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Dopamine receptor elevation in denervated tissues.

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LETTERS
Parhnson’s Disease, Twins,
and the DNA-Damage
Hypothesis
Jay H. Robbins, MD
Duvoisin’s editorial 121 discussed three developments leading to new approaches in the search for the cause of Parkinson’s disease (PD): (1) discovery of the selective dopaminergic neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine, which suggests that similar agents might cause PD;
(2) the finding that the Lewy body consists of neurofilament
fragments, which suggests that P D may be one of the “neurofilament disorders”; and (3) the suggestion that impaired
DNA-repair mechanisms may be present in PD. Literature
citations were presented for the first two developments but
not for the third. To this end, findings from our studies of
xeroderma pigmentosum [I, 71 led us to the concept that PD
is a genetic, but not hereditary, disease in which neurons die
prematurely because of the accumulation of unrepaired damage in neuronal DNA as a result of defective DNA-repair
mechanisms [5, 61.
The excellent study of PD in twins carried out by
Duvoisin and associates, which culminated in the report of
Ward and colleagues [lo], demonstrated that PD is not a
hereditary disease. However, the authors apparently used
the term genetic synonymously with hereditaty when they
concluded that “the major factors in the etiology of PD are
nongenetic,” a misleading usage repeated in the Annals by
others [3, 41 in their discussions of the twin study. The
importance of recognizing that preclusion of a hereditary
cause of PD does not necessarily exclude a genetic cause was
emphasized when we [S, 9} recently found that cultured
lymphoblastoid lines from patients with sporadically acquired
PD are hypersensitive to the lethal effects of x rays. Since
this hypersensitivity is maintained in culture in serially propagated cells from patients with PD, we concluded that it was
probably caused by a stable genetic defect that arose as a
somatic cell mutation, as opposed to a germ cell mutation,
very early in embryogenesis 191 (however, in the case of
discordant monozygotic twins, after their separation). Such a
somatic cell mutation in one member of a twin pair would
leave the other twin unaffected and would not be passed by
the patient to subsequent generations. This nonhereditary
genetic defect in PD, affecting D N A repair in the lineage of
the mutated embryonic cell, could cause both death of nerve
cells in vivo and radiosensitivity in the cultured cells [6,91.
National Cancer Institute
National Institutes of Health
Bethesda, M D 20892
Refences
1. Andrews AD, Barrett SF, Robbins JH: Xeroderma pigmen-
tosum neurological abnormalities correlate with colony-forming
ability after ultraviolet radiation. Proc Natl Acad Sci USA
75:1984-1988, 1978
2. Duvoisin RC: On heredity, twins, and Parkinson’s disease. Ann
Neurol 19:409-411, 1986
412
3. Jankovic J, Reches A: Parkinson’s disease in monozygotic twins.
Ann Neurol 19:405-408, 1986
4. Koller W, OHara R, Nutt J, et al: Monozygotic twins with
Parkinson’s disease. Ann Neurol 19402-405, 1986
5. Robbins JH: Workshop summary: xeroderma pigmentosum. In
Hanawalt PC, Friedberg EC, Fox CF (eds): DNA Repair Mechanisms. New York, Academic, 1978, pp 603-607
6. Robbins JH, Brumback RA, Polinsky RJ, et al: Hypersensitivity
to DNA-damaging agents in abiotrophies: a new explanation for
degeneration of neurons, photoreceptors, and muscle in Alzheimer, Parkinson and Huntington diseases, retinitis pigmentosa, and Duchenne muscular dystrophy. In Woodhead AD,
Blackett AD, Hollaender A (eds): Molecular Biology of Aging.
