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Elevated -aminobutyric acid level in striatal but not extrastriatal brain regions in Parkinson's disease Correlation with striatal dopamine loss.

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Elevated y-Ammobutyric Acid Level in
Striad but Not Extrastriatal Brain Regions
in Parhnson’s Disease: Correlation
with Striatal Dopamine Loss
Stephen J. Ksh, PhD,* Ali Rajput, MD,? Joseph Gilbert, MD,$ Bohdan Rozdilsky, MD,? Li-Jan Chang, MS,*
Kathleen Shannak, BS,* and Oleh Hornykiewicz, MD*§
We measured the concentration of y-aminobutyric acid (GABA), glutamic acid, and o-phosphoethanolamine in autopsied brain of 9 patients who died with idiopathic Parkinson’s disease and 10 control subjects. In the control striatum
GABA showed an uneven rostrocaudal distribution pattern with rostral subdivisions containing about 40 to 50%
higher levels. When compared with controls, GABA concentrations in Parkinson’s disease striatum were generally
elevated. The GABA elevation was most pronounced in the caudal subdivision of the putamen; this striatal subdivision
also showed the most severe dopamine loss. We observed in the caudal putamen a significant negative correlation
between the (elevated) GABA and (reduced) dopamine levels (the latter expressed as the sum of dopamine plus 3methoxytyramine). Milder nonsignificant elevations of GABA levels were observed in intermediate and rostral putamen followed by the caudate head subdivisions. GABA levels were normal in all extrastriatal brain areas examined.
Striatal glutamic acid levels were markedly elevated in 3 of the 9 patients with Parkinson’s disease. We suggest that the
altered GABA metabolism in the striatum, especially the putamen, is consequent to the nigrostriatal deficiency in this
disorder. This secondary change in striatal GABA function is likely to contribute to the basal ganglia dysfunction
produced by the striatal dopamine loss and thus may be related to certain aspects of parkinsonian symptomatology.
Kish SJ, Rajput A, Gilbert J, Rozdilsky B, Chang L-J, Shannak K, Hornykiewicz 0: Elevated y-aminobutyric
acid level in striatal but not extrastriatal brain regions in Parkinson’s disease: correlation with striatal
dopamine loss. Ann Neurol 20:26-31, 1986
It is well established that in Parkinson’s disease the
primary and characteristically severe loss of striatal
dopamine is often accompanied by less pronounced
changes in the other basal ganglia neurotransmitter systems (cf. 1131). Among the changes, alterations related
to the y-aminobutyric acid (GABA) neuronal system
in the basal ganglia are especially noteworthy in view
of the importance of the dopamine-GABA interactions in this brain area 171. In postmortem brain studies of patients with Parkinson’s disease, GABA levels
in the putamen have been reported to be either normal 1161 or elevated 1271. However, the activity of
glutamic acid decarboxylase (GAD), the marker synthetic enzyme for GABAergic neurons, has been
found to be reduced in Parkinson’s disease striatum 13,
10, 16, 18, 21, 281. In the single study that has addressed the question of GABA alterations in extrastriatal brain regions, Laaksonen and co-workers [ 161
reported significantly lowered GABA levels in cerebral and cerebellar cortex of non-L-dopa-treated, but
not in L-dopa-treated, patients with Parkinson’s disease.
The present study was designed to clarify further the
possible involvement in Parkinson’s disease of GABA
in (especially) striatal and extrastriatal brain regions. [n
addition, in view of our preliminary observations of
significant intraregional variations of GABA levels in
human striatal nuclei, a special attempt was made to
obtain a topographic distribution along a rostrocaudal
axis of both GABA and dopamine levels (the latter as
the primary biochemical disturbance in Parkinson’s
disease brain) in the caudate-putamen complex. Further, to assess the specificity of any observed GABA
changes, we examined the concentrations of two ocher
amino compounds, the neurotransmitter glutamic acid
and o-phosphoethanolamine (o-pea), which are sta.ble
post mortem in autopsied human brain 1261.
From the *Human Brain Laboratory, Clarke Institute of Psychiatry,
Toronto, the Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario, the ?University Hospital, Saska‘Oon,
the
London, Ontario,
Canada, and the $University of Vienna, Vienna, Austria.
Received Jul 29, 1985, and in revised form Oct 18. Accepted for
publication Oct 27, 1985.
