336
The Interaction Between
GABA and Dopamine:
Implications for
Schizophrenia
by James C. Garbutt Abstract
and Daniel P.
A role for y-aminobutyric acid
van Kammen (GABA) In the pathophysiology of
schizophrenia was first suggested by
Eugene Roberts in 1972. Since then
considerable work has been accom-
plished in both the clinical and basic
sciences regarding GABA and schizo-
phrenia. Although it was originally
thought that GABA might be useful
in treating schizophrenia because of
its inhibition of dopaminergic
activity, recent data have shown that
In certain models GABA has the
opposite effect on dopaminergic
functions. Regardless of the
relationship of GABA to dopamine,
neither biochemical nor pharma-
cological studies have been able to
demonstrate a clear and reproducible
GABA disturbance in schizophrenia.
A number of problems contribute to
the difficulty in studying GABA in
schizophrenia, including the lack of
specific and nontoxic GABA agonists
as well as the complexity of the
GABA system in brain. Interest in
GABA research in schizophrenia
appears to have waned, but several
areas nevertheless appear promising
for clinical investigation.
Schizophrenia has been hypothesized
to stem from a complex interaction
between the functioning of neuro-
transmitters in the brain and the
psychosocial milieu of an individual.
Although our understanding of how
neurotransmitter action contributes
to behavior is still quite primitive,
advances over the past several years
in our knowledge of the brain have
increased the prospect of better
understanding the biological
component of schizophrenia. Of the
many neurotransmitters and neuro-
regulators that have been identified
in the brain, dopamine (DA) has
generated the most interest regarding
schizophrenia. The hypothesis that
DA is involved in schizophrenia
began with Carlsson and Lindqvist's
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suggestion in 1963 that antipsychotic
drugs block DA receptors. Since
then, additional evidence in support
of that concept has been reported:
i.e., traditional antipsychotic drugs
act by blocking DA receptors in the
brain (Creese, Burt, and Snyder
1976; Seeman, Lee, and Chau-Wong
1976). Clinical observations have
confirmed that drugs that activate
DA in the brain produce psychotic
behavior in normal volunteers and in
schizophrenic patients. The
hypothesis, then, was put forth that
an increase in brain DA activity is a
critical factor in the development of
schizophrenia. Recent reviews have
addressed the strengths and
weaknesses of this DA hypothesis
(Meltzer and Stahl 1976; van
Kammen 1979).
One prominent weakness of the
DA hypothesis is that blocking DA
receptors in psychotic patients with
neuroleptics does not always
ameliorate psychotic symptoms.
Ninety-five percent of schizophrenic
patients show some response to
neuroleptic treatment initially, while
50 percent appear to have moderate
to excellent response (Cole 1964).
However, 30 percent of patients
relapse within 1 year of the inception
of neuroleptic maintenance treatment
(Davis 1975), and many patients
whose psychotic symptoms are
diminished by neuroleptics
nevertheless remain seriously
disturbed or show increasing
deterioration. Most likely, interindi-
vidual pharmacokinetic differences
partially contribute to the lack of a
homogeneous response. A second
weakness in the DA hypothesis is
Reprint requests should be sent to Dr.
J.C. Garbutt, Clinical Research Unit,
Dorothea Dbc Hospital, Raleigh, NC
27611.
VOL. 9, NO. 3, 1983
that D-amphetamine does not con-
sistently worsen schizophrenic
symptoms (van Kammen et al. 1982).
In fact D-amphetamine has been
reported to improve psychosis in
some patients, depending on their
clinical state. These findings, along
with other evidence, suggest diversity
in the pathophysiology of schizo-
phrenia and support the search for
additional biological disturbances in
the disorder. The neurotransmitter
y-aminobutyric acid (GABA) has
been investigated in regard to schizo-
phrenia, and is the focus of our
review.
A GABA disturbance in schizo-
phrenia was first suggested by
Roberts (1972). He hypothesized that
low levels of GABA in the brain
might lead to a state of disinhibition
which, in turn, could produce the
symptoms seen in schizophrenia.
Later, Roberts (1976) revised this
concept into a GABA-imbalance
hypothesis. In a previous article we
outlined research strategies to study
that might prove useful in the
investigation of a potential GABA
deficit in schizophrenia (van
Kammen 1977). Since then,
numerous studies have examined the
role of both GABA and DA in
schizophrenia. Here, we review the
evidence linking GABA to DA
functions and also consider those
actions of GABA that might be
important to schizophrenia
irrespective of mediation by DA.
Neurochemistry and Brain
Distribution of GABA
GABA is synthesized from the amino
acid glutamate by glutamic acid
decarboxylase (GAD) with pyridoxal
phosphate (vitamin B») as a cofactor.
GABA transaminase (GABA-T)
degrades GABA by transferring the
amino group to o-ketoglutarate. In
the process succinic semialdehyde
and glutamate are generated with
pyridoxal phosphate as a cofactor
(figure 1). Succinic semialdehyde is
converted to succinic acid, which
enters the Krebs cycle; GABA thus
has an integral connection to
metabolic function in addition to a
neurotransmitter action. Further-
more, a number of alternate
metabolic pathways also have been
proposed (Cooper, Bloom, and Roth
1974). However, the importance of
GABA as a neurotransmitter has
clearly been established by 'H-GABA
uptake studies which suggest that up
to 30 percent of neurons in rat
cerebral cortex use GABA in neuro-
transmission (Bloom and Iversen
1971) compared to less than 1
percent for the catecholamines
(McGeer, Eccles, and McGeer 1978).
GABA pathways in the brain do not
follow the model of major cell nuclei
with many projection fields as do the
catecholamines. Instead, GABA
neurons function within specific
brain regions, such as the striatum,
or between major brain regions, such
as the striatonigral pathway. In fact,
the measurement of GABA (Fahn and
Cote 1968; Balcom, Lenox, and
Meyerhoff 1975) and GAD (McGeer
and McGeer 1979) in mammalian
brain, including that of man,
suggests that GABA may be active in
neurotransmission throughout the
entire brain.
GABA acts postsynaptically
(Kmjevic 1976) by increasing
membrane conductance to chloride
ions. The net effect is to inhibit the
generation of an action potential in
the postsynaptic cell. This effect has
been demonstrated directly by
microiontophoretic studies in which
GABA was placed on nerve
membranes (Curtis and Johnston
1974). All neuronal pathways in
mammalian brain are inhibited by
GABA (Curtis 1979), which again is
337
indicative of the diffuse role of
GABA in brain. This widespread
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inhibitory action led Roberts (1972,
1976) to hypothesize a deficiency of
GABA in schizophrenia with
subsequent imbalance in brain
functioning.
Neurophysiologlcal Actions of
GABA on DA Neurons
