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Dopamine D2 receptor density remains constant in treated Parkinson's disease.

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Dopamine D2 Receptor Density Remains
Constant in Treated Parhnson's Disease
Mark Guttman, MD,* Philip Seeman, MD, PhD,t Gavin P. Reynolds,$ Peter Riederer, PhD,§
Kurt Jellinger, MD,§ and Wallace W. Tourtellotte, MD"
Dz dopamine receptor densities were measured in postmortem samples of the caudate nucleus and putamen from 36
parkinsonian patients. T h e relationship between the age of the patient, duration of the disease, and duration of L-dopa
therapy versus density of brain D2 dopamine receptors was examined using {'Hlspiperone. Receptor density in
parkinsonian tissues was constant over the age range of 56 to 90 years, as was the case for control tissues. Density did
not change with duration of disease up to 24 years. Treatment with L-dopa did not cause progressive reduction in
receptor density. T h e diminished clinical response in the final stages of Parkinson's disease is not due to receptor dropout, and must depend on other factors.
Guttman M, Seeman P, Reynolds GP, Riederer P, Jellinger K, Tourtellotte WW. Dopamine Dz receptor
density remains constant in treated Parkinson's disease. Ann Neurol 19:487-492, 1986
L-dopa therapy has been a major advance in the treatment of Parkinson's disease. Quality of life improves
and life expectancy increases with its administration 14,
41). There are, however, several clinical problems that
have become evident with the long-term administration of this drug {lo, 12, 141. The mechanism of these
effects is currently unknown. Dyskinesias may be the
result of L-dopa overdose in some cases. The on-off
phenomenon may result from altered pharmacokinetics, as suggested by the beneficial response to intravenous L-dopa administration and to changes in diet
C1, 151.
To account for the progressively diminishing clinical
efficacy of L-dopa, it has been suggested that there may
be a postsynaptic loss of dopamine receptors in the
striatum. This might be caused by direct transsynaptic
degeneration secondary to loss of trophic function
from the degenerating nigral neurons, or from a downregulation in the receptor density (Bmm)caused by Ldopa. Another hypothesis is that the receptors may
change configuration between the high-affinity and
low-affinity states to reduce dopaminergic transmission; this could occur independently of a change in
Brn,.
The purpose of this study was to measure dopamine
D2 B, and to relate it to clinical features of parkinsonian patients. D2 B,
in postmortem samples of cau-
date and putamen were examined in relation to the age
of the patient, duration of the disease, and duration of
L-dopa therapy. B,
was shown to be constant over all
of these variables; no progressive decline in B,
took
place with age, duration of the disease, or duration of
therapy.
From the Departments of "Medicine and "iharmacology, Faculty of
Medicine. Universitv of Toronto. Toronto. Ontario. Canada. 4MRC
Neurochemical Phaimacology Unit, Brain Tissue Bank, Department
of Neurological Surgery and Neurology, Addenbrooke's Hospital,
Cambridge, England CB2 2QQ, [he $Ludwig Boltzmann Institute
for Clinical Neurobiologv, Lainz HospitaL 1130 Vienna, Austria,
and the "National Neu&ogical Research Bank, VA Wadsworth
Medical Center, Neurology Research, Los Angeles, CA 9007 3.
Received Apr 11, 1985, and in revised form Sept 5. Accepted for
publication Sept 26, 1985.
Methods
The following methods were adapted from those described
in a previous report [34]. Briefly, brain tissue was homogenized in a buffer containing 50 mM Tris HCl, 5 mM KC1, 1.5
mM CaCI2,4 mM MgC12, and 1 mM EDTA, with or without
120 mM NaCI. NaCl did not affect the binding parameters in
separate studies. The homogenate was washed twice with the
buffer solution using centrifugation. The Dz B,
was measured by saturation analysis with [3H)spiperone (New England Nuclear, Boston, MA) (specific activity was between
20 and 25 Cdmmol). Each final test-tube contained 0.5 ml of
buffer solution or 0.5 ml of (+)-butaclamol, 0.5 ml of
L3H]spiperone, and 0.5 ml of tissue suspension. The final
[3H)spiperone concentrations ranged from 10 to 1,000 PM.