26
Address reprint requests to Dr Kish, Human Brain Laboratory,
Clarke Institute of psychiatry,Toronto, Ontario, Canada, M5T 1R8.
Table 1. Distribution of Amino Compounds in Striatum: Controls uersus Parkinson’s Diseasea
~~
Glutamic Acid
GABA
Brain Region
Controls
PD
Rostral caudate head
Intermediate caudate head
Caudal caudate head
Rostral putamen
Intermediate putamen
Caudal putamen
31.7 k 2.7
28.7 k 2.1
22.2 f 1.7
2.8
43.7
34.4
3.0
28.2 2 2.2
38.7
31.2
27.9
50.6
50.3
48.6
*
*
Controls
2.3
1.8
+- 1.7b
t 4.4
t 3.3‘
t 5.1‘
k
2
PD
123.6 k
128.8 -c
108.0 +133.7 ?
118.8 t
113.7 t
8.3
6.7
6.0
7.7
6.4
10.8
150.8 2
143.6 k
134.8 2
171.8 ?
157.0 2
161.4 2
11.6
14.1
14.2
16.3b
16.1b
15.9b
Controls
PD
0.7
1.2
11.6 t 1.4
11.4 k 1.9
10.7 2 0.8
7.9 k 0.7
12.3
10.5
12.3
13.5
11.2
8.4
13.2
2
7.8
2
2
0.8
t 1.0
2
1.4
t 1.2
t 1.2
2
0.7
“Values (mean ? SE) are expressed as pnoYgm protein. Seven to 10 controls and 7 to 9 patients with PD were used. Glutamic acid values were
elevated in the striatum of 3 (only) of the 9 patients with Parkinson’s disease.
’ p < 0.05; ‘ p < 0.01, Student’s two-tailed t test.
GABA = y-aminobutyric acid; PD = Parkinson’s disease.
Patients and Methods
Autopsied brain was obtained from 7 patients who died with
neuropathologically confirmed idiopathic Parkinson’s disease
and 10 (control) patients who died without evidence of
neurological or psychiatric disease. One half-brain was frozen
immediately at - 80°C and the other half-brain was fixed in
formalin for histological analysis. The mean ages and deathto-freezing intervals for the 9 patients with Parkinson’s disease (mean k SE: 74 -C 3 years; 14 k 1 hours) did not differ
significantly from those of the controls (73 +- 3 years; 11 f
3 hours; p > 0.05, Student’s two-tailed t test). It was necessary to control for postmortem time given that GABA concentration in human brain increases markedly after death
[26}. All patients with Parkinson’s disease had received Iongterm L-dopa therapy for varying periods.
For the striatal dissection, 10 coronal sections (each approximately 3 mm in thickness) were taken from the frozen
half-brain, beginning with the rostral limit of the caudate
head (Section 1). In all sections the caudate and putamen
were divided horizontally into dorsal, intermediate, and ventral positions. Only intermediate subdivisions were used
from each section. For the caudate head nucleus, Sections 2
(rostral), 4 (intermediate), and 7 (caudal) were employed,
whereas for the putamen, Sections 4 (rostral), 7 (intermediate), and 10 (caudal) were used. The cerebral cortex was
dissected according to the classification of Brodmann: frontal
(Area lo), temporal (Area 21), parietal (Area 7b), and occipital (Area 17).
Amino acid concentrations were determined using the
procedure of Fernstrom and Fernstrom [7]. Dopamine
and its metabolite 3-methoxytyramine were measured using
minor modifications of the high-performance liquid chromatography-electrochemical procedure of Felice and associates [6]. Protein concentration was determined by the
technique of Lowry and co-workers [17].
Results
Amino Compounds in the Striatum
As shown in Table 1, in the controls GABA showed
an uneven rostrocaudal distribution pattern in both the
caudate head and putamen (p < 0.01, one-way analysis
of variance {ANOVA]), with rostral subdivisions of
the caudate head and putamen containing about 40 to
50% higher levels than the caudal subdivisions. N o
significant rostrocaudal gradient in striatum could be
demonstrated for glutamic acid or o-pea (ANOVA, p
> 0.05).
