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Dopamine denervation does not alter in vivo 3H-spiperone binding in rat striatum Implications for external imaging of dopamine receptors in Parkinson's disease.

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Dopamine Denervation Does
Not Alter In Vivo 3H-Spiperone Binding
in Rat Striatum: Implications for External
Imagmg of Dopamine Receptors
in Parhnson’s Disease
James P. Bennett, Jr, MD, PhD, and G. Frederick Wooten, MD
Striatal particulate preparations, both from rats with lesion-induced striatal dopamine (DA) loss and from some
patients with Parkinson’s disease, exhibit increased ’H-neuroleptic binding, which is interpreted to be the mechanism
of denervation-induced behavioral supersensitivity to dopaminergic compounds. After intravenous ’H-spiperone (3HSP) administration to rats with unilateral nigral lesions, we found no differences in accumulation of total or particulate-bound 3H-SPin dopamine-denervated compared with intact striata. 3H-SPin vivo binds to less than 10% of striatal
sites labeled by ’H-SP incubated with striatal particulate preparations in vitro. Quantitative autoradiography of 3H-SP
binding to striatal sections in vitro also failed to reveal any effects of dopamine denervation. ‘H-SP bound to striatal
sites in vivo dissociates more slowly than that bound to striatal particulate preparations labeled in vitro. Striatal
binding properties of 3H-SP administered in vivo are quite different from the same kinetic binding parameters
estimated in vitro using crude membrane preparations of striatum. In addition, striatal binding of in vivoadministered 3H-SP is not affected by prior lesion of the substantia nigra, which results in profound ipsilateral striatal
dopamine depletion. Thus, behavioral supersensitivity to dopaminergic compounds may not be associated with altered
striatal binding properties for dopamine receptor ligands in vivo.
Bennett JP Jr, Wooten GF Dopamine denervation does not alter in VIVO jH-spiperone binding in rat
striatum implications for external imaging of dopamine receptors in Parkinson’s disease
Ann Neurol 19 378-381, 1986
Development of external imaging technologies and
syntheses of neuroleptic drugs labeled with either positron-emitting (carbon-1 1, fluorine-18, bromine-76) or
gamma-ray-emitting (bromine-77) isotopes have made
feasible in vivo external imaging of experimental
animal and human brain dopamine (DA) receptors
(i.e., high-affinity, saturable, stereospecific binding
sites) [l, 5 , 11, 20, 21). One goal for the application of
such techniques would be detection in vivo of alterations of brain DA receptors in conditions such as
Parkinson’s disease, Huntington’s disease, schizophrenia, and tardive dyskinesia.
Parkinson’s disease results from the selective loss of
dopaminergic afferents to the striatum. Denervation
supersensitivity of striatal DA receptors has been proposed as the mechanism responsible for several phenomena associated with dopaminergic therapy in Parkinson’s patients. Unilateral striatal DA depletion in
experimental animals leads to the development of denervated, “supersensitive” striatal DA receptors that
results in a shift to the left of the dose-response
curves for dopaminergic drug-induced behaviors.
Membrane preparations from DA-deprived rat striata
exhibit increased binding of ”H-neuroleptic drugs in
vitro [2, 17, 181. Likewise, increased 3H-neuroleptic
binding to particulate preparations from striatal nuclei
of Parkinson’s disease brains has been reported in
some studies E8, 151. In one study, the increased binding was partially reversed with L-dopa therapy 1151,
suggesting that denervated DA receptors increase
in number or affinity for ligand, thereby becoming supersensitive, and can be desensitized by pharmacological replacement of dopaminergic transmission. If external imaging of parkinsonian striatal DA
receptors in vivo is to reflect increased DA receptor
binding in parkinsonian striatal particulate preparations
From the Department of Neurology and the Clinical Neuroscience
Research Center, University of Virginia School of Medicine, Charlocresville, VA 22908.
Received May 15, 1985. Accepted for publication July 18, 1985,
with additional revisions on Jan 14, 1986.
