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Effect of L-DOPA on brain monoamines and their metabolites in Parkinson's disease
Life Sciences Vol. 10, Part I, pp. Printed in Great Britain
Pergamon Press
549-557, 1971 .
EFFECT OF L-DOPA ON BRAIN MONOAMINES AND THEIR METABOLITES IN PARKINSON'S DISEASE U .K . Rinne, Department of Neurology,
Y . Sonntnen, and M . Hyyppä
University of Turku, 20520 Turku 52, Finland
(Received in final form B April
1971)
Surtmary Biochemical analyses of autopsy brain samples of a patient with Parkinson's disease treated with L-DOPA (5 g dally, 70 mg/kg) showed clearly increased concentrations of dopamine and homovanllIic acid in the extrapyramidal brain regions as well as In the hypothalamus, thalamus, cerebral and cerebellar cortex as compared to the normal control and Parktnsonian brain samples. But there were no changes in the concentration of noradrenaline . However, the contents of serotonin and especially of 5-HIAA were somewhat higher in a patient with Parkinson's disease treated with L-DOPA than in controls . Deficiency of dopamine (1,2) in the brain of patients with Parkinson's disease provides the theoretical basis for the use of L-DOPA (L-3,4-dthydroxyphenylalanine)
in the treatment of this disease . The results of clinical trials
published during recent years have clearly indicated the considerable therapeutic effectiveness of L-DOPA (3-B) . However, very exact mechanism of the action of L-DOPA
little is known about the
to the brain of patients with Parkin-
son's disease.. It is generally assumed that L-DOPA corrects the deficiency of dopamine . This opinion is supported by the findings that
in experimental
ani-
mats L-DOPA increases the concentration of dopamine to the brain (9-II) . But there is a lack of diroct evidence of an increased amount of dopamine
in the
brain of patients with Parkinson's disease treated with L-DOPA . In this paper we present evidence that in patients with Parkinson's disease L-DOPA treatment also causes a marked Increase in the concentration of dopamine and its main metabolite, homovanillic acid (HVA), of the brain . The contents of noradrenaline,
549
In various regions
serotonin and 5-hydroxyindoleacetic
L-DOPA and Parkinson
550
acid (5-HIAA) were determined
Vol. 10, No. 10
In the same connection .
Material
and Methods
The brain samples were obtained from a 70-year-old male patient who had suffered from Parkinson's disease for at least four years . The disability of the patient was 76 according to Northwestern University Disability Scales (12) and stage V according to the scale described by Hoehn and Yahr (13) . The clinical
picture of the patient was characterized by a very marked akinesfa,
postural
instability and rigidity associated with moderate tremor in upper
extremities . The overall severity of the Parkinsonlan state was assessed on a rated scale, with criteria similar to those employed by Yahr et al . (5) giving 79 as the total score . Prior to his death, the patient was treated with L-DOPA (F . Hoffmann-La Roche $ Co . Ltd ., Switzerland)
for two months with a dally
dosage of 5 g (70 mg/kg) . During this treatment period the patient showed only slight
Improvement in tremor but there was no change In akinesia or rigidity .
The autopsy showed that the cause of death was bronchopneumonia associated with congestive heart failure . The last dose of 0.5 g of L-DOPA was given I
I/2 hours prior to death
and within six hours on the same day the patient was given,
in all,
2 .5 g of
L-DOPA . The autopsy was carried out seven hours after death . Various regions of the brain were dissected out and immediately deep-frozen for biochemical analyses . Control samples of corresponding brain regions were obtained for biochemical analyses from three patients (57, extrapyramldal
71, and 86 years old)
without
disorders who had died of pulmonary embolus, congestive heart
failure and pulmonary embolus,
respectively . Brain samples from a 68-year-old
patient who had suffered from Parkinson's disease for six years and died of bronchopneumonia were also analysed . Dopamine was determined by the slightly modified method of Anton and Sayre (14) and the values were calculated without correction of recovery, HVA according to Andén et al .
