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Nonaminergic striatal neurons convert exogenous l-dopa to dopamine in parkinsonism.

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Nonaminergic Striatal Neurons
Convert Exogenous L-Dopa to
Dopamine in Pxhsonism
Eldad Melamed, MD, Frant Hefti, PhD, and Richard J. Wurtman, MD
I n intact striatum, the enzyme dopa decarboxylase is localized predominantly in dopaminergic nerve terminals. In
Parkinson disease, loss of dopaminergic neurons is associated with massive depletion of striatal decarboxylase ac-
tivity. Nevertheless, efficacy of exogenous L-dopa in parkinsonism is generally believed to result from its enzymatic
derarboxylation to dopamine in the corpus striatum. It has previously been suggested that, after degeneration of
nigrostriatal pathways, decarboxylation of administered L-dopa may occur mainly at such striatal sites as surviving
dopaminergic terminals, serotonergic neurons, or capillaries; but currently available data do not favor these
Recent experimental studies indicate that a substantial amount of decarboxylase activity is localized in striatal
interneurons or efferent neurons that may not normally synthesize monoamines. We propose that after depletion of
dopaminergic terminals, these nonaminergic striatal neurons may contain a large fraction of residual dopa decarboxylase activity and may represent an important locus for conversion of administered dopa to functional dopamine
in the parkinsonian corpus striatuni.
Melamed E, Hefti F, Wurtman RJ: Nonaminergic striatal neurons convert exogenous L-dopa to dopamine in
parkinsonism. Ann Neurol 8:558-563, 1980
Although L-dopa has been the most effective and
widely used antiparkinsonian drug for more than a
decade [ 2 , 5 , 10, 481, its precise mechanism of action
is not yet fully established. I t is generally believed
[ 2 0 ]that the efficacy of L-dopa results from its ability
to cross the blood-brain barrier and replenish reduced striatal dopamine concentrations following its
enzymatic decarboxylation. However, the locus of
conversion of exogenous dopa to dopamine in the
parkinsonian corpus striatum remains an enigma.
In the mammalian striatum, dopa decarboxylase
(aromatic L-amino acid decarboxylase), the enzyme
that catalyzes the synthesis of dopamine from its precursor, L-dopa [ 111, is localized predominantly within the terminal ramifications of nigrostriatal dopaminergic neurons [ 2 9 ] . In Parkinson disease the
massive depletion of dopaminergic terminals is associated with parallel reductions in striatal dopa decarboxylase activity [ 2 4 ] . Nevertheless, administration
of L-dopa increases dopamine levels in the striata of
these patients [ 2 4 , 411 and of animals with lesions of
the nigrostriatal system [ 2 2 ] .This raises the question
of where in the striatum the enzymatic decarboxyla-
From the Laboratory of Neuroendocrine Regulation, Department
of Nutrition and Food Science, Massachusetts Institute of
Technology, Cambridge, MA.
Received April 15, 1980, and in revised form May 30. Accepted
for publication June 5 , 1980.
tion of administered dopa occurs after degeneration
of the dopaminergic neurons.
Identification of this striatal site o r sites is a prerequisite to understanding the mechanisms mediating
both the beneficial response to dopa and the limiting
side effects that frequently emerge during its longterm administration; these include dyskinesias, psychiatric reactions, gradual decline of therapeutic
efficacy, and the “on-off’ phenomenon [15, 2 1 ,
2 3 , 2 7 , 281. Recent progress in explaining the neurochemical activity of the corpus striatum prompts
us to reevaluate previous theories and to put forward a new hypothesis concerning the locus of
L-dopa’s conversion to dopamine in parkinsonism.
Localization of Decarboxylase in the
Corpus Striatum and Previous Hypotheses
on Its Metabolism
The neuronal circuitry of the mammalian striatum
and its neurochemical substrate is complex and has
been only partly delineated (for reviews see 18, 321).
The major neural connections of the striatum as they
are understood today (primarily from studies in ex-
Address reprint requests to Richard J. Wurtman, MD, Laboratory
of Neuroendocrine Regulation, Department of Nutrition and
Food Science, Massachusetts Institute of Technology, Cambridge,
MA 02139.