When compared with controls, GABA levels were
generally above normal in Parkinson’s disease striatum,
with most marked elevations found in the caudal subdivision of the putamen ( + 72%, p < 0.01). Milder or
nonsignificant GABA elevations were observed in the
intermediate (+46%, p < 0.01) and rostral putamen
( + 16%, not significant [NS], p > 0.05) and in the
rostral (+21%, NS, p > 0.05) and caudal (+26%, p
< 0.05) caudate head nucleus. Glutamic acid levels
were elevated by 28 to 42% in the putamen (p < 0.05)
and by 11 to 25% in caudate head subdivisions (NS, p
> 0.05). This elevated glutamic acid value was caused
by abnormally high levels (180 to 230 FmoVgm protein) in 3 of the 9 patients with Parkinson’s disease. N o
significant differences were observed in the striatal
concentration of o-pea (p > 0.05).
Amino Compounds in Extrastnatal Brain Areas
When compared with controls, no significant differences in extrastriatal Parkinson’s disease brain areas
were observed, with the exception of a 23% reduction
in o-pea concentration in the amygdaloid nucleus (p <
0.05, Table 2). Although GABA levels were elevated
by about 30% in the external and internal segments of
the globus pallidus of the patients with Parkinson’s
disease, these changes were not significant (p > 0.05).
Striatal Dopamine and 3-Methoxytyramine
Table 3 shows the mean levels of dopamine and its
metabolite 3-methoxytyramine in Parkinson’s disease
and control brain. In addition, to allow for a more
correct estimation of the antemortem dopamine levels,
we have calculated for each striatal subdivision the
sum of the dopamine plus 3-methoxytyramine concentrations. This was based upon an experimental
animal study [4, 51 indicating that most of the 3Kish et al: Brain GABA in Parkinson’s Disease
27
Table 2. Distribution of Amino Compounds in Extrastriatal Brain Regions: Controls versus Parkinson’s Disease”
GABA
Glutamic Acid
Brain Region
Controls
PD
Frontal cortex
Temporal cortex
Parietal cortex
Occipital cortex
Globuspallidus, external
Globus pallidus, internal
Substantia nigra
Red nucleus
Subthalamic nucleus
Ammon’s horn
Dentate gyrus
Hippocampal gyms
Uncinate gyrus
Am ygdala
16.0 2 1.2
16.6 t 1.1
15.6 t 1.5
16.2 rt 1.3
74.6 f 4.7
69.3
7.3
62.6 f 5.8
17.2 f 0.8
33.3 f 4.7
15.6f1.2
23.9 t 2.8
15.4 f 1.4
18.3 f 1.8
26.4 f 5.0
14.3 L
13.1 f
13.0
15.2 f
75.3 -+
87.7 rt
65.7 f
16.5 t
37.3 2
17.8f
23.7 f
15.2 f
22.0 f
21.2 f
*
*
1.5
1.4
1.0
1.4
7.9
8.7
10.4
1.1
4.8
1.7
3.7
1.7
3.4
2.1
Controls
PD
88.7 f 7.4
99.1 f 8.2
74.6 ? 10.3
92.6
6.6
64.3
6.7
53.7 t 5.7
67.0 f 5.7
68.6 rt 8.8
57.3 f 7.6
87.3t 6.1
112.4 t 6.9
93.7 f 6.4
102.0 rt 6.4
140.5
3.0
85.4 f
96.6 rt
77.3 f
88.5 f
65.6 2
58.2 f
73.8 f
70.7 &
68.5 rt
108.3f
120.7 f
112.6 rt
110.4 f
124.2 f
*
*
*
o-Phosphoethanolamine
8.2
8.5
13.4
8.8
7.8
5.5
7.5
4.5
7.5
8.1
7.0
13.0
16.7
10.7
Controls
PD
10.8 f 2.1
11.9 f 1.8
8.4 f 1.3
7.2 f 0.5
6.2 f 0.7
5.7 f 1.0
7.1 f 0.7
4.4 f 0.7
5.0 f 1.0
9.4 t 0.5
12.1 t 1.0
11.9 f 1.7
11.5 f 1.5
15.0 f 1.5
7.5 f 0.7
11.7 * 2.7
7.7 f 0.7
7.1 t 0.5
7.4 2 0.4
7.6 f 0.5
10.3 f 1.7
6.3 t 0.6
6.7 f 1.0
10.1 rt 1.1
11.7 rt 1.5
11.3 f 1.2
12.4 rt 1.6
11.5 t 1.0‘
“Values (mean 2 SE) are expressed as pmoVgm protein. Five to 10 controls and 7 to 9 patients with P D were used.
‘p < 0.05, Student’s two-tailed t test.
GABA
=
y-aminobutyric acid; P D
=
Parkinson’s disease.