Given the powerful inhibitory action
of GABA, it is not surprising that the
iontophoretic application of GABA,
or the GABA receptor agonist
muscimol, inhibits the firing of DA
neurons in the substantia nigra (SN)
(Waszczak and Walters 1979) and in
the ventral tegmental area (VTA)
(Wolf et al. 1978). The SN contains
the DA cell bodies of the nigro-
striatal DA tract, while the VTA is
the origin for the mesolimbic and
mesocortical DA tracts that have
been hypothesized to be overreactive
in schizophrenia. Thus it is critical to
the understanding of schizophrenia to
determine whether GABA acts
physiologically, as it does ionto-
phoretically, to inhibit the VTA or
SN DA cells. Evidence confirming
this action includes the following:
electrical stimulation of the caudate
nucleus inhibits SN DA cells
(Yoshida and Precht 1971) while
stimulation of the nucleus accumbens
inhibits VTA DA cells (Wolf et al.
1978); both of these actions are
blocked by bicuculline, a specific
GABA antagonist; bicuculline
injected directly into the VTA in cats
produces spiking in the nucleus
accumbens (Stevens, Wilson, and
Foote 1974) and lesioning the tracts
between caudate and SN produces a
fall in SN GABA content (Kim et al.
1971). These studies are partial
evidence that GABA functions as an
inhibitory feedback neurotransmitter
from striatum to SN and is involved
in feedback inhibition from nucleus
338
Figure 1. Synthesis and degradation of GABA
HHj
H - C - COOH
p y r i d o x a l phosphate
I
CHi
/^lui Canute Dccarboxylast
CH 2
H+
COOH
L-Glutanate
accumbens to VTA that dampens
excess DA cell activity. If this
evidence is correct, then GABA
should be an effective treatment for
states of DA overactivity in these
regions.
However, recent reports suggest
that DA neurons in the SN and VTA
may be activated by GABA.
Waszczak and Walters (1979)
reported that systemic muscimol in
the rat produced increased firing in
DA neurons in pars compacta of the
SN. But non-DA neurons in the
adjacent pars reticulata were
inhibited by systemic muscimol and
were found to be more sensitive to
iontophoretic GABA inhibition than
the pars compacta DA neurons.
Grace, Hommer, and Bunney (1980)
reported similar findings. These
studies have suggested the presence
of a GABA-sensitive intermediate
connection. Depressing the firing of
this inhibitory pathway with
systemic GABA leads to increased
DA cell firing. Waszczak and Walters
(1980) additionally reported that
COj
Gatna-anino butyric acid
a-Ketoglutaratt
intravenous GABA agonists increased
DA cell firing in the VTA. It would
appear, therefore, that GABA may
actually activate DA neurons in
certain cases.
GABA Effects on DA
Synthesis and Release
Because GABA activation in the
brain influences the firing of DA
neurons, an accompanying change in
DA synthesis and release would be
expected to occur. As might be
predicted from the anatomical and
electrophysiological data, however,
confusing results have been obtained
in studies of the effects of GABA.
For instance, GABA has been shown
both to increase and decrease DA
turnover depending upon the brain
region assayed, the duration of
stimulation, and whether DA
antagonists are administered
(Cheramy, Nieoullon,' and Glowinski
1978; Fuxe et al. 1979). As Cheramy,
Nieoullon, and Glowinski (1978)
observed, these findings suggest that
GABA acts at a number of sites to
SCHIZOPHRENIA BULLETIN
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pyridoxal phoaphat*
GABA Tranaaainu
toccinic
Saaialdahyde
influence DA neuronal activity. The
final outcome thus represents an
integration of several actions and is
not limited to monosynaptic
inhibition.
Effects of GABA on DA-
Mediated Behavior
Because the interaction between
GABA and DA is so complex, it is
difficult to predict the net effect of
GABA on DA-mediated behavior.
Therefore, whole animal studies are
necessary to determine the net
behavioral effect of GABA. Although
we use the term DA-mediated
behavior, DA is just one of several
neurotransmitters involved in any
given behavior.
Increasing and decreasing DA
activity in the brain can produce
specific and reproducible behaviors.
Behaviors occurring with increased
DA activity in rodents include stereo-
typies, locomotor activation, and
rotational movement; one behavior
associated with reduced DA activity
is catalepsy. Dopamine-induced
VOL. 9, NO. 3, 1983
locomotor activity is believed to be
mediated primarily through the
nucleus accumbens (Pijnenburg,
Woodruff, and Van Rossum 1973),
while stereotypies and rotational
movement have been linked to the
nigrostriatal DA system with input
from the nucleus accumbens (Creese
and Iversen 1974; Pijnenburg, Honig,
and Van Rossum 1975). Catalepsy
has been ascribed to diminished DA
activity in the striatum and nucleus
accumbens (Anden and Johnels 1977;
Sanberg 1980).
DA-Mediated Locomotor Activity.
GABA and GABAergic agonists have
been shown to antagonize locomotor
activity mediated by DA and
norepinephrine (NE) in a number of
different rodent models.
Systemic administration of
muscimol (Scheel-Kruger,
Christensen, and Arnt 1978) or
amino-oxy acetic acid (Cott and
Engel 1977), a GABA-T inhibitor,
blocks the hyperactivity normally
seen after systemic amphetamine,
apomorphine, or apomorphine with
clonidine, an Oj-adrenergic receptor
agonist. Biswas and Carlsson (1978)
reported that systemic GABA
antagonizes catecholamine-dependent
ethanol hyperactivity in mice with no
effect on activation caused by
combined apomorphine and clonidine
administration.
Localization of the GABAergic
effect to the nucleus accumbens has
been suggested by reports that intra-
accumbens muscimol (Scheel-Kruger,
Cools, and van Wei 1977; Scheel-
Kruger, Cools, and Honig 1977) or
ethanolamine-O-sulphate (Pycock
and Horton 1976), a GABA-T
inhibitor, counteracted the locomotor
effects of systemic apomorphine and
amphetamine and of intra-accumbens
injected DA or ergometrine, a DA
agonist.
These studies are particularly
interesting because they indicate that
GABA activation blocks the
locomotor effects of both indirect
(amphetamine) and direct (DA,
apomorphine, ergometrine) DA
agonists.
DA-Mediated Stereotypies.
Stereotypical behavior in rodents
includes repetitive gnawing, licking,
and sniffing with a reduction in more
typical forms of behavior such as
exploration. These behaviors have
been linked to increased DA activity
in the striatum (Creese and Iversen
1974).
Direct bilateral injections of
muscimol into the SN have been
reported to produce stereotypies
(Olianas et al. 1978) resistant to
neuroleptic administration (Scheel-
Kniger et al. 1979). Muscimol
injected into the nucleus accumbens
facilitated apomorphine stereotypies
(Scheel-Kruger, Cools, and van Wei
1977), although ethanolamine-O-
sulphate had no effect (Pycock and
Horton 1976).
Systemic muscimol differentially
affected methylphenidate-induced
stereotypies according to dosage
(Scheel-Kruger et al. 1979), and
antagonized apomorphine-induced
stereotypies (Fuxe et al. 1979;
Worms, Depoortere, and Uoyd
1979).
DA-Mediated Rotational Behavior.