(15), noradrenaline and
serotonin according to Malckel et al . (16) and 5-HIAA as described by Curzon
Vol . 10, No. 10
L-DOPA and Parkinson
551
and Green (17) . Results Microscopic examination of the substantia nigra showed the cell and the secondary gliosis but most of the surviving cell
loss
bodies contained a
considerable amount of melanin granules . On the other hand, histologlcal mination of the liver,
exa
kidneys, pancreas and heart did not show morphological
changes which could be related to the possible toxic effect of L-DOPA therapy. Biochemical analyses showed that the content of dopamine and HYA (Table I) was markedly decreased In brain samples of a patient with Parkinson's disease . However, there was a three to fourfold increase in the concentratton of dopamine
in the extrapyramidal
brain regions as well as In the thalamus of
a patient treated with L-DOPA as compared to the corresponding controls . A marked Increase In the amount of dopamine occurred also
in the cerebral
and
cerebellar cortex where its concentratton was very low in normal control samples . On the other hand, L-DOPA treatment Induced a more marked elevation in the content of HVA than that of dopamine canpared to the normal
in all brain regions studied as
control and Parktnsonlan brain samples (Table
I) . But
L-DOPA treatment did not have any significant effect on the concentration of noradrenaline (Table 2) . On the other hand, the contents of serotonin and especially of 5-HIAA were somewhat higher in the patient with Parkinson's disease treated with L-DOPA than in controls (Table 2) . The concentratton of HVA in the ventricular cerebrospinal fluid taken at the autopsy-was 7340 ng/ml . Analysts of HVA in the lumbar cerebrospinal fluid collected 1- en days before the death of the patient showed that L-DOPA treatment with a dally dosage of 5 g caused an from the pretreatment level of
increase in the level of HVA
14 .7 ng/ml to 128 ng/ml . Discussion
The results obtained clearly indicated that L-DOPA is metabolized in the brain of a patient with Parkinson's disease . L-DOPA treatment was able to
Vol. 10, No. 10
L-DOPA and Parkinson
552
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L-DOPA and Parkinson
Vol. 10, No. 10
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L-DOPA and Parkinson
Vol . 10, No . 10
increase the concentration of dopamine and its main metabolite, HVA, Parklnsonian brain, corresponding to the findings obtained animals (9-II) . Recently Yahr (18)
has reported an
in the
In experimental
Increased amount of HVA In
the brain of patients treated with L-DOPA . However, the dopamine
levels were
only approaching normal or below . The difference may be due to the variation of
Intervals between the administration time of the last L-DOPA dose and the
death of the patient.
It must be kept in mind that the metabolisatlon of
L-DOPA occurs very rapidly within few hours (9,11,19) . Our patient was given L-DOPA I
I/2 hours prior to death and thus the increased dopamine concentra-
tions in the brain regions of this patient would be explained . We did not notice any significant changes In the concentration of noradrenaline in any of the brain regions studied . Thus our results are in agreement with recent findings showing that exogenously administered L-DOPA is mainly converted to dopamine and Its degradation products, only a minor proportion undergoing ~ -hydroxylation to noradrenaline and its further metabolites (9,20) . L-DOPA treatment Increased the content of dopamine and HVA not only in the extrapyramidal brain regions but also
In the other parts of the brain .
This phenomenon may be related to some of the effects of L-DOPA . For Instance, among the effects of L-DOPA on Parklnsonian symptoms we have found that also has an aphrodisiac action on patients
(7,8,21) .
it
It is possible that In-
creased hypothalamic dopamine content in the Parklnsonian brain found In the present study might be responsible to this action . Many recent studies in experimental
animals on the relationship between hypothalamic dopamine and
gonadotrophin secretion (22) hand, there is experimental
lend support to this assumption . On the other evidence that brain serotonin might be related to
sexual
behavior
(23), and to gonadotrophin secretion (24) .
