase
induces
in synaptic
ble with
the notion
neuropathological
involve
neostriatum,
processes AMP
in Dl receptor
that Dl receptor
mechanisms
of genetic
which
maintain
re-
AMP sigmediated
long term
1990).
function
alterations
tran-
This
cyclic
mediating
(Sheng and Greenberg
changes
treat-
suggest-
interface.
is the DA receptor genes
proto-
Dl agonist
(not D2) triggered
- early
applica-
nuclear
by selective
production)
efficacy
in these biochem-
of DA in the neo-
importantly,
the Dl-cyclic
immediate
of lesion-induced
lesion
these
from microiontophoretic
Most
in that Dl-
(or protein which
that 6-OHDA
may
beyond
in accumbens,
support
but not non-lesioned
Dl efficacy
occur
transduction
from observations
to DA projections
data
are activated
lesioned,
ing that enhanced scription
damage
inhibition
Dl agonists. c-fos)
(i.e.,
signal
to DA terminal
Observaare compati-
are significant
chronic
conditions
for of
psychopathology. In conclusion, following pletion
given
6-OHDA
of PFC DA axons
interactions receptors
reviewed
in the following Coupling
an abundant
in animal tions,
which
and enhanced
Receptor
behavioral,
relatively
human
brain.
tions
in human
data
reveal
neural
enhanced
Dl/D2
receptor of Dl
or remaining
for this hypothesis,
derived
in central
efficacy
de-
activation
from surviving
disruptions
events
that partial
may uncouple
and/or
Dl receptor
Dl/D2
from
recep-
in schizophrenia,
are
section.
in Schizophrenia
experimental
literature
neurophysiological
few studies
Seeman
it follows
by DA released
Supporting
studies
tor coupling
While
independent
in this region,
post-mortem
of Dl-mediated
lesion,
in schizophrenia
and permit
PFC DA terminals.
4.3.
a facilitation
neurochemical
et al.
striatum
have probed
documents
receptor
(1989) recently
by incubating
the Dl/D2
and biochemical
tissue
associations
examined samples
Dl/D2 with
link
investigain
interacselective
807
SchizophreniaandtheDlreceptor radioligands or DAlow
affinity
antagonists therefore
state
for the endogenous
preferentially D2 agonists
occupation
at the DZhigh blockade
to normal
brain
and normal
could
history.
The authors
in some
schizophrenics.
the rat suggest and/or
though
binding
coupling
et al.
of the Dl site
D2 and
by Dl
in D2 antagonist
(1989) demonstrated in samples between
to previous
permit
that
from schizoschizophrenic neuroleptic
link may be "missing" lesion
independent
in schizophrenic
in schizophrenic
has not been made
effects
in
activation
brain.
(1987) report
Hess et al.
1987).
conformation
via noncompetitive
from 6-OHDA
would
a DAhigh
is evidenced
that the Dl/D2
Observations
determination
(Seeman
reductions
not be attributed
to Dl receptors
a similar
binding
that differences
concluded
port of this suggestion,
in either
ligand
was not present
that uncoupling
enhancement
tagonist
Dl/D2
Seeman
effect
and moreover,
tissue
antagonist
site.
tissue.
exist
to the low affinity
of agonist-induced
this Dl antagonist phrenic
bind
reduce
antagonist binding
Both sites
for the two sites.
In sup-
enhanced
Dl an-
neostriatum
(al-
for mesocorticolim-
bit regions). In addition, siveness
et al.
of adenylate
from chronic this enzyme ride.
Memo
cyclase
schizophrenics,
fluoride
ter recognition intracellular
enzymes
linked
Hess et al.
receptors
from schizophrenic
sodium
which
transduction
fluo-
activate (Bockaert
of second
in schizophrenia. a decrease
of
the transmit-
a modification
suggesting
functional
a similar
determination
of schizophrenic
brain
that structural
perturbation
and D2 receptor
sites,
for the neostriatum
inhibition tory
brain,
with
bypasses
to the Dl receptor
in striatum
stimulation
on G proteins
suggest
respon-
Fur-
in striatal
a compensatory
Dl
down-
activity
at the Dl-second
mes-
for cyclic
AMP activation
in PFC
junction.