378
Address reprint requests to D r Bennett.
in vitro, then increased in vivo neuroleptic binding to
denervated striatal DA receptors should be demonstrable in animal models.
We have examined the regional distribution of total
and particulate-bound radioactivity following intravenous injection of 3H-spiperone (3H-SP) in rats with
unilateral 6-hydroxydopamine (6-0HDA)-induced
degeneration of the nigrostriatal pathway (nsp) as a
function of time after lesion placement. Additionally,
we have characterized in vitro 3H-SP binding to both
thin tissue sections and striatal particulate preparations
from rats with 6-OHDA nsp lesions. We found that
increased neuroleptic binding to denervated rat striatal
DA receptors is demonstrable with filtration studies of
particulate preparations but not with quantitative autoradiography of 3H-SP binding to thin tissue sections or
in vivo binding techniques. The in vivo rate of dissociation of 3H-SP from rat striatal neuroleptic binding sites
is much slower than that found in vitro in particulate
preparations, and spiperone in vivo labels less than
10% of striatal binding sites detectable in particulate
preparations.
Materials and Methods
Male Sprague-Dawley rats (weight, 250 to 300 gm) were
used in all experiments. Unilateral (left-sided) perinigral injections of 6 k g of 6-OHDA in 2 kl of 0.9% NaCl-0.2%
ascorbic acid were performed 30 minutes after treatment
with desipramine (2 5 mg/kg, intraperitoneally) to protect
noradrenergic fibers. Only animals exhibiting brisk contralateral turning behavior in response to systemically administered apomorphine (0.5 mgikg, subcutaneously) were used.
O n various days (7, 21, or 42) after 6-OHDA lesion placement, 20 pCi of $H-SP (15.7 or 25 Cdmmol; New England
Nuclear) in normal saline was injected by tail vein. Ninety
minutes later, the animals were decapitated and brains dissected rapidly on ice into left and right cerebellar hemispheres, ventral mesencephalon (to include the substantia
nigra), striatum, and frontal cortex. The tissue samples were
immediately weighed and homogenized in 50 volumes or 3
ml, minimum, of ice-cold 0.05 M Tris HC1 buffer. Aliquots
(0.5 ml), representing at most 10 mg of tissue wet weight,
were immediately and rapidly filtered in quadruplicate
through Whatman GFB filter paper with a multiple-manifold
filtration apparatus (Brandel), followed by three 4-ml washes
with cold Tris buffer. Particulate-bound and total 3H activity
were assayed with liquid scintillation spectroscopy at 35 and
30% efficiency, respectively. To measure in vivo dissociation
of ’H-SP, control (nonlesioned) rats received 50 FCi of
isotope and 90 minutes later received saline, unlabeled
spiperone (2 mg/kg, intravenously), or haloperidol ( 5 mg/kg,
intravenously). At various times after injection of saline,
spiperone, or haloperidol, total and particulate-bound
radioactivities were measured in brain regions, as described
earlier.
Quantitative autoradiography of $H-SP binding to striatal
sections was performed on brains from rats at 7, 21, or 42
days after 6-OHDA lesion placement. Coverslip-mounted
forebrain sections of the body of the striata were incubated
in triplicate with varying concentrations (0.2 to 2.0 nM) of
’H-SP for 60 minutes at room temperature in 120 mM NaCli
50 mM Tris HCL (pH, 7.4) buffer containing 0.2% ascorbic
acid, rapidly washed three times in ice-cold buffer, dried, and
apposed to LJG3 film alongside tissue-calibrated ’H standards. Nonspecific ’H-SP binding was measured in the presence of 10 p~ d-( + )-butaclamol. Following film development, grain density over the bodies of left and right striata
was quantitated by manual densitometry using a Leitz varable-aperture microdensitometer, nonspecific binding values
were subtracted, and specific binding was converted to fmoY
gm of tissue.