mental
animals it has been shown that L-DOPA induced a decrease
concentration of the brain (25), but a clear increase
Indeed
in experi-
In serotonin
in the content of 5-HIAA
(25) was noted as we found also in the brain of our patient with Parkinson's
Vol. 10, No. 10
L-DOPA and Parkinson
disease treated with L-DOPA . Furthermore,
555
decreased amounts of 5-HIAA in the
cerebrospinal fluid of patients with Parkinson's disease during treatment (26)
long-term
produce further evidence of effects on brain serotonin metabol-
ism also In human beings . It must be taken Into consideration that the Interval
between death and
autopsy was t0-17 hours shorter in our patient with Parkinson's disease treated with L-DOPA than
to controls . A slow decrease of the concentration of dopamine
and noradrenaline during the Interval
between death and necropsy has been found
(27,28) although the changes seem to be very slight within 3 to 20 hours after death (I) . On the other hand, there Is evidence of a relatively rapid decrease in the content of serotonin (29) . Therefore the concentrations of monoamines In controls may be somewhat
lower than expected . It
is possible that especially
small differences in the content of serotonin between the patient with Parkinson's disease treated with L-DOPA and controls may be due to this phenomenon . Very
little Is known about the exact mechanism of the action of L-DOPA
in Parkinsonism . It is generally assumed that L-DOPA corrects the deficiency of dopamine In the substantta nigra - neostriatum system as a type of
replace
ment therapy. The results of the present study clearly showed that L-DOPA treatment is able to Increase the concentration of dopamine in the Parkinsonlan brain . This Is in keeping with the assumption that at least part of the therapeutic effect of L-DOPA might be mediated through this phenomenon .
It was of
same Interest that the amount of HVA was relatively more markedly increased than that of dopamine .
It may be due to a very rapid metabolism of dopamine
within the brain. On the other hand, there is biochemical evidence that the metabolism of dopamine would be increased in the surviving dopaminergic substantia nigra neurons in Parkinsonism (2) . Furthermore, this concurs with recent evidence on the role of the methylation process during L-DOPA treatment . It has been shown In the rat that L-DOPA therapy Induced a great loss of methyl groups from the brain Indicated by a very tration of S-adenosyl-methionine .
labile
large decrease in the concen-
It is possible that same of the effects of
558
Vol. 10, No. 10
L-DOPA and Parkinson
L-DOPA might depend on this deficiency as has been suggested by Wurtman et al . (30) . First, the metabolism of endogenous dopamine and noradrenaline In the brain would be decreased and thus their action potentlated . Secondly, a considerable accumulation of 3-0-methyldopa was found in the brain of the rat after the administration of L-DOPA (9) . during
It is possible that some etfects found
L-DOPA treatment may be derived from this compound or 3-0-methyldopamine
formed from
it . On the other hand, it must also be kept
In mind that products
of the quantitatively minor metabolic pathways may play a role In the actions of L-DOPA (20) . Acknowledgements This work was supported by a grant from the National
Research Council
for Medical Sciences, Finland . We wish to thank F. Hoffmann-La Roche 8 Co . Ltd . (Switzerland) for a gift of L-DOPA . References I .
H. EHRINGER and 0. HORNYKIEWICZ, KIin .Wschr . 38,
2.
0. HORNYKIEWICZ, Biochemistry and Pharmacology of the Basal Ganglia p .171 . Raven Press, New York (1966) .
3.
G.C . COTZIAS, P .S . PAPAVASILIOU and R . GELLENE, New EngI .J .Med . 280, 337 (1969) .
4.
M .D . YAHR, R.C . DUVOISIN, M .M . HOEHN, M .J . SCHEAR and R.E . BARRETT, Transact .Amer.NeuroI .Ass . 93, 56 (1968) .
5.
M .D . YAHR, R.C . DUVOISIN, M .J . SCHEAR, R.E . BARRETT and M.M . HOEHN, Arch .Neurol . 21, 343 (1969) .
6.
A . BARBEAU, Canad .Med .Ass .J . 101,
7.
U .K . RINNE, V . SONNINEN and T . SIIRTOLA, Acta neurol .scand . 46, suppl .43, 221 (1970) . -
8.
U .K . RINNE, V . SONNINEN and T . SIIRTOLA, Europ .Neu rol .
9.
G . BARTHOLINI
and A . PLETSCHER,
791
1236 (1960) .
(1969) .
J .Pharmacol .exp .Therap .
i n press (1970) . 161,
14 (1968) .
10 .