Table 3. Distribution of Dopamine and 3-Methoxytyramine in Striatum: Controls versus Parkinson’s Disease”
3-Methoxyt yramine
Dopamine
Brain Region
Controls
PD
Rostral caudate head
Intermediate caudate head
Caudal caudate head
Rostral putamen
intermediate putamen
Caudal putamen
17.4
27.2
24.6
34.0
30.8
36.5
1.7
5.3
2.7
4.6
t 1.7
f 4.3
t 2.8
f 5.8
rt
rt
8.0
1.4
0.7
0.2
Controls
0.6‘
1.7’
f 2.5’
0.6‘
i 0.3b
f 0.1’
?
?
*
*
7.6
1.8
12.8 f 1.5
13.4 ? 3.6
14.2 f 2.0
12.7 ? 1.8
13.7 f 2.3
PD
*
2.7 0.6‘
5.3 f 1.0‘
6.4 rt 1.2
4.8 f 1.4b
2.5 i 0.5b
1.9 f 0.4‘
Dopamine and
3-Methoxytyramine
Controls
PD
27.0 f 4.1
40.1 rt 5.6
38.0 t 4.7
48.2 f 5.7
43.8 4.2
50.5 f 7.7
4.6 t 1.1‘
10.6 f 2 h b
14.4 f 3.5’
6.2 f 2.0‘
3.2 t 0.&
2.1 t 0.4‘
“Values (nrnoVgm tissue wet weight) represent mean ? SE. Eight controls and 9 patients with P D were used for the analysis.
“ p < 0.01 (as compared to controls), Student’s two-tailed t test.
PD
=
Parkinson’s disease.
methoxytyramine present in the autopsied brain was
formed from dopamine post mortem.
In the caudate head but not putamen of controls,
dopamine and the sum of dopamine plus 3-methoxytyramine showed an uneven rostrocaudal distribution,
with the intermediate and caudal subdivisions showing
relatively higher levels (repeated measures ANOVA,
p < 0.05).
When compared with controls, dopamine and 3methoxytyramine levels in the Parkinson’s disease
striatum were significantly and markedly reduced in
each subdivision (p < 0.01), with the exception of a
52%, reduction of 3-methoxytyramine in the caudal
caudate head, which did not attain significance (p >
0.05). In the caudate head the reduction in dopamine
28 Annals of Neurology Vol 20
No 1 July 1786
and 3-methoxytyramine levels was most marked in the
rostral portion, whereas in the putamen the reverse
was true: the caudal subdivision was more severely
affected than was the rostral portion.
Relationship between Striatal Dopamine Loss
and GABA Elevation
To assess the possibility of dopamine-GABA interactions in the parkinsonian striatum, we subjected our
data to a regression analysis. A significant negative correlation ( Y = -0.677, p < 0.05) was observed between the (elevated) GABA levels and the (reduced)
dopamine levels (expressed as the sum of dopamine
plus 3-methoxytyramine) in the caudal putamen; this
region also had the greatest reduction in dopamine
concentration ( - 76%). The correlations between
GABA and dopamine levels observed in the other
striatal subdivisions were not significant (p > 0.05).
Discussion
The results of our study demonstrate, for the first
time, a significant rostrocaudal distribution of GABA
in human striatum with highest GABA levels in the
rostral subdivisions of both the caudate and putamen.
This finding is consistent with the report of a qualitatively similar distribution of the GABA-synthesizing
enzyme GAD in human striatum [lo}. When compared with controls, there was a significant but subregion-dependent elevation of GABA concentration in
Parkinson’s disease striatum; this was most pronounced in the caudal putamen. The increased GABA
levels were accompanied, in addition to the wellknown dopamine loss, by a less marked elevation of
glutamic acid levels in striatum (in only 3 of the 9
patients with Parkinson’s disease studied), but also by
normal concentration of another amino compound, opea. No significant alteration in any amino compound
was observed in extrastriatal brain areas with the exception of a slight but significant (-23%, p < 0.05)
reduction of o-pea in the amygdaloid nucleus.