‘H-SP binding to unwashed left and right striatal particulate preparations from rats 7 to 8 weeks after 6-OHI)A
lesion placement was performed following the guidelines of
Seeman and associates [ 161 with respect to tissue concentration. Pooled left (denervated) or right (intact) striatal pairs
from 7 rats were used, and 3H-SP concentrations were varied
from 0.01 to 2.0 nM. d-(+)-Butaclamol (10 kM) defined
nonspecific binding which was subtracted from total binding
at each 3H-SP concentration to yield specific binding. Aliquots (5 ml) of tissue in Krebs-Ringer-Tris buffer were incubated in quadruplicate (1 mg of tissue/ml final concentration) for 60 minutes at 37°C; particulate-bound radioactivity
was rapidly isolated on Whatman GFB paper, washed three
times with cold buffer, and measured by liquid scintillation
spectroscopy.
Results
The Table summarizes ’H content following in vivo
administration of 3H-SP in brain regions from rats at 7,
21, and 42 days after 6-OHDA lesions of the left nsp.
Striatudcerebellum ratios for total 3H tissue concentrations varied from 3.3 to 5.0, consistent with previous reports 14, 6, 71. Striatudcerebellum ratios for
particulate-bound 3H concentrations varied from 10 t o
25; the marked increase for particulate 3H ratios derived from the much higher percentage of total
radioactivity bound in striatal samples (average, 78%),
compared with the cerebellar samples (average, 22%).
Ventral midbrain and frontal cortex samples had intermediate values of total and particulate 3H concentrations and percentages of total 3H accounted for by
bound 3H. Subtracting particulate-bound 3H from total homogenate ’H yielded “free” 3H and dlowed estimation of tissue-unbound 3H-SP concentrations in
each region. These values ranged from 340 to 970 PM.
Left side/right side ratios for ?H-SP tissue concentrations in each region at each time point after nsp lesion
did not vary significantly from unity for both total and
particulate-bound radioactivity (see Table). Quantitative autoradiography of 3H-SP saturation to striatal tissue sections derived from animals at 7, 21, and 42 days
after successful nsp lesions likewise did not show any
left-right asymmetries (data not shown). Potencies of
unlabeled DA and apomorphine for displacing 3H-SP
from striatal binding sites in tissue sections were not
altered by nsp lesions (data not shown). Increased 3H-
Bennett and Wooten: Neuroleptic Labeling of Dopamine Receptors
379
In Vivo 'HSpiperone Binding after 6-Hydroxydopamine Lesions of the Left Nigrostriatal Pathway a
Time after
nsp Lesion
(Days)b
7 (4 rats)
Brainb
Region
Bound
(fmol/mg tissue)
Unbound
(PM)
cer -L
-R
str -L
-R
mid -L
-R
cot-L
0.181 t 0.025
0.205 t 0.034
2.01 t 0.27
1.99 2 0.33
0.665 t 0.095
0.639 t 0.120
0.999 t 0.116
0.921 f 0.102
0.141 t 0.033
0.143 t 0.033
1.92 f 0.22
2.04 t 0.24
0.523 4 0.040
0.647 f 0.034
0.854 t 0.088
0.799 t 0.046
0.054 t 0.005
0.039 t 0.080
1.07 t 0.13
1.07 ? 0.12
0.288 ? 0.079
0.310 t 0.013
0.527 t 0.093
0.499 t 0.057
610
690
970
960
672
600
7 70
880
490
500
900
950
520
490
780
7 10
430
380
580
550
400
340
480
5 00
-R
21 (8 rats)
42 ( 3 rats)
cer -L
-R
str -L
-R
mid -L
-R
cot-L
-R
cer -L
-R
str -L
-R
mid -L
-R
ctx-L
-R
t 100
?
t
Ifr
t
t
?
t
t
?
+t
t
?
?
.t
?
t
t
t
?
t
70
70
80
110
115
50
70
50
60
140
135
50
60
100
90
50
50
40
20
10
5
t 20
?