A . PLETSCHER, G . BARTHOLINI, K .F . GEY and A . JENNI, Schwelz .med .iVschr. 100, 797 (1970) .
II .
R.J . WURTMAN, A . CHOU and C . ROSE, J .Pharmacol .exp .Therap . 174,
351(1970) .
Vol. 10, No. 10
L-DOPA and Parkinson
557
12 .
G .J . CANTER, R. de LA TORRE and M. MIER, J .nerv.ment.Dis . 133,
143 (1961) .
13 .
M.M . HOEHN and M.D . YAHR, Neurology 17, 427 (1967) .
14 .
A.A . ANTON and D .F . SAYRE, J .Pharmacol . 145,
15 .
N .-E . ANDEN, B .-E . ROOS and B. WERDINIUS, Llfe Sciences 7,
16 .
R .P . MAICKEL, pharmacol . 7,
17 .
G . CURZON and A.R . GREEN, BrIt .J .Pharmacol . 39, 653 (1970) .
18 .
M .D . YAHR, paper read at Symposium Bel-Air IV, Monoamines et noyaux gris centraux (1970) .
19 .
R. TISSOT, G . BARTHOLINI
20 .
D.B . CALNE, F. KAROUM, C.R .J . RUTHVEN and M . SANDLER, BrIt .J .Pharmacol . 37, 57 (1969) .
21 .
M . HYYPPÄ, U .K . RINNE and V . SONNINEN, Acta neurol .scand . 46, supp1 .43, 223 (1970) . -
22 .
K. FUXE, T . HÖKFELT and 0 . NILSSON, Neuroendocrinology 5,
23 .
A. TAGLIAMONTE, P . TAGLIAMONTE, G .L . GESSA and B.B . BRODIE, Science 166, 1433 (1969) .
24 .
C. KORDON, Neuroendocrlnology 4,
25 .
G. BARTHOLINI, M. DAPRADA and A . PLETSCHER, J .Pharm .Pharmacol . 20, 228
26 .
M.H . Van WOERT and M.B . BOWERS, Jr ., Experientia 26,
27 .
P.O . GANROT, E. ROSENGREN and C .G . Gottfrles, Experientia 18, 260 (1962) .
28 .
U.K . RINNE and V. SONNINEN, Experientia 24, 177 (1968) .
29 .
A. BERTLER, Acta physiol .scand . 51, 97 (1961) .
30 .
R .J . WURTMAN, C .M . ROSE, S . MATHYSSE, J . STEPHENSON and R. BALDESSARINI, Science 169, 395 (1970) .
326 (1964) .
R.H . COX, Jr ., J . SAILLANT . and F .P . MILLER, 275 (1968) .
448 (1963) . Int .J .Neuro-
and A. PLETSCHER, Arch .Neurol . 20,
187 (1969) .
107 (1969) .
129 (1969) .
161 (1970) .
Pergamon Press
549-557, 1971 .
EFFECT OF L-DOPA ON BRAIN MONOAMINES AND THEIR METABOLITES IN PARKINSON'S DISEASE U .K . Rinne, Department of Neurology,
Y . Sonntnen, and M . Hyyppä
University of Turku, 20520 Turku 52, Finland
(Received in final form B April
1971)
Surtmary Biochemical analyses of autopsy brain samples of a patient with Parkinson's disease treated with L-DOPA (5 g dally, 70 mg/kg) showed clearly increased concentrations of dopamine and homovanllIic acid in the extrapyramidal brain regions as well as In the hypothalamus, thalamus, cerebral and cerebellar cortex as compared to the normal control and Parktnsonian brain samples. But there were no changes in the concentration of noradrenaline . However, the contents of serotonin and especially of 5-HIAA were somewhat higher in a patient with Parkinson's disease treated with L-DOPA than in controls . Deficiency of dopamine (1,2) in the brain of patients with Parkinson's disease provides the theoretical basis for the use of L-DOPA (L-3,4-dthydroxyphenylalanine)
in the treatment of this disease . The results of clinical trials
published during recent years have clearly indicated the considerable therapeutic effectiveness of L-DOPA (3-B) . However, very exact mechanism of the action of L-DOPA
little is known about the
to the brain of patients with Parkin-
son's disease.. It is generally assumed that L-DOPA corrects the deficiency of dopamine . This opinion is supported by the findings that
in experimental
ani-
mats L-DOPA increases the concentration of dopamine to the brain (9-II) . But there is a lack of diroct evidence of an increased amount of dopamine
in the
brain of patients with Parkinson's disease treated with L-DOPA . In this paper we present evidence that in patients with Parkinson's disease L-DOPA treatment also causes a marked Increase in the concentration of dopamine and its main metabolite, homovanillic acid (HVA), of the brain . The contents of noradrenaline,
549
In various regions
serotonin and 5-hydroxyindoleacetic
L-DOPA and Parkinson
550
acid (5-HIAA) were determined
Vol. 10, No. 10
In the same connection .