558 0364-5134/801120558-06$01.25 @ 1979 by Richard J. Wurtman
Fig I . The m i n known neuronal connections of the mammalian corpus striatum. (Glu = glutamic acid; ACh = acetylcholine; GABA = y-aminobutyric acid; ENK = enkephalins;
GP = globus pallidus; DA = doparnine; Sub. P = substance
P; 5-HT = serotonin.)
perimental animals) are schematically outlined in
Figure 1. The main known afferents include the
corticostriatal (perhaps using glutamate as their
neurotransmitter), nigrostriatal dopaminergic, raphestriatal serotonergic, and thalamostriatal pathways.
The main known efferents originating from the striatum are the striatopallidal and striatonigral projections, the latter using y-aminobutyric acid (GABA)
and substance P as transmitters. Intrinsic connections
consist of interneurons, some of which use acetylcholine, GABA, and enkephalins [19, 321. The
striatum also contains glial cells and blood vessels.
Four types of cells in the mammalian braindopaminergic, noradrenergic, and serotonergic neurons [ 181 and the capillary endothelium [4]-are
known to contain dopa decarboxylase, and each
could theoretically represent a site for dopamine
formation from exogenous dopa in the parkinsonian
Surviving Nigrostriutal Doparninergic Neurons
The nigrostriatal projection ramifies within the
striatum to form a dense network of dopaminecontaining nerve endings. Clinical [ 3 ] and experimental [ l ] data indicate that when the nigrostriatal system is partially destroyed, the remaining
dopaminergic neurons become hyperactive, fire
more rapidly, and synthesize and release more
dopamine than do controls. In animals with nigrostriatal lesions of increasing severity, we found
heightened dopamine synthesis and release by surviving neurons when 60 to 70% or more of the system had been destroyed [17]. This mechanism may
compensate for loss of the other neurons and may
account for the emergence of clinical manifestations
of parkinsonism only after an extreme reduction in
the number of dopaminergic terminals [31. O n that
basis it was suggested [20] that the residual hyperactive dopaminergic neurons (which contain dopa decarboxylase) represent the major striatal site of dopa
decarboxylation in parkinsonism and that they can
convert exogenous dopa to dopamine in sufficient
amounts to alleviate the, clinical symptoms in these
patients. Proof is largely lacking, however, and many
available lines of evidence fail to favor this hypothesis.
Exogenous L-dopa can increase striatal dopamine
concentrations even after nearly total destruction of
the nigrostriatal system, and it is also converted to
dopamine in brain regions that do not receive
dopaminergic projections [22, 24, 411. There is no
evidence that surviving hyperactive dopaminergic
neurons are indeed capable of converting more exogenous dopa to dopamine than are normal, quiescent neurons. In fact, exogenous dopa itself has been
shown to decrease firing rates of nigrostriatal
dopaminergic neurons [6]. In parkinsonian patients
given L-dopa, such inhibition may even counteract
and abolish the increases in dopamine turnover in
dopaminergic neurons that survive the nigrostriatal
degeneration. Furthermore, when L-dopa was administered to rats in combination with neuroleptic
drugs (haloperidol and chlorpromazine) that enhance
firing rates of dopaminergic neurons as well as
dopamine synthesis and release from terminals by
blocking dopamine receptors [7], striatal dopamine
concentrations did not increase beyond those observed after dopa alone (Hefti et al, unpublished observations, 1980).
These findings suggest that formation of dopamine
from exogenous dopa by dopaminergic neurons is
not necessarily enhanced when these neurons become hyperactive. If dopa increases striatal dopamine
levels by being decarboxylated exclusively or mainly
in surviving dopaminergic terminals, a negative correlation would be expected between the severity of
parkinsonism and the therapeutic response to the
drug. However, L-dopa's initial efficacy is not diminished in many patients, even in the most advanced stages of the disease [2, 31, or in those with
postencephalitic parkinsonism [9, 121, in whom the
numbers of residual dopaminergic terminals are extremely reduced.
It has been theorized that the gradual decline in
the efficacy of long-term dopa therapy is due to progressive degeneration of striatal dopaminergic terminals, which proceeds to a point at which the
administered dopa can no longer be adequately converted to dopamine. However, such a mechanism is
probably not responsible, as Fahn and co-workers
Hypothesis: Melamed
al: Dopa Metabolism in Parkinsonism
12 31 recently concluded that the deteriorating response to dopa is linked not to the duration of parkinsonism, but to that of dopa therapy. For all these
reasons it is unlikely that the residual dopaminergic
terminals represent the only or major site of dopa’s
conversion to dopamine in the parkinsonian striatum.
