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Brain dopamine-stimulated adenylyl cyclase activity in Parkinson's disease multiple system atrophy and progressive supranuclear palsy.

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Brain Dopamine-Stimulated
Adenylyl Cyclase Activity in
Parkinson’s Disease,
Multiple System Atrophy,
and Progressive
Supranuclear Palsy
Junchao Tong, PhD,1 Paul S. Fitzmaurice, PhD,1
Lee Cyn Ang, MD,2 Yoshiaki Furukawa, MD,3
Mark Guttman, MD,1 and Stephen J. Kish, PhD1
The dopamine D1 receptor is considered to participate in
levodopa’s antiparkinsonian action and levodopa-induced
dyskinesias. We examined the functional status of the D1
receptor in brain of patients with Parkinson’s disease
(PD), multiple system atrophy (MSA), and progressive
supranuclear palsy (PSP). Dopamine-stimulated adenylyl
cyclase activity was significantly increased in putamen
(ⴙ43%) and frontal cortex (ⴙ52%) in PD, normal in
PSP, but decreased by 47% in putamen in MSA. The
supersensitive dopamine D1 receptors in both striatum
and cerebral cortex in PD might compensate for dopamine deficiency, but could also contribute to long-term
complications of levodopa therapy.
Ann Neurol 2004;55:125–129
The dopamine D1 receptor (D1 receptor), originally
classified by its ability to stimulate adenylyl cyclase
(AC, EC4.6.1.1), recently was confirmed to contribute
to the antiparkinsonian function of L-dopa in Parkinson’s disease (PD) and also to the long-term complications of the therapy, because the selective D1 receptor
agonist ABT-431 possesses full antiparkinsonian effect
in PD patients and induces dyskinesias.1 On the other
hand, the D1 receptor is the predominant subtype of
dopamine receptors in human cerebral cortex and plays
a critical role in aspects of cognition, for example,
From the 1Human Neurochemical Pathology Laboratory, Center
for Addiction and Mental Health, Toronto; 2Division of Neuropathology, London Health Science Center, University of Western Ontario, London; and 3Movement Disorder Research Laboratory, Center for Addiction and Mental Health, Toronto, Ontario, Canada.
Received Jun 18, 2003, and in revised form Sep 16. Accepted for
publication Sep 16, 2003.
Address correspondence to Dr Tong, Human Neurochemical Pathology Laboratory, Center for Addiction and Mental HealthClarke Division, 250 College Street, Toronto, Ontario M5T 1R8,
Canada. E-mail: junchao_tong@camh.net
© 2003 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
125
working memory.2 Therefore, alterations of the D1 receptor in cerebral cortex might be involved in the cognitive difficulties often observed in PD, which also
could be exacerbated by L-dopa treatment.3 Studies using animal models of PD have suggested a supersensitive D1 receptor in the striatum4 and frontal cortex5
after dopamine depletion, possibly further enhanced by
6,7
L-dopa treatment.
However, the functional status of
the D1 receptor in brain of patients with PD, important for understanding the pathogenesis of L-dopa–induced complications,8 is uncertain.
Our investigation was designed to clarify the status
of dopamine D1–stimulated AC activity in both striatum and cerebral cortex of patients with PD using an
assay procedure that we recently established optimized
for autopsied human brain.9 Neurochemical data in
Table 1. Patient Information
Pathologya
Disease
Case Age (yr), PMI Duration
(yr)
No.
Sex
(hr)
Parkinson’s disease
1
73, M 18
2
79, F 15
3
77, F
6
4
66, F 18
5
81, F 19
6
69, M 18
7
79, M
8
70, M
9
71, F
10
83, M
Multiple system
1
68, M
2
72, F
3
40, F
4
73, F
5
63, M
6
69, F
7
70, M
8
66, F
9
63, M
10
69, M
7
19
16
⬎2
⬎10
?
10
⬎10
11
25
3.5
25
19
18
atrophy
25
8
6
?
19
8
9
7
10
7
17
6
13.5
4
14
6
10
14
12
?