Material
and Methods
The brain samples were obtained from a 70-year-old male patient who had suffered from Parkinson's disease for at least four years . The disability of the patient was 76 according to Northwestern University Disability Scales (12) and stage V according to the scale described by Hoehn and Yahr (13) . The clinical
picture of the patient was characterized by a very marked akinesfa,
postural
instability and rigidity associated with moderate tremor in upper
extremities . The overall severity of the Parkinsonlan state was assessed on a rated scale, with criteria similar to those employed by Yahr et al . (5) giving 79 as the total score . Prior to his death, the patient was treated with L-DOPA (F . Hoffmann-La Roche $ Co . Ltd ., Switzerland)
for two months with a dally
dosage of 5 g (70 mg/kg) . During this treatment period the patient showed only slight
Improvement in tremor but there was no change In akinesia or rigidity .
The autopsy showed that the cause of death was bronchopneumonia associated with congestive heart failure . The last dose of 0.5 g of L-DOPA was given I
I/2 hours prior to death
and within six hours on the same day the patient was given,
in all,
2 .5 g of
L-DOPA . The autopsy was carried out seven hours after death . Various regions of the brain were dissected out and immediately deep-frozen for biochemical analyses . Control samples of corresponding brain regions were obtained for biochemical analyses from three patients (57, extrapyramldal
71, and 86 years old)
without
disorders who had died of pulmonary embolus, congestive heart
failure and pulmonary embolus,
respectively . Brain samples from a 68-year-old
patient who had suffered from Parkinson's disease for six years and died of bronchopneumonia were also analysed . Dopamine was determined by the slightly modified method of Anton and Sayre (14) and the values were calculated without correction of recovery, HVA according to Andén et al .
(15), noradrenaline and
serotonin according to Malckel et al . (16) and 5-HIAA as described by Curzon
Vol . 10, No. 10
L-DOPA and Parkinson
551
and Green (17) . Results Microscopic examination of the substantia nigra showed the cell and the secondary gliosis but most of the surviving cell
loss
bodies contained a
considerable amount of melanin granules . On the other hand, histologlcal mination of the liver,
exa
kidneys, pancreas and heart did not show morphological
changes which could be related to the possible toxic effect of L-DOPA therapy. Biochemical analyses showed that the content of dopamine and HYA (Table I) was markedly decreased In brain samples of a patient with Parkinson's disease . However, there was a three to fourfold increase in the concentratton of dopamine
in the extrapyramidal
brain regions as well as In the thalamus of
a patient treated with L-DOPA as compared to the corresponding controls . A marked Increase In the amount of dopamine occurred also
in the cerebral
and
cerebellar cortex where its concentratton was very low in normal control samples . On the other hand, L-DOPA treatment Induced a more marked elevation in the content of HVA than that of dopamine canpared to the normal
in all brain regions studied as
control and Parktnsonlan brain samples (Table
I) . But
L-DOPA treatment did not have any significant effect on the concentration of noradrenaline (Table 2) . On the other hand, the contents of serotonin and especially of 5-HIAA were somewhat higher in the patient with Parkinson's disease treated with L-DOPA than in controls (Table 2) . The concentratton of HVA in the ventricular cerebrospinal fluid taken at the autopsy-was 7340 ng/ml . Analysts of HVA in the lumbar cerebrospinal fluid collected 1- en days before the death of the patient showed that L-DOPA treatment with a dally dosage of 5 g caused an from the pretreatment level of
increase in the level of HVA
14 .7 ng/ml to 128 ng/ml . Discussion
The results obtained clearly indicated that L-DOPA is metabolized in the brain of a patient with Parkinson's disease . L-DOPA treatment was able to
Vol. 10, No. 10
L-DOPA and Parkinson
552
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L-DOPA and Parkinson
Vol. 10, No. 10
N
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554
L-DOPA and Parkinson
Vol . 10, No . 10
increase the concentration of dopamine and its main metabolite, HVA, Parklnsonian brain, corresponding to the findings obtained animals (9-II) . Recently Yahr (18)
has reported an
in the
In experimental
Increased amount of HVA In
the brain of patients treated with L-DOPA . However, the dopamine
levels were
only approaching normal or below . The difference may be due to the variation of
Intervals between the administration time of the last L-DOPA dose and the
death of the patient.