Although
here
treated
(1987) have reported
to heightened
stimulation
for signal
findings
thermore,
regions
directly
an increased
maximal
AMP activation
responsible
these
systems
senger
NAS tissue
cyclic
messenger
regulation
to Dl receptor
site and acts
Therefore,
reported
and a greater
in schizophrenic
Sodium
1991).
(1983) have
of DA terminals
enhancing
Dl activity
and nucleus
of glutamatergic
influence
has not yet been
neurons
on DA terminals
in the manner Dl-induced
normally
in NAS would
it follows
in PFC may uncouple
accumbens. which
reported,
induce
exert
Dl
reported hyper-
an excita-
a hypodopaminer-
808
M.RLynch
gic state
at the subcortical
of schizophrenia tential
mechanisms
matergic
tion of cortical
might
include
Dl receptors corticofugal
of the Dl site to G-protein gand
binding
output,
events.
lesions
in the rat which
produce
region
induce
(Tassin
et al. 1982).
adenylate 1986).
Chronic
L-DOPA,
and apathy
through
similar
PFC regions,
a role
Pogluta-
in a popula-
a modulatory efficient
which
role
coupling
transduce
li-
of this hypothesis,
PFC
a 52% loss of DA in this cortical
chronic
symptoms,
also
cyclic
amphetamine,
remain
central
for enhanced
atten-
Dl-mediated
reverses
et al.
emotional
signal
et al. 1990).
transducAlthough
to be demonstrated
that DA agonists
schizophrenic
which
(Roberts-Lewis
attenuates
(Engber
drugs
AMP stimulation
down-regulates
partially
Dl receptors
by DA agonist
negative
more
of Dl-mediated
which
also desensitize
with
and/or
in rat neostriatum
the observation
for alleviating and L-DOPA)
serve
mechanisms
in schizophrenia,
striatal
effects
patible
activity
symptoms
on these
activation
In support
Moreover,
schizophrenic
cyclase
withdrawal tion
a sensitization
negative
at Dl sites
usually
effector
as negative
CSF DA metabolites.
functional
which
to cellular
uates
expressed
by reduced
for hyperinhibition
efferents
for DZ-mediated
level,
and reflected
which
symptoms
(i.e.,
Dl receptor
Dl stimulation
for
are efficacious amphetamine
function
is com-
in the schizophrenia
deficit'state.
5. Dl and Negative Psychopharmacological role
for hyperinhibition
substrate 2.
observations
of negative
First,
psychotic would
be effective
the ability events
which
pharmacotherapy is relatively
ineffective
schizophrenia
(Angrist
typical'
neuroleptic,
(florid)
positive
1988,
Meltzer
1991,
would
drugs,
for treating
clozapine,
Meltzer
and Zureick
while
the chronic
is efficacious symptoms
a
activity
symptoms, neuronal
neuroleptics),
defect
state
et al. 19781,
the
for relieving
Unlike
and
traditional
of this disease 1989).
in Fig
that anti-
neural
('typical'
et al. 1980, Johnstone
and negative
predict
Dl-triggered
Additionally,
D2 antagonist
schematically
schizophrenic
to desensitize
with
in the pathophysiological
Dl-induced
negative
this prediction. with
herein
or attenuate
in treating
are compatible
are diagrammed
proposed
block
of DA agonists
supports
which
at PFC Dl sites,
symptoms,
the hypothesis drugs
Symptoms
in 'a-
both
(Kane et al.
typical
neuro-
809
Schizophrenia and the D 1 receptor
’ Behavioral output/ reactivity
Fig 2. Potential pharmacotherapeutic mechanisms for reversing hyperinhibition of glutamatergic (glut) corticofugals in the schizophrenic deficit state. leptic drugs, this dibenzodiazepine has weak D2 antagonist properties and shows greater binding to the Dl site -in vivo (Andersen et al. 1986, Farde et al. 1989, Fuxe et al. 1989). Moreover, it preferentially binds to the high-affinity, adenylate cyclase-coupled Dl state (Andersen and Braestrup 1986).