Progressive supranuclear palsy
1
58, M 12
6
2
3
4
5
6
75, M 11.5
80, M 2.5
75, M 12
69, M 10.6
59, F
6
41
6
4
5
7
7
8
9
10
77, M 18.25
80, M 16.8
81, M 8.5
61, M 12
8
7
6
3
Clinical
Diagnosis
SN
PUT
CTX
L-Dopa
Pathological
Hallmark
LB
⫹ve
⫹ve
⫹ve
⫹ve
⫹ve
⫹ve
PD
PD
PD
PD
PD
“Degenerative
neurological
disorder”
PD
PD
PD
PD
⫹⫹⫹
⫹⫹
⫹⫹
⫹⫹
⫹⫹
⫹⫹⫹
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫺
⫹
⫹⫹⫹
⫹⫹⫹
⫹
⫹⫹⫹
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫹
MSA-C
MSA-C
MSA-P
MSA-P
MSA-C
MSA-P
MSA-C
MSA-C
MSA-C
MSA-C
⫹⫹⫹
⫹
⫹⫹⫹
⫹⫹
⫹⫹⫹
⫹⫹
⫹⫹
⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹
⫹
⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹
⫹
⫹⫹⫹
⫹⫹⫹
⫺
⫺
⫹⫹
⫹
⫺
⫺
⫺
⫹⫹
⫹⫹
⫺
“Atypical PD
syndrome”
PSP
PSP
PSP
PSP
“Atypical PD
syndrome”
PSP
PSP
PSP
PSP
⫹⫹⫹
⫺
⫺
⫹ve
⫹⫹⫹
⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫺
⫺
⫺
⫺
⫹
⫹⫹
⫹⫹
⫹
⫹
⫹
⫹ve
⫹ve
⫹ve
⫹ve
⫹ve
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹
⫹⫹
⫺
⫺
⫺
⫹
⫹
⫹
⫹
⫹ve
⫹ve
⫹ve
⫹ve
⫹ve
⫹ve
⫹ve
⫹ve
GCIs
⫹ve
NDc
⫹ve
NDc
NDc
NDc
NDc
⫹ve
⫹ve
ND,
NFTs
Dose
(mg/day)
Exposureb
Duration
(yr)
Dyskinesias
⬎3
⬎8
12
⬎2
⬎2
Yes
Yes
Yes
?
?
?
800
?
200
?
23
⬎10
⬎10
?
No
?
No
750
?
650
?
?
?
?
?
250
?
3
?
4
?
?
6
?
?
1
?
No
?
Yes
?
?
No
?
?
No
?
?
6
No
No response
?
2,000
600
?
?
4
2
0.5
No
?
No
No
?
No response
400
200
300
4.5
1
1
No
No
No
No
?
600
1,000
?
500
No L-dopa
Varying degree of degenerative changes also was observed in globus pallidus, locus ceruleus, inferior olives, pontine nuclei, and cerebellar
Purkinje cells in MSA and in globus pallidus, subthalamic nucleus, and brainstem in PSP.
⫺, no pathology; ⫹, mild; ⫹⫹, moderate; ⫹⫹⫹, severe.
Dose is most recent dose before death.
MSA cases in which the presence of GCIs was not examined as the analysis of these subjects was conducted before the consensus statement
on the diagnosis of MSA in 1999,10 which incorporated assessment of the neuropathology of GCI.
a
b
c
PMI ⫽ postmortem interval; PD ⫽ Parkinson’s disease; MSA-P ⫽ multiple system atrophy with predominant parkinsonian features; MSAC ⫽ multiple system atrophy with predominant cerebellar features; PSP ⫽ progressive supranuclear palsy; SN ⫽ substantia nigra; PUT ⫽
putamen; CTX ⫽ cerebral cortex; LB ⫽ Lewy body; GCI ⫽ glial cytoplasmic inclusion; NFT ⫽ neurofibrillary tangle; ⫹ve ⫽ verified; ND ⫽
not determined; ? ⫽ information not available.