It must be kept in mind that the metabolisatlon of
L-DOPA occurs very rapidly within few hours (9,11,19) . Our patient was given L-DOPA I
I/2 hours prior to death and thus the increased dopamine concentra-
tions in the brain regions of this patient would be explained . We did not notice any significant changes In the concentration of noradrenaline in any of the brain regions studied . Thus our results are in agreement with recent findings showing that exogenously administered L-DOPA is mainly converted to dopamine and Its degradation products, only a minor proportion undergoing ~ -hydroxylation to noradrenaline and its further metabolites (9,20) . L-DOPA treatment Increased the content of dopamine and HVA not only in the extrapyramidal brain regions but also
In the other parts of the brain .
This phenomenon may be related to some of the effects of L-DOPA . For Instance, among the effects of L-DOPA on Parklnsonian symptoms we have found that also has an aphrodisiac action on patients
(7,8,21) .
it
It is possible that In-
creased hypothalamic dopamine content in the Parklnsonian brain found In the present study might be responsible to this action . Many recent studies in experimental
animals on the relationship between hypothalamic dopamine and
gonadotrophin secretion (22) hand, there is experimental
lend support to this assumption . On the other evidence that brain serotonin might be related to
sexual
behavior
(23), and to gonadotrophin secretion (24) .
mental
animals it has been shown that L-DOPA induced a decrease
concentration of the brain (25), but a clear increase
Indeed
in experi-
In serotonin
in the content of 5-HIAA
(25) was noted as we found also in the brain of our patient with Parkinson's
Vol. 10, No. 10
L-DOPA and Parkinson
disease treated with L-DOPA . Furthermore,
555
decreased amounts of 5-HIAA in the
cerebrospinal fluid of patients with Parkinson's disease during treatment (26)
long-term
produce further evidence of effects on brain serotonin metabol-
ism also In human beings . It must be taken Into consideration that the Interval
between death and
autopsy was t0-17 hours shorter in our patient with Parkinson's disease treated with L-DOPA than
to controls . A slow decrease of the concentration of dopamine
and noradrenaline during the Interval
between death and necropsy has been found
(27,28) although the changes seem to be very slight within 3 to 20 hours after death (I) . On the other hand, there Is evidence of a relatively rapid decrease in the content of serotonin (29) . Therefore the concentrations of monoamines In controls may be somewhat
lower than expected . It
is possible that especially
small differences in the content of serotonin between the patient with Parkinson's disease treated with L-DOPA and controls may be due to this phenomenon . Very
little Is known about the exact mechanism of the action of L-DOPA
in Parkinsonism . It is generally assumed that L-DOPA corrects the deficiency of dopamine In the substantta nigra - neostriatum system as a type of
replace
ment therapy. The results of the present study clearly showed that L-DOPA treatment is able to Increase the concentration of dopamine in the Parkinsonlan brain . This Is in keeping with the assumption that at least part of the therapeutic effect of L-DOPA might be mediated through this phenomenon .
It was of
same Interest that the amount of HVA was relatively more markedly increased than that of dopamine .