Clozapine's behavioral profile
is also unlike that of D2 blockers in that it does not induce catalepsy or antagonize agonist-induced stereotypy (Maj et al. 1974, Stille et al. 1971).
On both behavioral and neurochemical assay it
resembles the prototypical Dl antagonist, SCH 23390 (Murray and Waddington 1990, Wood and Altar 1988): It increases intraneuronal metabolites, DOPAC and HVA, without affecting extraneuronally produced 3-MT (which reflects transmitter release). Secondly, clozapine blocks stereotyped behavior induced with NMDA antagonist treatment, suggesting that part of this drug's neuropharmacologic profile may involve enhancement of central glutamatergic activity (Schmidt et al. 1991).
In the present model, an-
tagonism at Dl receptors in schizophrenic PFC would release these sensitized sites from hyperinhibition, enhancing glutamatergic activation of DA in the NAS and thereby reversing the mesolimbic DA hypoactivity which gives rise to negative symptoms.
k4EA. R Lynch
810
Lastly, the prototypical Dl antagonist, SCH 23390, antagonizes social isolation in the Java monkey (Ellenbroek et al. 1989).
As
this behavioral profile has been proposed as an animal model for negative symptoms of schizophrenia, its antagonism by central Dl receptor blockade provides additional evidence to implicate ligand activity at the Dl site in producing the schizophrenic deficit state. 6. Modeling the Negative Profile 6.1. NAS DA Hypoactivity Increases of DA in the NAS induce behavioral hyperactivity in the rat (Costa11 and Naylor 1975, Pijnenburg et al. 1976) and are also believed to be the critical substrate for euphoragenic properties of reinforcing drugs (Koob and Goeders 1989, Wise and Rompre 1989).
On
the other hand, reductions of NAS DA induce hypoactivity on measures of spontaneous locomotion (Joyce and Iversen 1978, Koob et al. 1978).
Low doses of direct DA receptor agonists (e.g., the mixed
Dl/D2 agonist, apomorphine) decrease DA turnover and DA cell firing in subcortical DA regions (Aghajanian and Bunney 1973, Bannon and Roth 1983) and also induce hypomotility, which resembles the locomotor suppression observed after DA depletion of the NAS (DiChiara et al. 1976).
Moreover, low dose DA agonist treatment in-
duces a behavioral profile characterized by anhedonia and cognitive deficiency in operant behavior paradigms
(carnoy et al. 1986a, 198613). This low dose agonist-induced profile has been suggested as
an isomorphic model for the negative symptoms of schizophrenia (Carnoy et al. 1986b). Traditionally, low dose DA agonist effects have been attributed to DA inhibition from selective stimulation of central DA autoreceptors which have a greater affinity for the endogenous ligand than do postsynaptic sites (Seeman 1980).
However, recent studies point in-
stead, to a particularly agonist-sensitive population of post-synaptic DA receptors as the substrate for low dose DA agonist effects (Lynch 1991, Stahle and Ungerstedt 1987, 1989). Post-synaptic DA receptors in the PFC have been proposed to exist primarily in a DAhigh state, since this region has a low DA "tonus" (i.e., sparse innervation, compared to other forebrain DA terminal regions)(Ere-
811
SchizophreniaandtheDlreceptor shefsky
the neurocircuitry bury
et al. 1984)
the rat
for low dose and also
As VTA terminals ceptors
(Bannon
high-affinity effects
may be found
matergic
projections
population
proposed
PFC-NAS
DA agonist
receptors
induce
in
directly
et al. 1984).
suggests
mediating
in
(Brad-
yawning
infusion
(Bradbury
this observation
in the PFC.
circuitry,
hypoactivity
to PFC lack synthesis-regulating
regulating
would
as a component
agonist-induced
suppression
et al. 1987),
post-synaptic
agonist-induced
In fact,
locomotor
projecting
implicated
for low dose
(Hitri et al. 1989).
into the PFC induces
ceptor
The PFC has been
et al. 1990).
autore-
that the
low dose
DA agonist
Furthermore,
if located
on gluta-
NAS DA activity,
agonism
at this re-
hypoactivity
as diagrammed
of subcortical in the shematic
DA.