The final tissue concentration was 0.83 mg (of original wet
tissue) per milliliter or approximately 60 pg proteidml. The
mixture was incubated at room temperature for two hours
and filtered by a cell harvester (Skatron, Lier, Norway) with a
single glass-fiber filter mat. Specific binding was defined as
that amount of bound {3H]spiperone inhibited by the presand the dissociation
ence of 1 p~ ( )-butaclamol. The B,
constant (K,) were derived by Scatchard analysis. All tubes
+
Address reprint requests to D r Seeman, Department of Pharmacology, Medical Sciences Building, University of Toronto, Toronto,
Ontario, Canada MSS
487
X
D
m
AGE
(years)
were done in duplicate and tissue samples were analyzed
independently at least twice.
The diagnosis of Parkinson’s disease had been made clinically, and histological examinations ruled out other parkinsonian-like syndromes.
Regression analysis was done using a Texas Instruments
calculator. Each of the following sets of data was analyzed for
the caudate and putamen: age versus BmV;disease duration
versus Bmm;duration of L-dopa therapy versus Bmm.
Results
The relationship of B,
to age was analyzed in 36
patients. Two had received neuroleptic medication.
One had been diagnosed as having postencephalitic
parkinsonism. The average B,
for 35 putamen samples was 10.3 f 0.5 pmol/gm of wet original tissue.
The B,
for 34 caudate nuclei was 8.3 +- 0.4 pmoV
gm. Patient age at death varied from 56 to 90 years.
There was no change in B,
with age (Fig 1).
B, was examined in relation to disease duration in
3 1 patients. The average B, was 10.1 i 0.5 pmoVgm
for the putamen and 8.1 2 0.4 pmoVgm for the caudate. Fewer tissues were analyzed because of lack of
disease duration information in some patients. In addition, 2 patients had received neuroleptic medication.
There was no correlation between B,
and disease
duration in either the putamen or the caudate (Fig 2 ) .
The third analysis was to relate B,
with the duration of L-dopa therapy. Twenty-four patients were examined. The samples were reduced for the same reasons cited above. The mean B,
in the putamen was
10.1 -C 0.6 pmoVgm and for the caudate was 7.8 k
0.4 pmoVgm. B,
did not change with duration of
treatment in either the caudate nucleus or putamen
(Fig 3).
488
Annals of Neurology
Vol 19 No 5
May 1986
Fig I . Relationship between the age of patients with ParkinJon’s
disease and the D2 receptor density (Bmax) in the caudate nucleus and putamen. Diamond symbols represent patients treated
with neuroleptjc medication. The solid regression line did no1
differ significantlyfrom the horizontal (dashed) line, which indicates the mean value (stippled region = SD). The regression
coefficient was - 0.17 for the caudate and - 0.29for the
putamen.
The patient information is found in the Table. The
K, was not different in any of the groups of patients.
Clinical information was not sufficiently detailed to
grade patients on the severity of disease.
Discussion
Dopamine receptors can be divided into two classes:
D1 and D2 [91. It is generally accepted that the D2
receptor is involved in modulation of movement. The
D2 receptor can be divided into two conformational
states, DZHehand D2LOW,with nanomolar and micromolar affinities for dopamine, respectively [@. It is
not known what proportion of receptors was in high
or low states in our samples. A slight change in the
proportion of high to low states in human disease
may cause a profound alteration in the response in
dopamine. It has been suggested that the postsynaptic
D2 receptor may function in the low-affinity state in
brain tissue E32, 331.
Tritiated high-affinity antagonists are best suited for
studying receptor affinity and density. D2 receptors are
optimally studied using a ligand such as [ 3H]spiperone
[31]. This neuroleptic binds to DZHMhand D2L*’W
with
equal affinity, permitting the measurement of the total
Bm,. The final tissue concentration is important in assessing K, and B,
by Scatchard analysis. A final tis-
DISEASE DURATION
DISEASE DURATION
(yrs)
(yrs)
Fig 2. Relationship between the duration of disease and the D2
receptor density (Bmax) in parkinsonian caudate nucleus and
putamen. Diamond symbols represent patients treated with
neuroleptics. The regression coefficient was 0.21 for the caudate
and - 0.25 for the putamen.