As with stereotypy, rotational
behavior in rodents has been
associated with heightened DA
activity in the striatum. In particular,
an animal with increased DA
activation in the right striatum will
turn to the left and vice versa.
Rotational movement has been used
to monitor unilateral striatal DA
activity.
Muscimol injected unilaterally into
the SN caused contralateral turning,
339
exactly the same as DA activation in
the striatum (Olianas et al. 1978).
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However, haloperidol augmented this
action while apomorphine blocked
the behavior. Furthermore, lesioning
the nigrostriatal DA tract with 6-OH-
DA (6-hydroxydopamine) did not
attenuate the effect of muscimol, a
finding which suggests that the
GABAergic effect was not dependent
on the integrity of DA neurons.
Scheel-Kruger et al. (1979) reported
similar results and DiChiara et al.
(1978) noted that GABA antagonists
in the SN blocked apomorphine-
induced contralateral turning.
DA-Mediated Catalepsy. The
bilateral injection of picrotoxin or
bicuculline into the SN produced a
cataleptic state in rats which was
resistant to apomorphine adminis-
tration and similar to that induced
by the butyrophenones (DiChiara et
al. 1978). Conversely, muscimol in
the SN prevented haloperidol-induced
catalepsy (Olianas et al. 1978).
Muscimol or THIP (4,5,6,7-
tetrahydro-isoxazolo-[5,4-c]-pyridin-
3-ol), a potent GABA agonist,
injected into the ventral striatum or
the globus pallidus initially
augmented, but with time antag-
onized, haloperidol-induced catalepsy
(Scheel-Kniger et al. 1980). Injection
of muscimol into the ventral medial
or the ventral anterior nucleus of the
thalamus produced a cataleptic state
reversible by picrotoxin (DiChiara et
al. 1979). Additionally, injections of
picrotoxin in the ventral medial
thalamic nucleus reversed haloperidol
catalepsy. As several of the authors
involved with this work have pointed
out, these findings suggest that
certain GABA neurons function in
output pathways from the striatum
through the substantia nigra to
thalamic nuclei, reticular formation,
and superior colliculus (DiChiara et
340
al. 1979; Gale and Casu 1981). This
conclusion would seem equally
applicable for DA-stimulated
rotational behavior and stereotypies.
Other DA-Mediated Behaviors.
Ridley, Scraggs, and Baker (1979)
have reported that in the marmoset
amphetamine increased checking
behavior, decreased inactivity, and
did not produce gnawing behavior as
seen with rodents. When muscimol
was given before amphetamine
administration, it antagonized the
increased checking behavior and
decreased inactivity. Gnawing,
however, developed only after
combined muscimol and amphet-
amine administration. Casey,
Gerlach, and Christensson (1980)
have described an apomorphine-
induced behavior syndrome in
Ceropithecus aetiops monkeys after
long-term (4-14 months) haloperidol
administration. The syndrome
consisted of an increase in
locpmotion, arousal, and eye-
blinking followed by stereotypic
behaviors and oral hyperkinesia.
Pretreatment with muscimol or
y-acetylenic GABA (GABA-T
inhibitor) antagonized these
behaviors in a dose-related fashion.
The highest dose of muscimol (1.0
mg/kg) blocked both locomotion and
stereotypy.
Scheel-Kruger et al. (1980) noted a
complex behavioral effect in rats
after injections of GABA, GABA
agonists, or GABA antagonists in the
VTA. An agonist injected into the
caudal VTA produced a biphasic
motor response, intermale
aggression, and increased food
intake. Haloperidol and a
combination of reserpine and
o-methyltyrosine blocked the
hyperactive component of the motor
response. Agonist injection into the
rostral VTA, however, did not
induce hyperactivity while
antagonists injected in this area did.
These findings again support the idea
that GABA's behavioral effects
depend on anatomical location,
duration of action, and dosage.
Clinical Studies of GABA In
Schizophrenia
Clinical studies of the role of GABA
in schizophrenia can be divided into
two separate methodologies: clinical
trials with GABAergic agents and
assays of GABAergic function (van
Kammen 1977).
To our knowledge GABA never
has been given to schizophrenic
patients, although patients with
Huntington's chorea have received
oral GABA (Fisher, Norris, and
Gilka 1974). Primarily, GABA has
not been used in clinical trials
because it does not readily cross the
blood-brain barrier. Therefore,
clinical trials of GABA stimulation in
schizophrenia have used pharmaco-
logical agents that have an action
which is theoretically similar to that
of GABA. GABA antagonists cannot
be studied because of the risk of
seizures.
Baclofen (/3-parachlorophenyl-
GABA, lioresal) was the first
GABAergic agent to be tried in
schizophrenia. Because of its similar
chemical structure and similar
pharmacological profile (Kerwin and
Pycock 1978; Roberts, Gupta, and
Shargill 1978; Bowery et al. 1980),
baclofen was believed to be a GABA
agonist. Further investigation,
however, demonstrated that certain
of the pharmacological actions of
baclofen differed from those of
GABA (Naik, Guidotti, and Costa
1976) and that they were not blocked
by GABA antagonists (Davies and
Watkins 1974). While the clinical
studies of baclofen are valuable, they
cannot be accepted as good tests of
SCHIZOPHRENIA BULLETIN
GABA involvement despite the
likelihood of some degree of
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GABAergic action.
The first report of baclofen in
schizophrenia was a positive open
trial by Frederiksen (1975).
Subsequent trials could not confirm a
therapeutic effect of baclofen in
schizophrenia (Davis, Hollister, and
Berger 1976; Gulmann et al. 1976;
Kuhn 1976; Beckmann et al. 1977;
Bigelow et al. 1977; Schopf and
Hucker 1977; Simpson et al. 1978)
(table 1). A review of these studies
shows that 103 patients who
primarily had been diagnosed as
chronic schizophrenics received
baclofen; 31 patients concomitantly
received neuroleptics. Other than
Frederiksen's (1975) early positive
report on 13 patients, only 14 of the
remaining 90 patients improved while
36 worsened. Thus, even though
many of the patients were severely ill
with minimal neuroleptic response,
switching from neuroleptics to
baclofen was associated with
frequent clinical deterioration.
Baclofen was not helpful in this
patient group and, in fact, may have
been detrimental. Parenthetically,
two studies (Gulmann et al. 1976;
Beckmann et al. 1977) noted that
anxiety scores decreased despite the
lack of an antipsychotic response.
Structurally related to GABA, y-
hydroxy butyrate (GHB) has central
nervous system (CNS) effects in man
and purportedly acts through GABA
(Roth and Nowycky 1977), although
this has been disputed (Olpe,
Schellenberg, and Koella 1977). In a
double-blind, crossover trial of GHB
in seven chronic schizophrenic
patients who were off neuroleptics,
Schulz et al. (1981) reported mixed
effects. Two patients improved, three
worsened, and two did not change.
The authors rightly commented that
the small sample size precluded any
 o
r
z
o