This
of Fig 3,
Hypomotility/ yawning
Fig 3. Schematic of hypothesized post-synaptic DAhigh receptor substrate mediating peripherally administered, or PFC infused, low dose DA agonist behavioral effects which arise from hypodopaminergic activity in the NAS: (abbreviations as in Fig 2).
can account
for observations
for low dose the notion ioral
DA agonist
that hypoactivity
suppression
implicating
behavioral
in the rat.
PFC in the neurosubstrate
effects
and is compatible
in NAS DA systems
gives
with
rise to behav-
M. R Lynch
812 6.2. The PFC and Behavioral Several involved
previous with
of symptom
severity
symptoms,
in the rat induces crombie tory
influence
increased mate
a selective Thierry
in the NAS,
(e.g., greater
etc.).
Recently,
suggest
that
PFC DA, hances
Rosin
cortical
menter-induced
inducing
et al.
stress.
(hence,
disinhibition
concentration
is assessed
glutamatergic
system
with
hyperinhibition
hypo-
DA would latory
induce
hypoactivity tween
tions
release in the NAS
of glutamate
state,
opposite
(as in the Rosin
stress-induced
comparing
to removal
increases
genetically
bred
respectively.
that
in PFC moduis, DA
in investiga-
versus
In these
studies,
increase
of PFC DA to experimenter-induced
only hypo-emotional
be-
and behavioral
experimentally
significant
6.3. A Role
this
An association
for hypo-
en-
producing
increases
tionality.
olucci-D'Angio
Thus,
of corticofugal
of PFC DA activity
of
"in check",
release
et al. 1992 study):
has been demonstrated animals
depletion
(where DOPAC
behavior,
stress-induced
which
by experi-
in the NAS),
responsivity
in NAS DA-mediated
deficit
withdrawal,
findings
as an index of DA activity).
in the NAS and b-responsivity.
hypo-responsivity
of behavioral
severe
increases
or disinhibition
an effect
influences
reported
herein,
over gluta-
social
of glutamate
may keep behavioral
or hyper-reactivity
In the schizophrenic
exacerbation proposed
of NAS DA is influenced investigations,
(Aber-
increased
diminution
of speech,
(1992) have
DOPAC
stress
the modula-
hyperinhibition
a further
In their
footshock-induced
the model
In the
as increas-
Considering
stress-induced
poverty
modulation
manifest
of DA in the PFC
with
enhance
anergia,
1986).
on NAS DA activity,
underlying
would
is an exacerbation
Experimenter-induced
activation
In accordance
PFC DA activity
would
is especially
reactivity.
(Weinberger
et al. 1976).
of PFC corticofugals
symptoms.
release
output
to stress
decompensation
PFC DA may be the mechanism of negative
and behavioral
and amotivation.
et al. 1989b,
that PFC DA
in schizophrenia
in response
withdrawal
suggest
responses
'decompensation'
case of negative ed social
investigations
emotional
Stress-induced
Reactivity
animals
hyper-emoshow a
stress
(Bert-
et al. 1990).
for PFC Dl Receptors
The PFC has a higher (Farde et al. 1987,
density
Hyttel
of Dl receptor
1978)
and central
subtypes
than of D2
Dl receptor
sites
have
813
SchizophreniaandtheDlreceptor a ten-fold (Seeman
greater
1987).
are induced
affinity
Accordingly,
by agonism
1990)
can be visualized
onist
administration),
and Robertson
for endogenous
overlap
al. 1986,
Tassin
proto-oncogenes
at central
in untreated
Given
with
PFC
ascending
behavioral
prior
(Dragunow
(Savasta
Supporting Table
DA agonist
treat-
at this Dl release
in
NAS DA activity.
observations
For example,
3.