126
Annals of Neurology
Vol 55
No 1
January 2004
PD were also compared with those in brain of patients
with two other dopamine deficiency disorders, multiple
system atrophy (MSA)10 and progressive supranuclear
palsy (PSP),11 because patients with these conditions
are generally poorly responsive to L-dopa treatment and
show fewer drug-induced complications. We report
that D1 receptor function is differentially affected in
the three dopamine deficiency disorders.
Subjects and Methods
Autopsied brains (n ⫽ 10 each) were obtained from patients
with PD, MSA, and PSP and from age- and postmortem
time-matched control subjects. One half-brain was used for
neuropathological examination, whereas the other half was
frozen for neurochemical analyses. The characteristics of the
patients and available information on L-dopa treatment are
summarized in Table 1. Lewy bodies in the substantia nigra
were confirmed in PD but were absent in MSA and PSP. All
MSA brains also showed heterogeneous high molecular
weight ␣-synuclein–immunoreactive proteins (Y. Furukawa
and S. J. Kish, unpublished data; see Dickson and colleagues12). All control subjects had died without evidence of
neurological or psychiatric disease and showed no brain abnormality upon pathological examination.
All L-dopa–treated PD patients had good response to the
therapy, with dyskinesias specifically reported in three patients, whereas L-dopa treatment in MSA and PSP produced
only varying, at most moderate response, with one MSA patient showing dyskinesias. No detailed information on the
neuropsychological or mental function of the patients was
available, although two PD, one MSA, and nine PSP patients were reported to have “cognitive impairment.”
Homogenates of putamen and frontal cortex (Brodmann
area 9) were used. The procedure for tissue preparation and
the assay of AC activity was as reported previously.9 In addition to dopamine stimulation, AC activities in the presence
of forskolin or a nonhydrolyzable GTP analog guanylylimidodiphosphate [Gpp(NH)p] also were measured to establish the possible changes in AC itself or the stimulatory Gprotein–AC coupling, respectively. Stimulated AC activity
was assayed in the presence of GTP (10␮M), Gpp(NH)p
(100␮M), forskolin (100␮M), or dopamine (100␮M) plus
GTP (10␮M). Dopamine stimulation was expressed as percentage above AC activity in the presence of 10␮M GTP.
Dopamine levels (in nanograms per milligram wet weight,
mean ⫾ SEM) in putamen and frontal cortex were determined using high-performance liquid chromatography with
electrochemical detection. One-way analyses of variance
(ANOVA) followed by post hoc Duncan’s test were performed. Correlations were examined by Pearson product moment correlation or Spearman rank-order correlation analyses
as indicated in Results.
Results
As expected, dopamine levels were markedly decreased
in putamen in the three dopamine deficiency disorders
(control: 4.04 ⫾ 0.34 vs PD: 0.10 ⫾ 0.03, ⫺98%;
MSA: 0.23 ⫾ 0.09, ⫺94%; PSP: 0.09 ⫾ 0.05,
⫺98%; n ⫽ 10 each, p ⬍ 0.001), with no significant
difference in the extent of dopamine reduction among
the three patient groups. In the frontal cortex, a 77%
decrease in dopamine concentration, as compared with
control values (0.044 ⫾ 0.016, n ⫽ 10), in the patients with PD (0.010 ⫾ 0.005, n ⫽ 8) and MSA
(0.010 ⫾ 0.006, n ⫽ 7) just missed statistical significance ( p ⬍ 0.07; dopamine levels in autopsied human
cerebral cortex are low and highly variable13). Frontal
cortical dopamine concentration was normal in PSP
(0.043 ⫾ 0.013, n ⫽ 8), which is consistent with a
previous report.14
Maximal dopamine stimulation of AC (Fig) was significantly increased in both putamen (⫹43%) and
frontal cortex (⫹52%) in PD as compared with control values. Similar results were obtained under the
condition of a high (110mM) NaCl concentration
(data not shown). In contrast, basal AC activity and
activities in the presence of GTP, Gpp(NH)p, or forskolin were normal in both brain areas in PD (Table
Fig. Dopamine stimulation of adenylyl cyclase activity in autopsied brain of patients with Parkinson’s disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy
(PSP). Shown are mean ⫾ SEM of 10 subjects for each
group. In putamen, the average percentage dopamine stimulation was 17.7 ⫾ 1.6, 25.2 ⫾ 1.6, 9.3 ⫾ 1.9, and 20.9 ⫾
2.5 for the control, PD, MSA, and PSP, respectively. In frontal cortex, it was 18.8 ⫾ 3.2, 28.7 ⫾ 3.3, 13.8 ⫾ 1.0, and
20.5 ⫾ 1.8 for the control, PD, MSA, and PSP, respectively.