New York, Plenum, 1985, pp 315-344
7 . Robbins JH, Kraemer KH, Lutzner ML, et al: Xeroderma pigmentosum: an inherited disease with sun sensitivity, multiple
cutaneous neoplasms, and abnormal DNA repair. Ann Intern
Med 80:221-248, 1974
8. Robbins JH, Otsuka F, Tarone RE, et al: Radiosensitivity in
Alzheimer disease and Parkinson disease (letter). Lancet I :468469, 1983
9. Robbins JH, Otsuka F, Tarone RE, et al: Parkinson’s disease and
Alzheimer’s disease: hypersensitivity to X rays in cultured cell
lines. J Neurol Neurosurg Psychiatry 48:916-923, 1985
10 Ward CD, Duvoisin RC, Ince SE, et al: Parkinson’s disease in
65 pairs of twins and in a set of quadruplets. Neurology
33~815-824, 1983
Dopamine Receptor
Elevation in
Denervated Tissues
Philip Seeman, MD, PhD, and Mark Guttman, MDX
The striata of untreated patients with Parkinson’s disease
(who did not receive L-dopa pre mortem) reveal elevated
densities of D2 dopamine receptors when measured in vitro
[41.A recent paper by Bennett and Wooten [I] in the Annals, however, while confirming that such an elevation can be
detected in vitro in tissues from dopamine-lesioned rats, reported that no such elevation could be detected in vivo following an injection of C3H)spiperone. The editorial [7]
which accompanied the article appropriately indicates that
important quantitative aspects were neglected when this
negative in vivo data was assessed. We suggest that there may
be two possible explanations for it: (1) low occupancy of
receptors; and (2) inappropriate measurement of nonspecific
binding.
Receptor occupancy: It is essential to point out that the elevated receptor density found in vitro was measured under
conditions in which 100% of the receptors were occupied.
The in vivo measurement, however, was done under conditions in which only 7% of the receptors were occupied. Such
a low degree of receptor occupation would minimize the
ability to reveal elevated receptor density in denervated tissue. In fact, inspection of the in vitro data [l] reveals that
there was no significant difference between normal and denervated tissues when only 7 % of the receptors were occupied.
This technical problem has been observed previously. For
example, Saelens and associates [ 8 ] found that the longterm administration of haloperidol did not elevate the Dz
dopamine receptor density in vivo under conditions of 16%
occupancy. However, haloperidol-induced elevations were
readily detected in vivo under conditions approaching 100%
occupancy [9}.
Thus, for the receptor elevation to be more readily seen in
vivo, it is helpful to add a nonradioactive neuroleptic agent to
the isotope injected so that at least 80 to 90% of the receptors are occupied, as is currently being done in positron
emission tomography (PET) studies in volunteers and patients 131.
Non-specific binding: A second important point is that
“specific binding” in vivo must be defined as the amount of
{3H]spiperone that is displaced by an excess amount of injected nonradioactive neuroleptic agent IS}. The “. . . cerebellum cannot be regarded as an appropriate blank value for
the other regions” I51 because the density of nonspecific
sites for f3H)spiperone is high in the striatum 15, 61, higher
than that in the cerebellum {GI. Thus, denervation may alter
the density of nonspecific sites for [3H)spiperone,offsetting
the increase in D2 receptors. Therefore, as recommended by
Laduron and associates {5}, it is essential to define specific
binding in vivo in the same way as it is defined in vitro,
namely, by co-injecting an excess amount of the nonradioactive neuroleptic agent [21 to inhibit specific binding of
f3H]spiperone from the receptors, thus properly measuring
nonspecific binding.
Hence, in the future there is reason to expect that changes
in Dz dopamine densities may be imaged by PET in patients
with Parkinson’s and other diseases, providing that the above
principles are used.
Departments of Pharmacology and ‘Medicine
Medical Sciences Building
University of Toronto
Toronto. Canada M5S lA8
References
1. Bennett JP Jr, Wooten GF: Dopamine denervation does not alter
in vivo 3H-spiperone binding in rat striatum: implications for
external imaging of dopamine receptors in Parlunson’s disease.