et
that the high affinity
of low dose
is the PFC -Dl receptor. Hence, DA agonist binding ment cortical site might be the event that inhibits glutamate the NAS, decreasing
Dl ag-
of PFC Dl receptors, from VTA
it is possible
which
et al.
neostriatum
DA terminals
effects
(Graybiel
(i.e., without
this high density
et al. 1978),
DA site mediating
(such as c-fos)
Dl receptors
but not in untreated
1988).
and their
DA than the D2 receptor
for this hypothesis
peripheral
are summarized
administration
in
of selective
Dl
Table 3
Consequences of Central Dl Activation peripheral
SCH 23390
t locomotor + yawning
PFC SCH 23390 infusion
4 amphetamine-induced
PFC a-flupentixol
t NAS DOPAC
Dl
infusion
agonism
6-OHDA induced Dl/D2 uncoupling
(e.g., SCH 23390)
antagonists dose
DA agonist
et al. 1990)
al. 1991).
Similarly,
NAS D2-stimulated behavioral the NAS
[Vezina
voltammetric substrate
locomotor
efferents
findings
also
affinity
t apomorphine-induced
yawning yawning
the opposite spontaneous
yawning
amphetamine
suggesting
for the Dl site,
of
DA.
which
re-
may be the
Louilot
extracellular
in into
In vivo --
inhibition.
NAS
et
increases infusion
that this antagonist
of a-flupentixol, increases
activity
(Hietala
that PFC Dl receptors
modulation
that PFC infusion
of low
in PFC enhances
(i.e., greater
from Dl-mediated indicate
effect
locomotor
in the rat
of Dl receptors
concurrent
et al. 1991]),
locomotion
4 apomorphine-induced
activation
with
for glutamatergic
(1989) report high
and reduced antagonism
hyperactivity
glutamate
induces
- increased
treatment
(Maldonado
leases
activity
et al.
exhibits DOPAC
a
in the
814
M.
NAS
(versus
which
infusion
had no effect
central
apomorphine
DA with
allowing induces
(Longoni
a higher
controls
(Morelli
mental
findings
implicate
in low dose whereas
DA agonist
antagonism
hyperactivity
frequency
agonism
effects
from
fibers
from raphe
1987).
Both ascending
regulating
locomotor
tral NE and central volved
systems below
projection
5-HT activity
of schizophrenia. in modulating
and depicted
Forebrain
noradrenergic
(Oades
enhanced
nist treatment
[Tassin
ly to mesocorticolimbic However,
ing NE terminals that
systems
and 5-HT projecand Loughlin
have been
implicated
have been
Moreover,
hypothesized giving
both
in cen-
to be in-
rise
to negative
role of these
transmitter
is described
in the discussion
in Fig 4.
to PFC
these NE terminals
to frontal
Moreover,
the sensitivity
as 6-OHDA
nuclei
midbrain
(in addition must
of
sparing
infusion
in order
to Dl ago-
electrolytic
send axons
anterior-
ascending
destroys
to DA projections),
be intact
lesion
in response
which
while
innervation
Dl supersensitivity
Significantly,
DA cell bodies
activity
in this re-
but not 6-OHDA,
AMP production
terminal
have been
noradrenergic
to PFC develop
et al. 19821).
cortex
behavioral
of Dl receptors
electrolytic,
cyclic
of the VTA destroy
projections.
behavioral
(Fallon
for NAS DA-mediated
projections
(specificaliy,
lesions
and hypolocomotion,
coeruleus,
mechanisms
et al. 1986).
sustaining
tegmental
experi-
PFC) Dl sites
(or facilitates)
the PFC
projections
in the rat
to the PFC may modulate
ventral
(possibly
Symptoms
in the substrate
as animals
in normosen-
these
NAS DA.
PFC DA activity
implicated
gion
than
Collectively
The potential
schematically
7.1. NE and Negative
receptor
of yawning
from DA in the NAS.
in the pathophysiological
symptoms
Dl/D2
apode-
for Dl Regulation
innervate
output
in animals
to
of the Dl site),
induces
from the locus
nuclei,
and
"uncouples"
at central
increased
binding
facilitates
activation
such as yawning
at this site
arising
Noradrenergic
(which
et al. 1986).