*p ⬍ 0.05, **p ⬍ 0.01, PD, MSA, or PSP vs control (oneway ANOVA followed by post hoc Duncan’s test).
Tong et al: Dopamine, AC, and Parkinsonism
127
2). The percentage dopamine stimulation of AC in putamen of the three PD cases with dyskinesias was 22.5,
31.6, and 20.3, whereas that of the two PD cases without dyskinesias was 20.3 and 20.7.
All basal and stimulated AC activities measured were
decreased by 48 to 74% in putamen in MSA, whereas
levels were normal in frontal cortex, although there was
a nonsignificant trend for decreased dopamine stimulation (⫺27%). In PSP, all activities measured in both
brain regions were normal.
No significant correlation (Spearman) was observed
in the disease groups between any of the biochemical
outcome measures in putamen or frontal cortex and
the estimated duration of disease, regional dopamine
levels, or brain pathological rating. No significant correlation (Pearson) was observed between age or postmortem time of the subjects, either controls or disease
groups, and levels of any of the biochemical outcome
measures.
Discussion
The major findings of our study are that dopamine D1
receptor–stimulated AC activity is enhanced in both
putamen and frontal cortex of patients with PD,
whereas dopamine stimulation is normal or decreased
in PSP and MSA, respectively.
Consistent with studies of animal models of PD,4,5
we found that dopamine stimulation of AC was significantly increased in both striatum and cerebral cortex
in PD using a low (approximately 10mM) NaCl concentration, which also was replicated under a high
(110mM) NaCl condition in our study. Our finding in
putamen of PD differs from that of Pifl and colleagues,15 who could detect significant sensitization
only under a high (120mM) NaCl concentration. The
explanation for the discrepancy is not clear but might
relate to the selection in the two studies of patients
with different extent of dopamine neuronal loss or exposure to dopaminergic drugs. A direct comparison of
our results (and those of Pifl and colleagues15) with
several earlier reports of either sensitized16 or desensitized17,18 dopamine stimulation of striatal AC in PD is
not possible because the earlier studies were conducted
without addition of GTP, the substrate of G-protein
required for mediating receptor–AC coupling.
Our finding of D1 receptor supersensitivity in PD is
in contradistinction to previous studies reporting a lack
of change or even a decrease in D1 receptor concentration in PD (see Stoessl19 and Mattila and colleagues20
for reviews), highlighting that caution should be exercised in interpreting such data. The normal basal and
forskolin- or Gpp(NH)p-stimulated AC activity in PD
suggests that AC activity itself or the stimulatory Gprotein–AC coupling is normal. Thus, the increased
dopamine-stimulated AC activity is likely the result of
enhanced coupling between the D1 receptor and the
stimulatory G-protein. Because receptor–G-protein
coupling is under the regulation of G-protein–coupled
receptor kinases, arrestin, and regulators of G-protein
signaling, changes in these desensitizing factors might
be the underlying in vivo mechanism. In addition, the
absence of D1 receptor sensitization in putamen of
PSP, despite little pathology (see Table 1) and similar
near-total dopamine depletion as that in PD, suggests
that development of D1 receptor supersensitivity might
involve local neural circuit feedback, which was disrupted in PSP by more extensive degeneration in the
basal ganglia. The general decrease in basal and stimulated AC activity in putamen of MSA is possibly related to severe neuronal loss (see Table 1).