Dopamine
All patients with Parkinson’s disease had a profound
reduction in the striatal dopamine concentration, and
the dopamine loss was, as expected {2), more severe in
the putamen than in the caudate nucleus. There was
also an even more striking difference between these
two striatal subdivisions: whereas in the caudate head
the degree of dopamine loss became less pronounced
in the rostrocaudal direction, the reverse was true
in the putamen, in which the caudal subdivision was
the most dopamine-depleted portion of the whole
striatum. This remarkably uneven striatal dopamine
loss can be presumed to reflect the pattern of loss of
the nigral (compacta) dopamine cell bodies, suggesting
a very specific topography of nigral damage in
idiopathic Parkinson’s disease {2, 123. This observation
is noteworthy in view of the functional heterogeneity
that exists within the striatal structures (as indicated,
inter alia, by the topographic arrangement of the corticostriatal projections { 111). As each of the subregions
of the caudate nucleus and putamen analyzed in our
study may subserve a relatively specific function, our
observation of a markedly uneven dopamine loss in
these striatal subdivisions has important implications
for the pathophysiology and symptomatology of Parkinson’s disease.
Glutamic Acid and 0-pea
The significantly elevated glutamic acid concentration
present in Parkinson’s disease putamen was caused by
grossly elevated levels (in striatum only) in only 3 of
the 9 patients. The increased glutamic acid level was
unlikely to be related to the elevated GABA levels
as no significant correlations between GABA and
glutamic acid levels were observed in any striatal subdivision (data not shown). This elevation, which was
not observed in the study by Perry and associates {27),
was unlikely to be caused by hyperammonemia at
death (which can elevate glutamic acid levels {24)) because the glutamic acid elevations were restricted to
striatum and because the concentration of brain
glutamine (which is greatly elevated in hyperammonemia [241) was normal in the 3 patients (data not
shown). It may be interesting that a similar (although
more regionally widespread) elevated glutamic acid
value was observed in the brains of 3 patients with
progressive supranuclear palsy [ 151, a disorder that
shares many clinical features with Parkinson’s disease.
The importance of our demonstration of mildly reduced o-pea in the amygdaloid nucleus, an o-pea-rich
brain area {25] assumed to be histologically unaffected
in Parkinson’s disease, is unknown.
GABA
With regard to the question of elevated GABA concentration in Parkinson’s disease striatum, our data
demonstrate a significant and marked elevation of this
neurotransmitter in intermediate and (especially)
caudal putamen, with less marked increases in the rostral putamen and the rostral and caudal caudate head.
Thus, our data confirm and greatly extend the previous
observation of elevated GABA concentration in the
whole putamen [27}. The earlier finding of normal
GABA levels in Parkinson’s disease putamen El61
possibly may have been caused by the selection in this
study of a relatively rostral subdivision of this nucleus
for biochemical analysis; this, as indicated in the present study, exhibits a less marked and nonsignificant
elevation of this amino acid.
As all of our patients with Parkinson’s disease had
undergone L-dopa therapy for varying periods, the influence of this treatment on striatal GABA levels must
be considered. Manyam [20) observed a significantly
higher GABA concentration in cerebrospinal fluid of
L-dopa-treated versus non-L-dopa-treated patients
with Parkinson’s disease. Laaksonen and co-workers
[161 have reported significantly elevated levels of
GABA in the globus pallidus of L-dopa-treated versus
non-L-dopa-treated patients with Parkinson’s disease;
however, prolonged administration of L-dopa did not
affect GABA levels (which were normal as compared
to controls in this study) in either the caudate or putamen. Perry and co-workers 127) observed in their
study that the 2 (of 13) patients with Parkinson’s disease who had apparently never received L-dopa had
putamen GABA values as high as patients who had
Kish et al: Brain GABA in Parkinson’s Disease 29
been treated with L-dopa; the authors concluded that
drug therapy was unlikely to have accounted for the
increased GABA concentration.
The GABA-Dopamine Relationship
More likely than the drug effects, the increased striatal
GABA levels in patients with Parkinson’s disease may
be related to the loss of the nigrostriatal dopaminergic
influence, characteristic of Parkinson’s disease. In this
regard, evidence exists suggesting that the nigrostriatal
dopaminergic projection forms (inhibitory?) synapses
with medium spiny neurons in the striatum which are
probably GABAergic (cf. Eli’)). This argument is
strengthened by (1) our general observation that in
Parkinson’s disease striatum GABA levels are more
markedly elevated in the striatal regions with the most
severe dopamine loss, i.e., the putamen, than in the
caudate head (which is distinctly less affected by the
dopamine loss), and (2) our finding of a negative correlation in caudal putamen between the (elevated)
GABA and (reduced) dopamine levels. Some additional support is derived from the demonstration of
increased GABA levels in the striatum of rodents with
lesions (induced by 6-hydroxydopamine) of the nigrostriatal dopaminergic projection [S, 27, 32). However,
in this respect the 6-hydroxydopamine-lesioned rat
may not be an appropriate model of human parkinsonism. This can be concluded from the observation that
in Parkinson’s disease the activity of striatal G A D is
reduced [3, 10, 16, 18, 21, 28) rather than increased,
as is the case in the 6-hydroxydopamine animal model.