Serotonergic Neurons
The mammalian striatum receives a serotonergic
projection from the midbrain raphe nuclei and its
terminals contain the decarboxylating enzyme, which
is not substrate specific for dopa and also converts
5-hydroxytryptophan to serotonin [ 181. In vitro
studies have shown that exogenous dopa can be taken
up and decarboxylated in serotonergic terminals [36].
It was also suggested that decreases in brain serotonin concentrations after large doses of dopa are due
to displacement of serotonin from serotonergic nerve
endings by the formed dopamine [14].It was therefore hypothesized [36]that in parkinsonism, the administered dopa can be decarboxylated in striatal
serotonergic terminals, and that the formed dopamine could be released as a “false neurotransmitter” and reach and act upon postsynaptic dopaminergic receptors.
If serotonergic terminals mediate the effects of
L-dopa in parkinsonism, the increases in striatal
dopamine formation from exogenous dopa after degeneration of dopaminergic neurons should be
abolished or reduced after additional destruction of
the serotonergic projection to the striatum. However, we have recently shown [34] that in rats with
destruction of striatal dopaminergic neurons, the increases in striatal release of dopamine after dopa administration were not prevented by additional destruction of the raphe-striatal serotonergic pathway.
Also, dopa-induced contraversive circling behavior in
rats with unilateral nigrostiiatal lesions, which is apparently mediated by dopamine synthesized from
dopa in the lesioned striatum [45],was not reduced
in animals with combined raphe-striatal lesions. In
addition, we found thac selective destruction of
serotonergic terminals in the striatum failed to reduce striatal dopa decarboxylase, indicating that
these neurons contribute little to the total decarboxylating capacity of the striatum [34]. These
findings suggest that striatal serotonergic terminals
do not represent an important locus for dopa decarboxylation in parkinsonism.
Striatal Capillaries
Endothelial cells of cerebral microvessels contain
dopa decarboxylase activity [4].It was suggested [45,
461 that the clinical and behavioral effects of dopa
and the dopa-induced increases in striatal dopamine
levels after loss of dopaminergic terminals [22, 24,
411 may derive from its decarboxylation in capillaries. However, capillary decarboxylase is largely localized outside the blood-brain barrier [38].In fact,
the enzyme contained in cerebral microvessels constitutes part of the blood-brain barrier and acts as an
enzymatic trapping mechanism, preventing some of
the circulating dopa from penetrating into brain by
converting it to dopamine, which is then rapidly
metabolized in the endothelial cells by monoaminedegrading enzymes [4]. Furthermore, systemically
administered dopamine cannot pass through the
capillary endothelium into brain parenchyma [37].
For all these reasons, it is unlikely that the
dopamine formed from dopa in microvessels is able
to reach striatal dopaminergic receptors and to become functionally important in parkinsonism. In rats
with severe nigrostriatal lesions, we found that increases in dopamine levels in lesioned striata after
dopa administration were reduced, but not prevented, if animals were also given carbidopa (a peripheral decarboxylase inhibitor) to inhibit the
enzyme in the microvessels (Melamed et al, unpublished observations, 1980). Despite blockade of dopa
decarboxylase in striatal capillaries, carbidopa potentiates both dopa’s efficacy in parkinsonism [26, 471
and dopa-induced circling behavior in rats with unilateral nigrostriatal lesions [ 131. All these findings
suggest that, after the degeneration of dopaminergic
terminals, dopa decarboxylation in the striatum proceeds despite inhibition of the enzyme in capillaries
and that such fraction of formed dopamine can be
available to dopaminergic receptors.
Noradrenergic Neurons
Noradrenergic neurons contain dopa decarboxylase,
which is required for norepinephrine synthesis. Although noradrenergic neurons are widely distributed
in brain, the corpus striatum contains only a few, if
any, noradrenergic terminals [44]. Therefore this
system is an unlikely candidate for striatal decarboxylation of administered dopa.
Nonenzymutic Decurboxylation of Exogenous L-DOPU
It was also suggested that decarboxylation of exogenous dopa in brain may not necessarily be enzymatic
[42]. However, this possibility is ruled out by the
demonstration that when L-dopa is administered with
a drug that inhibits central decarboxylase, the dopainduced increases in brain dopamine levels are completely abolished [6].
Nonaminergic Striatal Interneurons and
Efferent Neurons-A Possible Site for Dopa
Decarboxylation in Parkinsonism
In rats, despite near-total destruction of dopaminergic terminals, the decreases in striatal dopa decar-
560 Annals of Neurology Vol 8 No 6 December 1980
boxylase activity are relatively less severe (by approximately 80%) [34]. Likewise, in parkinsonian
striata-even in the most advanced cases-the enzyme is low but still present [ 2 4 , 2 5 ] .Taken together
with data described in the previous section, these
findings indicate that another striatal compartment,
in addition to dopaminergic and serotonergic terminals and capillaries, also contains dopa decarboxylase.