Experimental animal studies also suggest that the extent of D1 receptor sensitization after dopamine deple-
Table 2. Adenylyl Cyclase Activities in Brain of Patients with Parkinson’s Disease, Multiple System Atrophy, Progressive
Supranuclear Palsy, and Matched Control Subjects
⫹GTP (10␮M)
Brain Region
Putamen
Controls
PD
MSA
PSP
Frontal cortex
Controls
PD
MSA
PSP
⫹Gpp(NH)p (100␮M)
⫹Forskolin (100␮M)
Basal
(pmol/min/mg)
pmol/min/mg
Stimulation
(%)
pmol/min/mg
Stimulation
(%)
pmol/min/mg
Stimulation
(%)
34.5 ⫾ 3.0
35.8 ⫾ 2.2
16.7 ⫾ 2.0a
35.8 ⫾ 4.4
48.1 ⫾ 4.2
52.3 ⫾ 3.6
20.9 ⫾ 2.9a
50.9 ⫾ 8.0
40 ⫾ 3
46 ⫾ 5
23 ⫾ 3b
39 ⫾ 7
65.7 ⫾ 13.0
78.3 ⫾ 11.1
23.0 ⫾ 3.5b
78.6 ⫾ 21.9
81 ⫾ 19
112 ⫾ 19
33 ⫾ 6b
96 ⫾ 25
215.9 ⫾ 43.4
259.5 ⫾ 39.0
56.2 ⫾ 9.9a
249.0 ⫾ 51.8
494 ⫾ 75
602 ⫾ 71
216 ⫾ 26b
547 ⫾ 67
26.5 ⫾ 2.5
27.4 ⫾ 4.2
32.3 ⫾ 2.1
28.9 ⫾ 3.4
45.2 ⫾ 6.9
49.6 ⫾ 12.9
63.7 ⫾ 8.2
57.1 ⫾ 11.9
64 ⫾ 11
66 ⫾ 12
92 ⫾ 14
84 ⫾ 15
60.8 ⫾ 14.9
84.1 ⫾ 28.8
93.3 ⫾ 15.5
90.2 ⫾ 23.6
112 ⫾ 32
159 ⫾ 38
176 ⫾ 31
176 ⫾ 37
137.4 ⫾ 13.2
135.5 ⫾ 21.0
159.9 ⫾ 10.8
148.1 ⫾ 16.8
420 ⫾ 21
391 ⫾ 16
397 ⫾ 19
417 ⫾ 24
Data represent mean ⫾ SEM of 10 cases each of control subjects, PD, MSA, and PSP. Stimulation expressed as percentage above basal.
a
p ⬍ 0.01; bp ⬍ 0.05, PD, MSA, or PSP vs controls (one-way ANOVA followed by post hoc Duncan’s test).
PD ⫽ Parkinson’s disease; MSA ⫽ multiple system atrophy; PSP ⫽ progressive supranuclear palsy.
128
Annals of Neurology
Vol 55
No 1
January 2004
tion might be enhanced by exposure to dopaminergic
drugs,6,7 which most if not all of the patients with PD
had received. Although enhanced D1 receptor function
in PD could be helpful as a compensatory attempt to
ameliorate parkinsonism and cognitive difficulties in
this condition, and in enhancing responses to dopamine substitution therapy acting directly1 or indirectly
at the dopamine D1 receptor, D1 receptor supersensitivity also might contribute to the development of Ldopa–induced dyskinesias8 and L-dopa–induced exacerbation of cognitive problems in some patients.3 In this
regard, a limitation of our retrospective investigation is
the absence of information on L-dopa–induced dyskinesias and L-dopa–related cognitive function for many
of the patients with PD, which could have addressed
this important issue.
In conclusion, we demonstrate that the dopamine
D1 receptor is supersensitive in brain of patients with
PD. Further studies will be needed to address specifically the relationship between such supersensitivity and
long-term L-dopa–induced complications.
This study was supported by the William S. Storey, Al Silverberg,
and Society for Progressive Supranuclear Palsy PSP funds, the Friedman MSA fund, a Centre of Excellence Award from the National
Parkinson Foundation Inc. (Miami) (M.G.) and USA National Institutes of Health NIDA (DA7182, S.J.K.).
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progressive, dopamine, adenylyl, disease, parkinson, system, brain, atrophy, cyclase, activity, palsy, multiple, stimulate, supranuclear
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