Ann Neurol 19:378-383, 1986
2. Bischoff S: Increased in vivo (3H)-spiperone binding in the rat
hippocampal formation and striatum after repeated treatment
with haloperidol. Experientia 37: 1008, 1981
3. Farde L, Hall H, Ehrin E, Sedvall G: Quantitative analysis of D2
dopamine receptor binding in the living human brain by PET.
Science 231:258-261, 1986
4. Guuman M, Seeman P L-Dopa reverses the elevated density of
Dz dopamine receptors in Parkinson’sdiseased striatum. J Neural
Transm 64:93-103, 1985
5. Laduron PM, Janssen PFM, Leysen JE: Characterization of
specific in v i m binding of neuroleptic drugs in rat brain. Lfe Sci
23:581-586, 1978
6. List SJ, Seeman P: Resolution of dopamine and serotonin receptor components of [3H]spiperone binding to rat brain regions.
Proc Natl Acad Sci USA 78:2620-2624, 1981
/ . Perlmutter JS, Raichle ME: In vitro or in vivo receptor binding:
where does the truth lie? Ann Neurol 19:384-385, 1986
8. Saelens JK, Simke JP, Neale SE, et al: Effects of haloperidol and
7
d-amphetamine on in vivo 3H-spiroperidol binding in the rat
forebrain. Arch Int Pharmacodyn Ther 246:98-107, 1980
9. Schwanz J-C, Baudry M, Mmres M-P, et al: Increased in vivo
binding of 3H-pimozide in mouse striatum following repeated
administration of haloperidol. Life Sci 23:1785-1790, 1978
Reply
Joel S. Perlmutter, MD, and Marcus E. Raichle, M D
Drs Seeman and Guttman suggest that “there may be two
possible explanations,” in addition to the quantitative issues
that we raised [2}, for the results found by Bennett and
Wooten {I]. We applaud this attempt to consider carefully
confounding factors that might affect in vivo measurements
of radioligand-receptor binding. The two specific issues
raised-low occupancy of receptors and inappropriate measurements of nonspecific binding-are important. In general,
one must understand the capability of any proposed method
to measure such factors. But even more importantly, one
must calculate the effects errors in these measurements have
on the final estimate of radioligand-receptor binding. In this
manner, the relative importance of these potentially confounding factors can be assessed.
Washington University School of Medicine
Louis, MO 63110
St.
Refreences
1. Bennett JP Jr, Wooten G F Dopamine denervation does not alter
in vivo 3H-spiperone binding in rat striatum: implications for
external imaging of dopamine receptors in Parkinson’s disease.
Ann Neurol 19:378-383, 1986
2. Perlmutter JS, Raichle ME: In vitro or in vivo receptor binding:
where does the truth lie? Ann Neurol 19:384-385, 1986
Reply
James P. Bennett, MD, PhD,
and G. Frederick Wooten, M D
With respect to the letter from Seeman and Guttman and the
editorial by Perlmutter and Raichle {S} accompanying our
recent paper [ 11in the Annals, we offer the following comments.
If two receptor populations are heterogeneous with respect to ligand-binding affinity (Kd) alone, the mass action
laws for reversible ligand-receptor interactions predict that
receptor occupancy (ligand binding) will be consistently different in the two populations when ligand concentrations are
below Kd. As ligand concentrations exceed Kd, receptor
occupancy in the two populations will approach each other
and eventually equalize if both populations have the same
maximum number of binding sites (Bmm).If the receptor
populations differ only on the basis of B,
(i.e., Kd’S are
equal), receptor occupancy should be different over the entire range of ligand concentration. Depending on the signall
noise ratio (specificlnonspecific binding) for a given ligandreceptor system, receptor heterogeneity based solely on B,
differences may be detectable at low (below Kd) ligand condifferences are most reliably
centrations. In practice, B,
detected when ligand concentrations exceed Kd.
Annals of Neurology Vol 2 1 No
4 April 1987 413
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