40
=
nigrostriatal pathway; cer
=
cerebellum; str
=
Bound 'H
Total
27
26
78
78
59
60
0.91 t 0.05
0.88 t 0.04
1.02 t 0.04
1.02
0.93 t 0.07
0.97 t 0.02
1.08 t 0.02
0.99
0.95 t 0.05
0.99 t 0.04
0.95 t 0.03
0.94 t 0.03
0.81 t 0.05
0.95 t 0.12
1.06 +. 0.06
1.08 t 0.06
1.38
0.21
0.73
1.00 t 0.05
1.01
t 1
t2
t2
?
t
65 +.
59 t
25 t
25
80
80
58
67
62
62
19
10
75
76
46
55
60
57
380 Annals of Neurology Vol 19 No 4 April 1986
f
0.03
c3
7
5
3
?
0.01
1
4
4
t 1
?
t2
t
t
t
t
t
t
t
3
3
1
1
1
?
f
0.11
4
2
4
c8
0.05
?
0.12
1.05 t 0.12
1.03 t 0.06
1.00 t 0.05
1.12
t 1
t5
t4
striatum; mid = ventral midbrain; ctx
SP binding to DA-denervated striatal particulate preparations derived from animals was observed 7 to 8
weeks after nsp lesion placement (Fig 1). Scatchard
plots of the binding isotherms demonstrated a single
population of d-( + )-butaclamol-sensitive, high-affinity 'H-SP binding sites in control (intact nsp) striata.
'H-SP binding to DA-deprived striata could be resolved into two components: one with about twice the
affinity (half the KD) and similar binding site density
(Bmw) of control striata, the other with much lower
affinity than control. Comparison of striatal 3H-SP
binding in vivo as a function of unbound 3H-SP tissue
concentration with the level of striatal particulate 3HSP binding at equivalent 3H-SP concentration suggests
that only about 792 of striatal spiperone binding sites
observed in particulate preparations in vitro are
labeled in vivo.
T o attempt to explain the marked differences between striatal 3H-SP binding in vivo and in vitro, we
examined the kinetics of 3H-SP dissociation from its in
vivo and in vitro binding sites. The dissociation rate at
37°C of 3H-SP, incubated with control striatal particulate preparations to equilibrium, was examined by iso-
'H
3H Bound
"Results are expressed as mean +- SEM.
bRats at 7 and 2 1 days after nsp lesion received 20 pCi of 'H-spiperone (specific activity [s.a.),
received 20 pCi of 'H-spiperone (s.a., 25.0 Cdmmol).
nsp
LeftRight Ratios
94 Total
?
15.7 Cdmmol). Rats at 42 days after nsp lesion
=
frontal cortex; L
=
left; R
=
right
lation of labeled particulate pellets and resuspension in
100 volumes of buffer alone ("infinite dilution") or
100 volumes of buffer containing 1 pM unlabeled spiperone (Fig 2). Dissociation in the presence of unlabeled spiperone followed first-order kinetics with a
half-life of about 20 minutes, similar to values found in
the literature f77. Dissociation by infinite dilution proceeded at a slower rate for the first 2 0 minutes until
about 25% of the initial bound 'H had dissociated, and
then reached a plateau for the next 30 minutes.
Dissociation of 3H-SP from striatal binding sites
labeled in vivo also proceeds slowly. Dissociation in
vitro by infinite dilution of 3H-SP bound in vivo is
demonstrated in Figure 3. First-order dissociation is
apparent for the first 2 to 3 hours, with a half-life of
about 4 hours, followed by a plateau after 3 0 to 35%
of initial bound 3H had dissociated. In vivo 3H-SP
dissociation from striatal and cerebellar binding sites
was studied by intravenous administration of excess
unlabeled haloperidol ( 5 mg/kg) or spiperone ( 2 mg/
kg) 70 minutes after intravenous injection of 50 pCi of
3H-SP (Figs 4 and 5 , respectively). Without unlabeled
neuroleptic drug injection, maximum striatal levels of
40
30
r
I-
STRIATAL.