7. Mechanisms
tions
et al. 1987),
reserpine
sulperide,
ligand
at the Dl site)
for independent
sitive
D2 antagonist,
Furthermore,
(i.e., agonism
yawning
of brain
interactions,
the selective
on NAS DOPAC).
Dl receptors
morphine-induced pleted
with
R. Lynch
NE
ascend-
it appears
for Dl upregulation
815
SchizophreniaandtheDlreceptor
J Behavioral output
Fig 4. Potential transmitter interactions in the pathophysiological substrate of negative schizophrenic symptoms. (tPFC Dl denotes enhanced efficacy or independent activation as a result of Dl/D2 uncoupling.);(abbreviations as in Fig 2).
to develop
(Tassin
van Kammen lation
the severity
of both
CSF NE remained apy with
activity
receptors
(Grossman
Considering
with
Dl sites
the modulatory
Dl receptors,
activity
in the negative
tates
with
ligand
region.
alphal,
and Schumann
cortical
agreement
who relapsed
1982,
of these
clozapine
et al. 1977, Perry
noradrenergic
(Goldman-Rakic
of increased
model)
profile
elevated
at PFC Dl sites
central
might
receptor
et al. 1990). of
noradrenergic
suggest
that
PFC NE activity
following
therhas
and beta-adrenergic
Peroutha
in PFC
symptom
the present
binding
alpha2
and
MHPG.
role of PFC NE in sensitization
reports
corre-
symptoms
from neuroleptic
Moreover,
haloperidol.
at central
a high positive
schizophrenic
CSF NE and the NE metabolite
and the distribution
overlaps
reported
of negative
in patients
the D2 antagonist,
et al. 1983),
recently
(drug-free)
high
antagonist
subtypes
(1990)
et al.
between
elevations
et al. 1986).
terminal
(in facili-
loss
in this
818
M.R.Lynch
7.2. 5-HT and Negative Forebrain logical
5-HT systems
disturbances
schizophrenic wherein
have also been
of central
symptomatology.
greater
and greater
DA activity
Indirect
citing
decreased (Bennett
compensatory
density
et al. 1979, Mita
adaptation
5-HT2
tant
even greater effective
schizophrenia
Evidence
antagonist
(Bersani
DA by ascending
tors may be located (DeBelleroche afferents
to PFC may differ
cortex
cortex may
gestion
facilitate
5-HT agonist
(Rasmusson 5-HT/DA comotor
lesion
posed should
two transmitter of NAS and
In fact,
forebrain modulation
raphe 5-m
structures
regula-
decreases
DA in
5-HT projections
and in agreement increases
sys-
recep-
of DA by 5-HT
of inhibitory
raphe
Hence,
administration
interactions
are also
cortex
disinhibiting
model, reduce
induce
suggests
that reductions
generating
involved
from DA in the NAS.
to frontal
herein)
thereby cuitry
of the median
DA activity,
et al. 1989) which
posed
these
from the midbrain
from this pattern
are also
et al. 1990).
inhibition
in these
et al. 1981).
site)
(which
with
to the
this sug-
DA turnover
in the PFC
et al. 1990).
activity
nervation beek
(Herve
Mizuki
However,
et
in treatment-resis-
et al. 1979).
1982).
(Altar
and mianserin
between
a
for negative
at the 5-HT2
terminals
on DA terminals
may represent
of clozapine
for tonic
Nicolaou
(Meltzer
from two reports
5-HT systems.
efficacy
symptoms
connection
and Gardiner
as electrolytic
frontal
potency defect
a role 5-HT
(Herve et al. 1979,
profile
in schizophrenic
risperidone
et al. 1990,
for a functional
in the rat favors
striatal
tion,
as both
for reducing
profile,
comes
properties
to
proposed
of central
in this drug's
rise
symptom
et al. 1986) which
blocking
of schizophrenia,
systems
tem
receptor
give
has been
a positive
to overactivity
may be important
possess
balance
of PFC 5-HT receptors
al. 1986)
markedly
in NAS),
in pathophysiowhich
a negative
for this hypothesis
Moreover,
symptoms
predicts
(e.g.,
evidence
implicated
neurotransmission A 5-HT/DA
5-HT activity
1989).