D U R A T I O N L-DOPA
Rx
D U R A T I O N L-DOPA
(yrs)
Fig 3. Relationship between the duration of L-dopa treatmrnt
and the 0 2 receptor density (Bmax) in parkinsonian caudate
nucleus and putamen tissues. Diamond symbols represent patients treated with neuroleptics. The solid regression line did not
differ significantly fvom the horizontal (dashed) line, which indicates the mean value (stippled region = SD). The regression
coefficient was - 0.18 for the caudate and - 0.33 for the putamen.
Rx
(yrs)
sue concentration of less than 1 mgiml is essential for
reducing the error caused by nonspecific depletion of
ligand [35}. The B, value is generally not affected by
the antemortem administration of L-dopa in either humans or animals (unpublished data). Although 20% of
C3H}spiperone binding sites are serotonin receptors
in rat striatum, only 4% of C3H)spiperone sites are
serotonin receptors in human striatum (unpublished
data).
Guttman et al: Dopamine Receptors in Parkinson’s Disease
489
D> Densities in Parkinson's Disease
D2 Density CKD1
Caudate
Brain
Number
Code
Disease
Duration
Duration
of L-Dopa
Therapy
Sex
(Y
(yr)
VBH
VKW
VSCJ
VKE
VCJ
VLF
VLJ
CMC321
CMP44
CMP43
CMP42
CMP40
CMP39
CMP35
CA823
CA850
CA782
CA662
CA504
CA534
80"
6bb
75
74'
77
73
83
88
80
83
90
70
88
78
73
71
74
67
89
60
F
M
F
M
M
F
F
F
F
F
M
M
M
F
M
M
M
M
M
M
3
24
8
6
CA571
CA577
CA594
CA6 18
CA628
CA762
77
89'
74
56
61
66
M
F
M
M
M
M
10
10
12
16
18
8
CA647
CA795
CA786
CMP37
VBOC
VLE
W R
VAN
CMC377
63
70
62
85
71
82
88'
73'
65d
M
M
M
F
M
M
M
F
M
4
7
?
8
3
16
5
14
5
24
1
2 mo
13
16
4.5
6
5
20
9
10
5.5
11
11
12
0
0
7 mo
7
5
6 rno
6.5
1.5
6
5
11
5
0
1
2 rno
13
3
Putamen
Bmax
pmol
KD
(F)(PM)
12.6
6.7
6.1
4.1
38
118
31
46
...
...
8.8
7.1
8.1
6.6
6.4
10.7
7.1
7.6
3.9
7.6
10.4
8.7
7.8
9.7
35
80
57
55
72
69
67
47
335
61
60
77
79
83
?
?
4.3
9.8
8.8
10.0
9.9
8
8.6
61
68
52
72
9.4
5.2
9.1
6.4
7.3
9.5
8.9
13.6
9.3
73
59
77
34
57
84
113
171
69
7
4
10
3 mo
1
8
5 days
3
0
0
5
0
Bmax
pmol
52
67
K,
(PM)
10.6
15.0
12.2
15.4
13.7
2.8
10.8
7.7
8.6
7.1
6.9
13.2
7.8
10.3
7,9
15.3
11.1
11.3
9.2
11.3
42
55
53
95
55
34
37
53
47
65
67
49
58
71
43
49
48
46
100
76
4.3
13.2
11.2
9.9
8.7
11.0
50
53
70
66
55
50
12.6
8.3
10.7
6.4
9.7
11.1
...
14.1
11.8
63
71
77
45
100
50
Anti-Parkinson
Medication
None
A; lisuride 2 mg bid
Total of 125 mg M
M 125 mg bid; A; 6 wk N
A; M 62.5 mg tid
M 125 rng qid + A
M 62 mg x 5lday; A
M 125 rng tid
S 110 rng
L-dopa 250 mg tid
S 110 mg tid
None
M 250 rng tid
S 110 mg tid
S 100125 rng tid; B 2.5 rng tid
S 50112 rng bid; A
S 100110 rng qid; A
S 100125 rng bid; B 5 rng bid
S 100110 rng tid; ? last yr
S 100110 rng x 12lday;
? last yr
S
S
S
?
S
? dose; ? last rno
100125 rng tid
? dose
250125 mg tid x 3 yr
S 250125 rng q4h; A;
? last 8 mo
220
69
S 100110 mg qid; A
S 100/10 rng tid; A
S 250125.5 mg q2h
L-dopa dose?