HOMOGENATE:
2(
O’
260
4bO
660
8hO
lOd0’
\\\
DILUTION +
I p M SPIPERONE
w
2000
C3H- SPIPERONE] ( pM)
Bmaxl=23 fmollmg
KD = 6 8 pM
3 H - SPIPERONE
13,,,=31 frnol/mg
400
B,;
STRIATUM
20 fmol
10 20 30 40 50
10 2 0 3 0 40 50
[3H- SPIPERONE] BOUND (fmol/mg tissue
10
B
Fig 1. (A) Saturation binding isotherms at 37°C for 3Hspiperone binding to particulate Preparations of 6-hydroxydopamine-lesioned (left side) and intact (right side) rat striata.
(B) Scatchard plots ofthe same binding akta. @M = picomokzr.)
total and particulate radioactivity were observed 3.5
hours after intravenously administered 3H-SP, with
85% of maximum particulate-bound values found 90
minutes after the radiolabeled injection (Fig 4). Unlabeled haloperidol or spiperone injection caused loss
of bound 3H to 20 to 4594 of initial values in striatum
and cerebellum over the 4 hours of observation. Rates
of loss of bound 3H over the first 2 hours were similar
in cerebella and striata for each drug treatment and
were more rapid over the first 2 hours following
haloperidol administration compared with spiperone
administration. For both haloperidol and spiperone
treatments, rates of loss of striatal total tissue 3H concentrations were slower than for corresponding particulate 3H concentrations.
Discussion
Radiolabeled spiperone has emerged as one of the best
available probes for studying striatal DA receptors of
the D2 class, both in vitro 19, 10) and in vivo [l, 4-7,
11, 191, and has been used in studies of external imaging of experimental animal and human brain DA receptors 111, 20, 21). Following intravenous injection
of tracer doses, spiperone partitions into striatal and
other DA receptor-rich tissues to concentrations
several-fold higher than in other regions {b]. Com-
20
30
40
50
TIME (MINI AFTER 100 VOL DILUTION
Fig 2. Dissociation in uitro a t 37°C of ’H-spiperone from control striatal particulate preparations labeled in uitro. Data are
the means of quadruplicate determinations.
&
-
I-
z
8
&
0
I
2
3
4
5
TIME (HRS) AFTER 100 VOL DILUTION
Fig 3. Dissociation in uitro at 37°C by “infinite dilution” of
3H-spiperone bound to striatal sites in uiuo following intravenous
injection of50 FCi 0f’H-spiperone. Data are the means of
quadruplicate deteninations from three separate experiments.
petition experiments using the simultaneous injection
of unlabeled neuroleptics have demonstrated doseresponse curves for inhibition of in vivo striatal
spiperone accumulation that parallel closely the pharmacological potencies of the neuroleptics at D2 receptors 14, 6, 7, 14, 19). Thus, spiperone appears to label
Bennett and Wooten: Neuroleptic Labeling of Dopamine Receptors
381
60- /’
50
40
g
~
WHOLr HOMOGFNATE
WHOLE HOMOGENATE
~
CEREBELLUM
iTRlCTUM
30\
0
- 1
u
,
1
2
3
4
2
0
1
0 2
4h
3
TIME (HRS) AFTER HALOPERIDOL (5mg/kg I V,-)
SALINE (*--) INJECTION
OR
Fig 4. Decline in vivo of total tissue (upper graphs) and particulate-bound (lower graphs) 3H concentrations afer in vivo labeling with 50 FCi of ’H-spzperonefollowed b./ saline or
haloperidol injection. Data are the means of quadruplicatedeterminatiom from two separate experiments.
.I/
WHOLE HOMOGENATE
STRIATUM
CEREBELLUM
E 40
$ 30
30
PARTICULATE BOUND
STRIATUM
30
PARTICULATE
BOUND CEREBELLUM
TIME (HRS) AFTER UNLABELED SPIPERONE (2mg/kg) INJECTION
Fig 5 . Same as Figure 4, except that unlabeled spiperone was
injected 90 minutes after 50 pCi of 3H-spiperone had been
given.
pharmacologically relevant striatal DA receptors both
in vitro and in vivo.