brain
Symptoms
the opposite DA activity
the regulation
behavioral
(in agreement
innervation
behavior.
hyperactivity with
effect
- increased
at the level
upon
in-
(Kals-
the model cortical
of the NAS
Based
of lo-
of serotonergic
of PFC 5-HT decrease
efferent
locomotor
with
Reductions
pro-
DA tone,
DA neurocir-
the currently
PFC 5-HT activity
of the NAS and give
rise
proto
SchizophrentaandtheDlreceptor
817
negative symptoms seen in the defect state of schizophrenia. In summary, evidence from animal experimentation suggests that cortical 5-HT modulates PFC
DA activity in a facilitatory manner. Increased central 5-HT activity, which has been previously implicat-
ed in the pathophysiological substrate for the negative schizophrenic profile, would enhance activity in remaining PFC DA terminals. In conjunction with increased efficacy of cortical Dl sites on glutamatergic efferents to NAS, 5-HT facilitation of PFC DA activity could enhance
NAS
DA
hypoactivity and therefore the expression
of negative schizophrenic symptoms. 8. DA Receptors and Schizophrenia: Future Challenges Although a great deal is known about the way in which brain Dl and D2 receptor types interact to influence behavior, these interactions have been characterized in striatal, and less often, accumbens, substrates.
The profile of DA activity in PFC is quite different from
these more posteriorly located terminal regions (Bannon and Roth 1983, Bannon et al.
19871, and some of these differences have been
discussed (see also, Table 4 below).
As the cortex receives a more
Table 4 Differentiating Characteristics of the PFC DA systema tfiringrate
Bannonet al. 1987
4DA turnover
Bannonand Roth 1983
DA release independent of neural activity
Chrapusta et al. 1991
Lack of impulse-regulatingand synthesis-modulatingreceptors
Wolf and Roth 1987
xeceptors in DAhigh conformation
Ereshefsky et al. 1990
Dl
> 02
density
Farde et al. 1987, Hyttel 1978
basal c-fos activation
Dragunow and Robertson 1988
acompared to more subcortically located DA terminal regions (i.e., NAS and dorsal striatumf
sparse innervation of DA terminals, firing rate of PFC neurons is greater and DA turnover is enhanced.
DA in the PFC is released in-
dependently of neuronal activity t whereas striatal DA release is impulse flow dependent.
\ITA cells projecting to PFC, unlike those in-
818
M.R.Lynch
nervating
mesolimbic
modulating tively.
This
the nature striatum
profile
clude
case,
this,
for low dose agonist
at a neurochemical this region. substrates for these
hypotheses studies
have
of hypotheses minations control ceptor
further might
effects
included
presented
in the present density
PFC, and an examination substrate
following
ever,
in post-mortem
investigations
treatment.
density
An additional
changes
enhanced
reported
neuromechanisms for hypo-
ity to the behavioral of changes
al. 1985,
Hjorth
analysis.
review
with
atypical
deter-
symptoms.
there
is a problem
which
represent
to
in this re-
neuroleptic
negative
concern
await
Tests
as compared
alterations
attributable
in functional
Dl-stimulated
drugs How-
differentiat-
etiopathological
to previous
pharma-
for both -in vivo and -in in density do not nec-
effects
assays
adenylate
of altered
et al. 1983, Tassin
dependent
in their
is that alterations
in the absence
1986, Murugaiah
and
into
of PFC DA receptor
critical
these
from those
assessment
parallel
For example, been
of receptor
of the disease
essarily
of Dl and
infusion
in schizophrenic,
treatment
for treating
receptor
a
symptomatology.