Table 1. Baclofen trials in schizophrenia

Study Diagnosis (n) Drug Dosage Duration Design Results

Frederiksen (1975) Chronic schizophrenia Baclofen 15-60 mg/day? ? Open with Positive response in
(13) neuroleptlcs • many patients
Davis, Hollister, & Schizophrenia (4) Baclofen 80-100 mg/day ? Open, no Vt patients worsened,
Berger (1976) neuroleptics 2 became assaultive
Gulmann et al. Chronic schizophrenia Baclofen 60 mg/day 10 weeks Double-blind: No change in BPRS
(1976) (20) 10 patients with baclofen;
received baclofen; patients in both
10 patients re- groups worsened.
ceived placebo; Anxiety score
chlorpromazine as decreased with
needed baclofen
Beckmann et al. Acute and chronic Baclofen 75-125 mg/day > 20 days Single-blind: 7 patients improved, 5
(1977) schizophrenia (21) no neuroleptics— did not change, 9
1-week washout. worsened. Anxious,
4 patients dropped fearful subscale
2* to psychotic decreased
exacerbation
Schopf & Chronic schizophrenia Baclofen 15-60 mg/day 30 days Open, 9 patients on 3 patients improved
Hucker (1977) (10) neuroleptics
Bigelow et al. Chronic schizophrenia Baclofen 60-80 mg/day 4-weeks Double-blind No Improvement
(1977) 0) crossover, on
neuroleptics
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Simpson et al. Chronic schizophrenia Baclofen 20-120 mg/day 7 weeks Blind not 10/12 patients
(1978) (12) stated, no worsened
neuroleptics
after 4-week
washout
Kuhn (1976) Schizophrenia (24) Baclofen Up to ? ? 4 patients improved,
75 mg/day 4 patients worsened
342
definitive statement, although they
did note that the two responders had
higher pretrial cerebrospinal fluid
(CSF) homovanillic acid (HVA) than
the nonresponders (table 2).
Simeon et al. (1970) studied 10
psychotic patients with varied
diagnoses who were off neuroleptics
while they were receiving
D-cycloserine, which reportedly
inhibits GABA-T. They observed a
worsening of psychosts in seven
patients with confusion in several
and grand-mal seizures in two.
Because of the induced delirium and
seizures, these findings appear to
reflect acute organic brain syndrome
rather than a worsening of psychosis.
Dipropylacetic acid (DPA, sodium
valproate), a GABA-T inhibitor, has
been used in man for the treatment
of seizures. Several studies have
looked at DPA in the treatment of
tardive dyskinesia and have
monitored psychopathology.
Linnoila, Viukari, and Hietala (1976)
studied 31 patients, 24 with organic
psychosis and 7 with chronic schizo-
phrenia. They administered 800 mg
of DPA daily for 2 weeks using a
randomized, double-blind crossover
design. Neuroleptics were continued.
Psychopathology scores on the Brief
Psychiatric Rating Scale (BPRS)
improved significantly on DPA
compared to placebo. However, no
comment was made as to the
relationship between diagnostic
subtype and drug effect. Nagao et al.
(1979) studied seven chronic schizo-
phrenic patients on neuroleptics in an
open trial in which 400-600 mg of
DPA was given daily for 3 weeks.
BPRS scores improved significantly
at the end of the study, although the
average change was only 2 points.
The open design, the small patient
group, and the minimal change score
make it difficult to interpret these
findings. Lautin et al. (1980) studied
eight chronic schizophrenics who
were given DPA at dosages of 750-
3000 mg daily for 2 to 31 days.
Patients were recent admissions, drug
free, and studied under nonblind
conditions. DPA blood levels in five
patients were within the range
suggested for anticonvulsant activity
(Pinder et al. 1977). Six of the eight
patients were reported to be worse or
even very much worse after receiving
DPA as shown by an increase in
BPRS scores. The authors point out
that the effects of neuroleptic discon-
tinuation were not controlled, so it is
unclear whether DPA or neuroleptic
withdrawal was responsible for the
exacerbation of psychosis.
The DPA trials have not been
good tests of the efficacy of GABA in
schizophrenia. Problems exist in
design (nonblind ratings), diagnosis,
and control of neuroleptic effect.
In another study of tardive
dyskinesia, Casey et al. (1980)
reported on the behavioral effect of
y-acetylenic GABA (GAG, a
GABA-T and GAD inhibitor) in 10
chronically ill patients, 6 of whom
were schizophrenic patients. Dosages
of GAG were increased over an 8-
week period and no changes in BPRS
scores were reported. However, the
patients had a mean duration of
illness of 20 years and received
antipsychotic medication. Four
patients had undergone lobotomies.
Two studies have used direct
GABA agonists. Tamminga,
Crayton, and Chase (1978) gave
muscimol to six chronic schizo-
phrenic patients who had been
withdrawn from neuroleptics for 5
days. Muscimol was given double-
blind in single oral doses,
randomized with placebo. Ratings of
psychosis were obtained hourly for 4
hours. At dosages of 7-10 mg,
patients experienced increased
confusion and demonstrated a
SCHIZOPHRENIA BULLETIN
worsening of thought disorder which
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lasted several hours. At dosages of
less than 5 mg, several patients
reported feeling less anxious. These
results do not support the use of
muscimol in schizophrenic psychosis.
However, effective treatment of
psychosis may only be apparent after
several days or weeks, as with the
phenothiazines, so that a longer
treatment design would be necessary.
Additionally, muscimol is known to
have psychotomimetic actions in man
(Waser 1967) and may have toxic
metabolites (Menon 1981) which may
explain the worsening of psychosis in
these patients. Morselli et al. (1980)
have tested another GABA agonist,
SL-76-002, in chronic schizophrenics,
some of whom remained on neuro-
leptics. The design was open and
lasted for up to 60 days. No signif-
icant beneficial effects were noted.
In almost all of the clinical studies,
it is possible that patients were
refractory to any treatments in view
of the clinical description of the
majority of patients. Nevertheless,
almost all the trials have been
uniformly disappointing. The
reported improvement in some
patients might be due to chance
alone. Furthermore, patients
receiving muscimol, baclofen, GHB,
D-cycloserine, and DPA were
reported to worsen; one must, there-
fore, also consider that GABA
activation promotes psychosis. A
study of GABAergic agents in acute
psychotic states, neuroleptic-
responsive psychoses, and in normal
volunteers, with careful attention to
dosage, would help clarify the issue.
GABAergic Measurements in
Schizophrenia
Cerebrospinal fluid provides the most
direct access to brain neurotrans-
mitters and their metabolites in living
 o