It may be due to a very rapid metabolism of dopamine
within the brain. On the other hand, there is biochemical evidence that the metabolism of dopamine would be increased in the surviving dopaminergic substantia nigra neurons in Parkinsonism (2) . Furthermore, this concurs with recent evidence on the role of the methylation process during L-DOPA treatment . It has been shown In the rat that L-DOPA therapy Induced a great loss of methyl groups from the brain Indicated by a very tration of S-adenosyl-methionine .
labile
large decrease in the concen-
It is possible that same of the effects of
558
Vol. 10, No. 10
L-DOPA and Parkinson
L-DOPA might depend on this deficiency as has been suggested by Wurtman et al . (30) . First, the metabolism of endogenous dopamine and noradrenaline In the brain would be decreased and thus their action potentlated . Secondly, a considerable accumulation of 3-0-methyldopa was found in the brain of the rat after the administration of L-DOPA (9) . during
It is possible that some etfects found
L-DOPA treatment may be derived from this compound or 3-0-methyldopamine
formed from
it . On the other hand, it must also be kept
In mind that products
of the quantitatively minor metabolic pathways may play a role In the actions of L-DOPA (20) . Acknowledgements This work was supported by a grant from the National
Research Council
for Medical Sciences, Finland . We wish to thank F. Hoffmann-La Roche 8 Co . Ltd . (Switzerland) for a gift of L-DOPA . References I .
H. EHRINGER and 0. HORNYKIEWICZ, KIin .Wschr . 38,
2.
0. HORNYKIEWICZ, Biochemistry and Pharmacology of the Basal Ganglia p .171 . Raven Press, New York (1966) .
3.
G.C . COTZIAS, P .S . PAPAVASILIOU and R . GELLENE, New EngI .J .Med . 280, 337 (1969) .
4.
M .D . YAHR, R.C . DUVOISIN, M .M . HOEHN, M .J . SCHEAR and R.E . BARRETT, Transact .Amer.NeuroI .Ass . 93, 56 (1968) .
5.
M .D . YAHR, R.C . DUVOISIN, M .J . SCHEAR, R.E . BARRETT and M.M . HOEHN, Arch .Neurol . 21, 343 (1969) .
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and A . PLETSCHER,
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351(1970) .
Vol. 10, No. 10
L-DOPA and Parkinson
557
12 .
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M.M . HOEHN and M.D . YAHR, Neurology 17, 427 (1967) .
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R .P . MAICKEL, pharmacol . 7,
17 .
G . CURZON and A.R . GREEN, BrIt .J .Pharmacol . 39, 653 (1970) .
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M .D . YAHR, paper read at Symposium Bel-Air IV, Monoamines et noyaux gris centraux (1970) .
19 .
R. TISSOT, G . BARTHOLINI
20 .
D.B . CALNE, F. KAROUM, C.R .J . RUTHVEN and M . SANDLER, BrIt .J .Pharmacol . 37, 57 (1969) .
21 .
M . HYYPPÄ, U .K . RINNE and V . SONNINEN, Acta neurol .scand . 46, supp1 .43, 223 (1970) . -
22 .
K. FUXE, T . HÖKFELT and 0 . NILSSON, Neuroendocrinology 5,
23 .
A. TAGLIAMONTE, P . TAGLIAMONTE, G .L . GESSA and B.B . BRODIE, Science 166, 1433 (1969) .
24 .
C. KORDON, Neuroendocrlnology 4,
25 .
G. BARTHOLINI, M. DAPRADA and A . PLETSCHER, J .Pharm .Pharmacol . 20, 228
26 .
M.H . Van WOERT and M.B . BOWERS, Jr ., Experientia 26,
27 .
P.O . GANROT, E. ROSENGREN and C .G . Gottfrles, Experientia 18, 260 (1962) .
28 .
U.K . RINNE and V. SONNINEN, Experientia 24, 177 (1968) .
29 .
A. BERTLER, Acta physiol .scand . 51, 97 (1961) .
30 .
R .J . WURTMAN, C .M . ROSE, S . MATHYSSE, J . STEPHENSON and R. BALDESSARINI, Science 169, 395 (1970) .
326 (1964) .
R.H . COX, Jr ., J . SAILLANT . and F .P . MILLER, 275 (1968) .
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