Although it has been suggested that reduced G A D
activities observed in autopsied brain may be a consequence of protracted terminal illness or prolonged
hospitalization rather than the neurological disorder
per se 123, 27, 311, this seems unlikely to be a
complicating factor in view of the demonstration
that G A D activities were still reduced (although not
significantly) by 40% in the putamen of patients with
Parkinson’s disease as compared with controls closely
matched with respect to agonal status (antemortem
conditions) [27]. In a more recent study, mean G A D
activity was significantly reduced in the caudate (but
not the putamen) of 26 patients with Parkinson’s disease compared with controls matched with respect to
the antemortem conditions of hypoxia and hypovolemia [22). However, in a smaller subgroup of patients with Parkinson’s disease in this study ( n = l o ) ,
in which the antemortem conditions were “approximated to sudden death,” caudate G A D activity was
found to be normal. Taken together, the evidence
derived from human studies suggests that in Parkinson’s disease the greatly deficient nigrostriatal dopamine activity may lead to reduced striatal G A D activity and elevated GABA levels. The mechanism of
these changes may involve either loss of a “trophic”
influence of the dopamine neurons on the striatal
30 Annals o f Neurology
Vol 20
N o 1 July 1986
GABA system, or, even more likely, a downregulation of GABA neuron activity. In either case,
the reduction of GABA release would have to be
greater than the reduction in GABA synthesis. In this
respect, there is evidence to show that the physiological effect of dopamine is to inhibit the activity of
the striatal GABA neurons. Thus, in short-term experiments, removal of the dopaminergic influence by
lesioning the nigrostriatal dopamine fibers (with
6-hydroxydopamine) increased both striatal GABA
turnover {7] and the firing rate of the striatal, presumably GABAergic, neurons f30). However, in a longterm study, the increase in firing rate was not seen 14
to 1 7 months after the 6-hydroxydopamine-induced
lesion, indicating a readjustment to normal of the
striatal neuron hyperactivity 1301. In view of this experimental evidence, down-regulation of GABAergic
activity in Parkinson’s disease striatum may be one of
the compensatory adaptive measures aimed at readjusting the activity of the disinhibited GABA neurons,
thus restoring the disturbed balance between the
dopamine and GABA neuronal activity. The insidious,
slowly progressive, and protracted loss of dopamine
neurons in Parkinson’s disease would be expected to
favor greatly the development of such an adaptive process. It is interesting that prolonged treatment with Ldopa has been demonstrated to increase G A D activity
in the striatum of both patients with Parkinson’s disease [ 14, 16) and experimental laboratory animals
(rodents) 114). This suggests that long-term L-dopa
therapy may partially compensate for the deficient
dopaminergic influence on the striatal GABA neuron
system in Parkinson’s disease.
With respect to functional considerations, Lehmann
and Langer El71 have suggested, on the basis of experimental evidence, that the striatal GABAergic neuron
is the primary synaptic target of the nigrostriatal
dopaminergic terminals. This suggests that part of the
parkinsonian symptomatology is likely to be related
to secondary changes in activity of the striatal
GABAergic neurons (interneurons andor striatopallidal and nigrostriatal projections). In this respect, the
possibility exists that the L-dopa potentiating effect of
the GABAergic drug progabide El) may be mediated
by the proposed inhibitory GABAergic influence on
the striatal cholinergic activity [27]. This possibility
underlines the potential clinical importance of 1he
GABA-dopamine interrelationship found in our study.
Supported by the Parkinson Foundation of Canada and the Clarke
Institute of Psychiatry. S. J. K. is a Career Scientist of the Ontario
Ministry of Health. Some brain material was obtained from Drs
Emson and Nyssen, Department of Pathology, University Hospital,
Saskatoon, and the Canadian Brain Tissue Bank. L. M. Dixon provided help in the statistical analyses of the data.
Presented in part at the Eighth lnternational Symposium on Parkinson’s Disease, June 9-12, 1985, New York, NY.
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