z
o

Table 2. GABAergic drug trials in schizophrenia

Study Diagnosis (n) Drug Dosage Duration Design Results

Morselll et al. Chronic schizophrenia SL-76-002 1200-2400 > 60 days Open, 16 patients No improvement
(1980) (26) (synthetic mg/day off neuro-
GABA leptics
agonist)
Tammlnga, Crayton, Chronic schizophrenia Muscimol < 10 mg Acute Double-blind Psychosis worsened
& Chase (1978) (6) dosages increasing at dosages of
dosages of 7-10 mg.
drug over Anxiety decreased,
several days. dosages < 5 mg
5-day washout,
no neuro-
leptics
Casey et al. Chronic schizophrenia y-Acety- < 225 mg/day 8 weeks Single-blind, No improvement in
(1980) (6) lenlc on neuroleptlcs psychosis
GABA
Llnnolla, Vlukari, OrganiG psychoses (24) Dipropyl- 900 mg/day 2 weeks Double-blind, BPRS significantly
& Hletala (1976) Chronic schizophrenia acetic crossover, on Improved on drug
(7) acid neuroleptics
(DPA)
Nagao et al. Chronic schizophrenia DPA 400-600 3 weeks Open, on BPRS significantly
(1979) (7) mg/day neuroleptics. improved on drug
Lautln et al. Chronic schizophrenia DPA 750-3000 2-31 days Open, Clinically worsened
(1980) (8) mg/day neuroleptic- on drug
free
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Pennsylvania State University on September 11, 2016