for possible
are efficacious
cologic
ligand
may be relevant
PFC regions
which
vitro
through
in vivo or -in vitro binding, or func-(e.g., measures of cyclic AMP activation), of Dl
for Dl receptor
features
which
in-
in the high af-
significance
by analyzing
of schizophrenic
dif-
might
both behaviorally
investigation
proceed
regions
employing
seldom
ing aberraGons
selective
in
in the neurosubstrate
functional
following
Moreover,
assessment
receptors
level
low dose agonist
Likewise,
The
in neoeven
for sparse
regulation
(as is proposed
that
post-synaptic
existing
in PFC can be dissected
for behavior
dopaminergic
Thus,
behavioral
effects).
activation
identified
innervated
of DA receptors
respec-
processes,
to adjust
region.
densely
and perhaps
of PFC Dl receptors
D2 receptor
tional
and more
and synthesisregions,
in PFC suggests
from that
may be up-regulated
proportion
conformation,
population
activity
may be different
of DA to this terminal
between
a greater
finity
impulse-regulating soma and terminal
and that pre- and post-synaptic
the normosensitive innervation
lack
on their
of dopaminergic
of coupling
or NAS,
ferences
regions,
autoreceptors
cyclase
D1 density
et al. 1982),
of Dl stimulation
in Bmax or affinity
et al. 1988).
of neural
Therefore,
activity.
activity
has
(Hess et al. and supersensitiv-
can be induced
for the Dl site functional
in-
(Breese
measures
et
of Dl
819
SchizophreniaandtheDlreceptor sensitivity substrate
ioral
likely
to reflect
changes
of the underlying
in psychopathology.
Lastly,
drug
may be more
results
from biochemical,
investigations treatments
Veaugh-Geiss
in the rat suggest
vary with
1984,
electrophysiological
schedule
Csernansky
that effects
may show regional
specificity
of neuropharmacological
neostriatal
substrates
Chiodo
and Bunney
may also differ strate Grace
1983,
(Abercrombie 1989).
This
latter
from normosensitive
cautions
may not yield
effects
by neuropathologic
effects
and Wang
of these
1991,
19831)
and
sub-
Hollerman
and
that data derived
information drugs
(e.g.,
1987,
in the underlying
Bean and Roth
observation
animals
lels neuropharmacologic compromised
of integrity
et al. 1989ar
et al. 19861,
[Blaha and Lane
Drew et al. 1990, White
as a function
(Carey and De-
Kashihara
mesolimbic
versus
of neuroleptic
of administration
et al. 1990,
and behav-
which
in a neural
paralsystem
perturbation.
9. Conclusions Sensitization to result
of Dl receptor
from perturbation
leased
from surviving
tergic
efferents
ity.
treatments features
which
for this symptom
ture
for this drug's hand,
L-DOPA)
chronic
the functional effector
reducing
effects
profile, although
Hence,
is furof schiz-
low dose agonist
clozapine
by blocking
antagonism
treatments
critical
negative
ligand
these
symptoms.
(e.g., amphetamine
Dl receptors, receptors
may be
of modulatory
NE) may also be a significant
in treating
between
DA activ-
symptoms
with
DA re-
in the rat paralleling
in part,
efficacy
junction
mesolimbic
of the accumbens
state.
DA agonist
may desensitize
of glutama-
in the negative
defect
5-HT and/or
(e.g.,
with
at the level
behavioral
at this PFC Dl site;
transmitters
other
produce
DA projections, hyperinhibition
by PFC Dl agonism
of the schizophrenic
efficacious activity
state
expression
and may be induced
ophrenia,
inducing
to NAS DA and thereby
to gain
in the PFC is hypothesized
of ascending
terminals
A hypodopaminergic
ther suggested
activity
possibly
feaOn the or
by altering
and their
cyclic
system.
Acknowledgements The author
would
like to acknowledge
funding
from the Department
AMP
820
M.R.Lynch of Veterans ments
Affairs
of Drs. Ernest
versions
Medical
Research
Damianopoulos
Service
and Helena
and the thoughtful
com-
I. Ryer on earlier
of this manuscript.
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