M 125 mg tid; B 10 mg
A
A; clopenthixol
M 125 rng tid; A
None
"Vascular Parkinson's disease.
bPostencephalitic Parkinson's disease.
'Neuroleptic usage.
"Asymptomatic patient with neuropathological evidence of Parkinson's disease
M
=
Madopar (benserazide); S
490 Annals of Neurology
=
Carbidopa-levodopa (Sinemet); A
Vol 19 N o 5 May 1986
=
amantadine; B
=
brornocriptine; N
=
nruroleptic
Animal studies have characterized the response of
D2 dopamine receptors to various experimental protocols. Neuroleptics increase D2 B,,
and cause hyperdopaminergic behavior. This may be reversed with agonist therapy c5, 7, 13, 20). Stereotactic lesioning of
the substantia nigra increases D2 B,
in the ipsilateral striatum Il8, 30, 38). The mechanism is different, however, with these two experimental maneuvers
c i s , 371.
Dopamine agonist administration can reverse the
elevated D2 B,
in nigra-lesioned rats 118, 30, 38). In
all of these studies, agonist therapy was used for relatively short periods (weeks).
Dopamine receptors have been studied in postmortem tissues of patients with Parkinson’s disease. Some
authors have found an increase in neuroleptic binding
to brain tissues from patients never exposed to L-dopa
Cll, 24-26, 28, 29). These findings suggest that there
is a postsynaptic supersensitivity in this disease, similar
ta that found in nigra-lesioned animals. Other studies
have shown a reduction in neuroleptic binding to tissues from patients who had received L-dopa medication [11, 16, 21, 27, 401. Still others found no change
117, 22, 23, 36) or a slight increase in treated patients
12). In no previous studies has B,
been analyzed in
relation to age, duration of illness, and duration of Ldopa therapy in a large number of patients. Also, in
previous studies, full saturation analysis was not done
on each tissue, as it was in this study.
Rinne and associates [27], in their analysis of 44
patients, divided patients into L-dopa-treated and nontreated groups. In the L-dopa-treated group they subdivided 10 patients into low or high C3H]spiperonebinding groups. They claimed that patients with low
binding had had a diminished response to L-dopa.
Those with high binding had responded better to Ldopa and had had fewer long-term adverse effects, although they had experienced dyskinesias and hallucinations. This analysis was based on 5 patients in each
group.
Since the publication of these studies, there has
been speculation on the role of L-dopa in the possible
reduction of D2 receptor binding in parkinsonian patients with deteriorating clinical response to L-dopa.
Some authors favor delaying treatment with L-dopa
because of the possible down-regulation of the D2 receptor [6, 38). The concept of the L-dopa “drug holiday” [3, 391 was based on the putative alteration of
postsynaptic receptors. Our findings suggest that there
is no correlation between B,
and duration of disease
or L-dopa therapy. B,
also does not change with age.
This is similar to findings in normal control tissues
(Seeman, unpublished data).
We have recently found in a separate study (Guttman and Seeman, unpublished data) that tissues from
L-dopa-treated patients have D2 densities lower than
those from untreated parkinsonian patients. The present data indicate that further reduction does not occur
with the duration of treatment or disease. This has not
been appreciated in the past. It implies that drop-out
of D2 dopamine receptors is not the cause of clinical
deterioration evident after long-term L-dopa treat ment. Dopamine receptors may be responsible for the
diminishing clinical response (to L-dopa) by changing
their proportion of high-affinity and low-affinity states
C3, 321. This may be the mechanism of the “drug holiday” clinical response. It is not possible to study this
hypothesis in human tissue at this time because of
spontaneous shift from a high to low conformation as a
function of time in the freezer. Animal studies using
nigra-lesioned rats treated with L-dopa for at least six
months may help answer this question.
~~~~~
Supported by the Parkinson Foundation of Canada.
We thank Carla Ulpian, Natalie Bzowej, Dr F. Tyndel, Dimitri
Grigoriadis, Iris Rosario, and Randall Thomsen for their assistance.
We thank Dr E. D. Bird (NIH Grant No. MWNS 31862) for
providing some additional postmortem brain tissue samples. Some
of the tissue for this research was obtained from the National
Neurological Research Bank, VA Wadsworth Medical Center, Los
Angeles, CA 90073, which is sponsored by NINCDSINIMH,
NMSS, HD Foundation, and Veterans Administration.
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