Schulz et al. Chronic schizophrenia r-Hydroxy 8-16 g 10-29 days Double-blind, 2 improved,
(1981) (7) butyrate increasing 3 worsened,
dosages of GHB, 2 no change
no neuroleptlc
Simeon et al. Schizophrenia (6) D-Cyclo- 1-3 g 21-111 days Open, off Many patients
(1970) Other psychoses (4)' serlne neuroleptics . worsened, confusion
noted, 2 had grand-
mal seizures
344
subjects. Although CSF GABA arises
from the spinal cord as well as the
brain and an unknown proportion is
of nonneuronal origin, assaying CSF
GABA provides important screening
information. In fact, CSF GABA has
been reported to be abnormal in
Huntington's chorea (Neophytides,
Suria, and Chase 1978), suggesting
that brain pathology can be
associated with altered CSF GABA
levels.
Eight studies (Lichtshtein et al.
1978; Bowers, Gold, and Roth 1980;
Gold et al. 1980; van Kammen et al.
1980; Gemer and Hare 1981;
McCarthy et al. 1981; Zander et al.
1981; Zimmer et al. 1981; van
Kammen et al. 1982b), and one
methodological report (Faull et al.
1978) have evaluated CSF GABA
levels in schizophrenia (table 3).
Zander et al. (1981) did not statis-
tically compare patients to controls,
but they did note that stopping long-
term antipsychotic medication had
no effect on CSF GABA. Zimmer et
al. (1981) found no differences in
untreated acute schizophrenics, while
increased and decreased levels of
GABA were found in chronic
patients treated with neuroleptics.
Prospective treatment with sulpiride
led to a significant increase in CSF
GABA. The initial study by van
Kammen et al. (1980) found lower
mean CSF GABA levels in schizo-
phrenic patients (p < .01), although
most of the patient values fell within
the normal range. The subsequent
study (van Kammen et al. 1982),
which incorporated the first study,
did not find differences between
schizophrenics and controls, but the
patient and control groups differed
significantly in age. Hare et al. (1980)
recently reported significant decreases
in CSF GABA with age, particularly
in women. When age and gender
were controlled, van Kammen et al.
(1982b) noted that female schizo-
phrenic patients had significantly
lower CSF GABA levels.
Furthermore, duration of illness was
significantly associated with an
increase in GABA levels opposite to
what would be expected on the basis
of age in normal subjects. This
suggested that the length of schizo-
phrenic illness was affecting GABA
levels, perhaps because of chronic
neuroleptic treatment. McCarthy et
al. (1981) found significantly higher
CSF GABA in patients with chronic
schizophrenia, mean age 38.5, but
not in patients with acute schizo-
phrenia, mean age 23.2; concurrent
neuroleptic treatment did not explain
the increased GABA levels.
Lichtshtein et al. (1978) did not
find significant group differences in
CSF GABA but noted that six of the
seven lowest GABA values were
found in schizophrenic patients. The
age and gender of their group are
unclear. The studies by Gold et al.
(1980) and Bowers, Gold, and Roth
(1980) appear to contain the same
chronic patients rather than being
completely separate studies. Gold et
al. (1980) found that depressed
patients had low CSF GABA while
schizophrenic patients did not. Their
control subjects were older than the
schizophrenic patients and were
women, a fact which may have
blurred differences between the
schizophrenic patients and controls.
Gerner and Hare (1981) reported no
differences in CSF GABA between 11
chronic schizophrenic patients off
neuroleptics for at least 2 weeks and
29 normal subjects. Twenty-four
depressed patients had significantly
lower GABA, similar to the findings
of Gold et al. (1980).
In summary, these studies failed to
show consistent GABA abnormalities
in the CSF of schizophrenics
although methodological problems
SCHIZOPHRENIA BULLETIN
existed. The suggestion in the van
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Pennsylvania State University on September 11, 2016
Kammen et al. (1982b) study that
CSF GABA is decreased early in
schizophrenia and increases with the
duration of illness derives partial
support from McCarthy et al. (1981)
but was not confirme\d by Gerner
and Hare (1981). Furthermore, the
study of Gold et al. (1980) and
Gerner and Hare's (1981) finding of
low CSF GABA in depressed patients
suggest that other psychopathology
may affect CSF GABA. The issues of
duration of illness, medication,
motor activity, age, gender, and
diagnosis will need to be carefully
controlled before the significance of
CSF GABA results can be
understood.
Samples of schizophrenic brain
obtained at autopsy provide the only
opportunity for direct measurement
of alterations in GABA and its
related enzymes in brain. Unfortu-
nately, the confounding variables are
many and complicated: e.g.,
premorbid medical condition and
time between death and autopsy.
Furthermore, the CSF data indicate
the importance of longitudinal rather
than cross-sectional data. GAD
activity has been assayed in schizo-
phrenic brain more than any other
component of the GABA system
(Bird et al. 1977; Crow et al. 1978;
Perry et al. 1978; Bennett et al. 1979;
Iversen et al. 1979; McGeer and
McGeer 1979) (table 4). The initial
report that GAD was lower in
schizophrenia has not been verified.
In fact, Iversen et al. (1979) noted
that the pre-mortem condition
strongly affected the levels of GAD
at autopsy. Subjects who died with
conditions predisposing to anoxia
had lower GAD than those who died
sudden deaths. When this variable
was considered, no alteration in
GAD activity was noted in schizo-
phrenic patients.
VOL. 9, NO. 3, 1983
GABA levels (Cross, Crow, and
Owen 1979; Perry et al. 1979;
Spokes et al. 1980) and GABA
receptor binding (Bennett et al. 1979;
Lloyd and Dreksler 1979) have been
assayed in schizophrenic brains with
conflicting results (table 5). Perry et
al. (1979) found significantly lower
mean levels of GABA in the nucleus
accumbens and thalamus in schizo-
phrenic patients compared to normal
and neurological control subjects.
Cross, Crow, and Owen (1979)
found no differences in GABA levels
in the nucleus accumbens or
thalamus between controls and
schizophrenic patients. Spokes et al.
(1980) found significantly lower
GABA levels in the amygdala and
nucleus accumbens of psychotic
patients compared to controls. Of
further interest was their finding that
the more rigorously diagnosed
schizophrenic patients who had an
early onset of illness (<25 years)
were the only group to have low
GABA levels in the nucleus
accumbens. All three studies
controlled for the effect of age, type
of death, and time to autopsy, brain
freezing, and assay. All patient
groups, for the most part, had
received neuroleptics. Differences
may have existed in the dissection
technique of the nucleus accumbens
as noted by Spokes et al. (1980).
Both the JH-GABA binding studies of
Bennett et al. (1979) in the frontal
cortex and of Lloyd and Dreksler
(1979) in the cerebellum were
negative. The small number of
patients studied and the limited brain
regions assayed make these findings
preliminary.
Discussion
The original.hypotheses of Roberts
(1972, 1976) that GABA is deficient
or imbalanced in schizophrenia have
yet to be corroborated by clinical
studies. In our view, though, the
complexity of the GABA system and
the heterogeneity of schizophrenia
suggest that GABA still may play a
role in the disorder. Researchers will
need to delineate the type of schizo-
phrenia and the stage of the illness to
characterize a GABA involvement in
schizophrenia. For instance, the
suggestions that GABA is decreased
early in the illness (van Kammen et
al. 1982) or in patients with an early
age of onset (Spokes et al. 1980)
should be followed up. In general,
however, the animal and clinical data
are not sufficiently developed to
permit predictions of the clinical
usefulness of GABAergic agents or to
say whether GABA is imbalanced in
schizophrenia. Nevertheless, several
concepts should be considered in
the further evaluation of GABA
involvement in schizophrenia.
Perhaps one of the most important
considerations is that, whereas
GABA is an inhibitory neuro-
transmitter, it does not always
inhibit DA function. Therefore, data
derived from studies such as
GABAergic drug trials or measure-
ments of CSF GABA activity cannot,
in our opinion, be used to solidify or
refute the DA hypothesis of schizo-
phrenia. However, within anatomi-
cally discrete areas, GABA influences
DA-mediated behaviors in a more
predictable fashion and several of
these actions are also noted after
systemic GABAergic administration.
Thus one can make clinical predic-
tions based on animal findings and
test these predictions in clinical
studies.
One of the more consistent animal
findings is the inhibitory effect of
GABA on catecholamine-dependent
locomotor activation. This effect has
been noted in rodents and primates
after systemic GABAergic adminis-
tration or after intra-accumbens
345
administration. It is well known that
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Pennsylvania State University on September 11, 2016
acute psychotic states, regardless of
diagnosis, are frequently accom-
panied by motor activation which
responds to treatment with neuro-
leptics even before major antipsy-
chotic effects are observed. Bowers et
al. (1980) recently reported in a
study with 20 psychotic patients that
CSF GABA was negatively correlated
with measures of arousal and agi-
tation but that HVA was positively
correlated. But Lichtshtein et al.
(1978) noted no correlation between
psychomotor activity and CSF
GABA in schizophrenic patients, and
Gerner and Hare (1981) reported no
differences in CSF GABA between
agitated or psychomotor retarded
depressed patients. Furthermore,
both DPA (Lautin et al. 1980) and
badofen (Davis, Hollister, and
Berger 1976) have been reported to
aggravate agitation or to have no
beneficial effect (Bigelow et al. 1977).
Of related interest is that anxiety
levels were reported to decrease in
two baclofen studies (Gulmann et al.
1976; Beckmann et al. 1977) and in
the muscimol study at low dosages
(Tamminga, Crayton, and Chase
1978). Therefore, although the
clinical data are conflicting, the
target symptoms of anxiety-arousal-
agitation may be amenable to
treatment with certain GABAergic
agents. This therapeutic potential is
intriguing given the recent findings of
the interaction between benzodi-
azepine and GABA receptors
(Tallman et al. 1980). In fact,
Jimerson et al. (1982) and Beckmann
and Hass (1980), in preliminary
studies, have observed a beneficial
effect of high dose diazepam in some
schizophrenic patients.
Of considerable theoretical interest
is the effect of GABA on nigro-
striatal DA-mediated behaviors. A
number of complex behaviors are
Table 3. GABA in CSF from schizophrenic patients