In the present study, we have shown that the increased 3H-SP binding to particulate preparations of
DA-deprived rat striatum cannot be demonstrated by
quantitative autoradiography in vitro or by binding
studies in vivo. Seventy-five to eighty percent of in
vivo striatal 3H-SP accumulation is particulate bound,
which is similar to values reported for ‘lC-SP [l], but
this in vivo binding labels less than 10% of the sites
observed in particulate preparations at equivalent
ligand concentrations. These findings call into question
the relevance of particulate D2 receptor binding studies as predictors of both binding site densities and de382 Annals of Neurology Vol 19 No 4
April 1986
nervation-induced changes observed in vivo. Our results compare favorably with the model of in vivo
spiperone binding presented by Friedman and colleagues [3], if one assumes that striatal in vivo D2
receptor density is approximately 1 nM (1 pmoygm
tissue). The model of Friedman’s group also predicts
that at a tissue DA concentration of 5 nM, a very low
dose of spiperone (about 20 pg/kg) will label only
about 25% of available striatal D2 receptors because
of competition from endogenous DA (see Fig 11 in
C31). Our intravenously administered 3H-SP doses represent about 1 pglkg of chemical spiperone. Our
finding that only 7% of the D2 sites labeled in particulate preparations in vitro is labeled in vivo might seem
to arise on the basis of tissue DA competition for these
sites. However, we found no change in in vivo 3H-SP
binding after successful nsp lesions which deplete
greater than the 95% of the striatal DA concentration.
Thus, competition from tissue DA does not offer a
satisfactory explanation for our observed differences
between in vivo and in vitro binding.
Our results are in disagreement with those of Neve
and associates who found increased in vivo 3H-SP accumulation in DA-denervated striata [13} and increased 3H-SP binding to DA-denervated striatal sections using quantitative autoradiography 1121. We are
unable to discern any substantive differences in our
techniques that would explain our different results.
Our findings suggest that external imaging of striatal
spiperone binding sites in Parkinson’s patients will not
reflect the increased neuroleptic binding reported in
postmortem particulate studies C8, 151.
Our studies of in vivo 3H-SP dissociation from
striatal binding sites show that dissociation induced by
excess unlabeled neuroleptics (spiperone or haloperidol) occurs more slowly than in particulate preparations labeled in vitro. A similar slow decline in striatal
total 3H-SP concentration following unlabeled spiperone injection was found by Laduron and colleagues
[7]. These findings suggest that kinetic parameters observed in striatal particulate preparations in vitro are
not always reflected in vivo.
When altered in vivo spiperone binding site density
and neuroleptic-induced dissociation rates are compared with those in in vitro particulate preparations,
the suggestion is that homogenization of brain tissue
“unmasks” additional D2 binding sites with different
kinetic but similar pharmacological properties compared with in vivo binding sites. Our results do not
negate the usefulness of labeled spiperone as a probe
for both regional tissue distribution of DA receptors
and determination of in vivo potencies of DA antagonist drugs at neuroleptic binding sites. Rather, they
show that altered kinetic parameters of ligand binding
and availability of binding sites can be observed in vivo
compared with particulate preparations in vitro. Cur-
rent concepts of denervation-induced DA receptor
supersensitivity, based on increased D2 antagonist
ligand binding to DA-deprived striatal particulate
preparations, are not demonstrable in vivo in our rat
model for striatal DA loss in human Parkinson's disease.
Research was supported by the Mary Anderson Harrison Endowment and the Pharmaceutical Manufacturer's Association Foundation.
J. P. B. is a George Cotzias Fellow of the American Parkinson
Disease Association.
We thank Marina Ferrari and Claire Brill for technical assistance.
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383
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