GABA (pmoles/ml)
Study Diagnosis (n) Medication Assay method Mean ± SEM
Uchtshtein et al. Schizophrenia (17) None Enzymatic 273 ± 15
(1978) Hospital controls (9) Fluorometric 301 ± 23
Zander et al. Chronic schizophrenia (13) On and GC/MSwith On drug = 460 ± 70
(1981) Controls (9) off neuro- selective ion Off drug = 340 ± 90
leptics monitoring
van Kammen et al. Schizophrenia (11) \ None Ion exchange 191 ± 9 (p < .01)
(1980) Schizoaflectlve (6) / column chromatog-
Normal controls (40) raphy and 233 ± 13
fluorescence
detection
Faull et al. Schizophrenia (6) ? GC/MS with 370 ± 70
(1978) Huntlngton's chorea (3) selective ion 380 ± 110
monitoring
Gold et al. Schizophrenia (7) None Receptor assay 186 ± 31
(1980)' Schizoaffectlve (5) 117 ± 20
Neurological controls (20) 218 ± 26
Bowers, Gold, & Schizophrenia (10) None Receptor assay 209 ± 30
Roth (1980)' Schizoaffectlve (6) 130 ± 21
Neurological controls (20) 218 ± 26
Garner & Hare Schizophrenia (11) Schizophrenia— Ion exchange 177.4 ± 9.5
(1981) Primary depression (24) neuroleptic column chroma- 134 ± 4.89 ifi = .006)
Normal volunteers (29) free for tography and 183.2 ± 11.6
Anorexia nervosa (15) 2 weeks fluorescence . 2 0 0 ± 14
Mania (6) Others—none detection 186 ± 19
van Kammen et al. Schizophrenia (25) None Ion-exchange 275 ± 11.2
(1982/))' Schizoaffectlve (5) column chromatog- 232 ± 12.5
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Pennsylvania State University on September 11, 2016

Normal controls (41) raphy and

flourescence
detection
McCarthy et al. Acute schizophrenia (9) Several patients Receptor assay 334 ± 1331
(1981) Chronic schizophrenia (7) on neuroleptics 398 ± 73 (p < .007, vs. CO
controls) o
Psycho-organic disorder (14) 275 ± 126
Personality disorder (20) 219 ± 67 o
Neurological controls 273 ± 122 TJ

without identified 3D

pathology (41) m
>
09

3
z
Zlmmer et al. Acute schizophrenia (9) Acute schizophrenia— GC/MS with 380 ± 701
(1981) Chronic schizophrenia none selective ion 250 ± 70
with acute exacerbation (7) Chronic schlzophrenia- monitoring and (p < .05, vs. controls)
Chronic schizophrenia (13) neuroleptics amlno acid analyzer 440 ± 100
Depressed (6) Depressed- with fluorescence' 280 ± 110
various psycho- detection
tropics
Surgical controls (17) Controls—none 340 ± 90
1
These studies contain the same patients to an unknown degree.
' This study contains patients and normal control sub|ects from van Kammen et al. (1980)
1
SD.

Table 4. Glutamic acid decarboxylase (GAD) levels In schizophrenic brain

Study Patient diagnosis (n) Brain regions assayed Results

Bird et al. Schizophrenia (26) Nucleus accumbens, putamen, GAD significantly lower in all brain
(1977) Schizophrenia-like (15) amygdala and hippocampus regions assayed in patients vs.
Nonneurologlcal controls (61) controls
Perry et al. Nuclear schizophrenia (6) Frontal cortex, temporal cortex, Nonsignificant reduction In GAD
(1978) Paranoid schizophrenia (3) hippocampus, amygdaloid nucleus, in schizophrenia vs.
Unipolar depression (10) and caudate controls. Depressive patients
Nonneurological controls (12) had significantly lower GAD than
controls
Crow et al. Schizophrenia (18) Nucleus accumbens, caudate, No difference in GAD between
(1978) Controls (18) putamen, amygdala, and frontal schizophrenia and controls
cortex
McGeer & Chronic schizophrenia (11) 50 brain regions GAD significantly lower in 3/50
ownloaded from http://schizophreniabulletin.oxfordjournals.org/ at Pennsylvania State University on September 11, 2016

McGeer (1979) Nonneurologlcal controls (28) brain regions in schizophrenics

vs. controls (insula
p < .02, sensory association p <.O2,
and calcarlne fissure p < .05)
Bennett et al. Paranoid schizophrenia (7) Right frontal cortex No difference in GAD
(1979) Chronic undlfferentlated (5)
Morgue controls without
mental disease (12)
Iversen et al. Schizophrenia (7-14) Caudate, putamen, and nucleus No difference in GAD noted in
(1979) Controls (7-51) accumbens. patients between groups who
died sudden death; but
patients and controls who died of
bronchopneumonia had lower GAD
Table 5. GABA content and GABA receptor binding in schizophrenic brain

Study Patient diagnosis (n) Brain regions assayed Assay Results

Perry et al. Schizophrenia (7 nucleus Nucleus accumbens Amino acid GABA significantly
(1979) accumbens) (18 thalamus) and thalamus analyzer lower in nucleus
Controls, several with neuro- accumbens and
logical illness (16 nucleus thalamus In both
accumbens) (23 thalamus) schizophrenia and
Huntington's chorea (7 nucleus Huntington's chorea
accumbens) (26 thalamus) vs. controls
Cross, Crow, & Schizophrenia (19 nucleus Nucleus accumbens Radloreceptor No significant
Owen (1979) accumbens) (9 thalamus) and thalamus assay difference In
Controls (19 nucleus accumbens) either nucleus
(13 thalamus) accumbens or
thalamus
Bennett et al. Paranoid schizophrenia (7) Right frontal cortex Sodium-Inde- No significant
(1979) Chronic undlfferentiated pendent bind- difference
schizophrenia (5) ing of *H-
Morgue controls without GABA to -
mental disease (12) cortical
membrane
Uoyd& Schizophrenia (4) Cerebellum •H-GABA bind- Huntington's chorea
Dreksler (1979) Controls (9) ing to patients had sig-
Huntington's chorea (12) cerebellar nificantly in-
membrane creased affinity.
Schizophrenics did
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not differ from

controls
Spokes et al. Schizophrenia, age of onset < 25 Amygdala, nucleus accumbens, Enzyme GABA significantly
(1980) years (9) lateral pallidum, dentate fluorlmetrlc lower in amgydala
Schizophrenia, age of onset > 25 (9) nucleus, subthalamic method in all four psy-
Schizophrenia-like, age of nucleus, ventrolateral chotic groups.
onset < 25 years (5) thalamus, premotor GABA significantly o
I
Schizophrenia-like, age of cortex, hippocampus, lower In nucleus N
O
onset > 25 years (7) and cerebellar cortex accumbens in TJ
X
Controls (28) early onset schizo- 3J
m
phrenics only z
>
CD
c
VOL. 9, NO. 3, 1983
elicited or inhibited by DA in this
region and are strongly influenced by
GAB A. Of relevance to schizo-
phrenia is that in many instances
GABA exhibits actions similar to DA
and, in fact, may function as an
efferent neuron "downstream" from
DA. What is not known is whether
these dopaminergic-like actions,
which can mimic amphetamine, may
provide a basis to explain why in
several clinical studies GABAergic
activation worsened psychosis.
Conceivably, GABA stimulation
could be a model for schizophrenia
similar to amphetamine. This
requires careful examination.
Of course, the traditionally known
function of the substantia nigra and
its '-utpiit pathways is the control of
posture and muscle movement. Since
motor disturbances occur in catatonic
schizophrenia and are produced by
neuroleptics, GABA may be useful in
this area. Recently, GABAergic
modulation has been suggested to
benefit tardive dyskinesia Qeste and
Wyatt 1982), although studies of
acute extrapyramidal symptoms or of
catatonia are lacking.
Throughout this review we
continually noted the role of GABA
as a modulator of behavior at
multiple levels. This role surely
contributes to the difficulty in
determining whether brain GABA is
disturbed in schizophrenia, or in the
affective disorders. Furthermore, it
suggests that GABA activation in
man will produce myriad effects that
will yield confusing and, at times,
conflicting results. The discovery of
highly specific and nontoxic
GABAergic drugs would greatly help
this problem. Regardless of the
ultimate clinical usefulness of GABA,
however, the study of this major
inhibitory neurotransmitter should
provide important information about
mechanisms regulating behavior and,
perhaps, schizophrenia.
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Acknowledgment
We wish to thank Dr. Karen Gale,
Assistant Professor of Pharmacology
at Georgetown University School of
Medicine, for helpful comments. We
would also like to express our appre-
ciation to Ms. Kathy Ayers of the
Clinical Research Unit, Dorothea Dix
Hospital for her contribution to the
manuscript.
The Authors
James C. Garbutt, M.D., is Psychia-
trist, Clinical Research Unit,
Dorothea Dix Hospital, Raleigh,
N.C. Daniel P. van Kammen, M.D.,
Ph.D., is Assistant Chief, Psychiatry
Service, Veterans Administration
Medical Center, Pittsburgh, PA.;
and Professor of Psychiatry,
Department of Psychiatry, University
of Pittsburgh Medical School, Pitts-
burgh, PA.