The residual enzymatic activity in parkinsonism
could theoretically be localized in striatal systems
such as interneurons, efferents, afferent nerve endings (besides the dopaminergic and serotonergic),
and glial cells (Fig 2).
Recent studies in experimental animals provide
new information on compartmentation of the decarboxylating enzyme in mammalian striatum. Intrastriatal injections of the neurotoxin kainic acid selectively destroy neurons with cell bodies originating
within the striatum (interneurons and efferent neurons) but spare traversing axons and afferents, including the dopaminergic and serotonergic terminals
[31, 431. We have recently shown in the rat that intrastriatal injections of kainic acid reduce striatal
dopa decarboxylase activity by as much as 20% without damaging dopaminergic terminals [351. Furthermore, the increases in striatal dopamine levels after
systemic dopa administration were markedly smaller
in kainate-lesioned striata [35]. Since kainic acid lesions also induce marked glial proliferation in the
striatum [ S l , 431, the observed reduction in decarboxylase suggests that the glia probably do not contain a substantial amount of the enzyme.
Apparently, an important fraction of striatal decarboxylase is localized within perikarya and dendrites
of interneurons or efferents susceptible to kainic acid
destruction. Not all of these neurons are biochemically characterized, but some striatal interneurons are
known to utilize acetylcholine, GABA, and even enkephalins as their transmitters, and striatonigral efferents contain GABA or substance P (see [ 19, 321 and
Fig 1). This fraction of dopa decarboxylase may be
localized in one or more of these neuronal systems.
Further studies are needed to identify the precise
neuronal element (or elements) that contains the enzyme within this striatal compartment and to determine the functional importance of the presence of
dopa decarboxylase within neurons that probably d o
not normally synthesize monoamines.
The enzymatic conversion of administered L-dopa
to dopamine in Parkinson disease is made possible
because, fortunately, an adequate amount of dopa
decarboxylase remains in the striatum despite massive loss of dopaminergic terminals. In the intact
striatum, the relative fraction of dopa decarboxylase
localized in interneurons or efferents may be far
smaller than that in dopaminergic nerve endings
--- -- - _-/’
F i g 2. Decarboxylation of exogenous L-dopa in nonaminergic
striatal iwterneuron.r or efferent neurons containing dopa decarboxylase (DDC). Alternative A : dopamine (DA) molecules
formed in such neurons may leak out, diffuse oter short distances, and activate postsynaptic dopaminergic receptors localized on other striatal interneurons or d$rents. Alternatioe
B: dopamine molecules formed from admini.rtered dopa in
decarboxylase-containing neurons may activate dopaminergir
receptors localized on the same neurons.
(probably 10 to 2 0 % of total striatal decarboxylase
activity). This situation may be reversed after degeneration of the nigrostriatal system, and in parkinsonism, interneurons may contain the major part
of residual striatal decarboxylase. We suggest that
decarboxylation of exogenous L-dopa in the parkinsonian striatum occurs, to a large extent, in
decarboxylase-containing nonaminergic interneurons
or efferent neurons. Since the dopamine molecules
synthesized from dopa in these neurons probably
cannot be stored in a vesicular form, they would leak
out, diffuse over short distances, become accessible
to and stimulate dopaminergic receptors, and thus
mediate the effects of systemically administered Ldopa.
At present, the precise topographical organization
of dopaminergic synapses and of the postsynaptic
dopaminergic receptors in the striatum is unknown.
Although it has been speculated that striatal
dopaminergic terminals make synaptic contacts on
cholinergic neurons [ 3 2 ] , such synapses may also
occur on other interneurons, on efferent neurons, or
on both sites. There is evidence that postsynaptic
dopaminergic receptors are localized on interneurons
and efferents in the striatum, since intrastriatal injections of kainic acid greatly decrease the number of
such receptor sites in experimental animals [ 161.
Taken together with our findings, these data indicate that both dopa decarboxylase and postsynaptic
dopaminergic receptors are localized in kainic acidsusceptible striatal interneurons and efferents. Since
Hypothesis: Melamed et al: Dopa Metabolism in Parkinsonism
it is still undetermined which of these striatal neuronal constituents contain the dopaminergic receptors and the decarboxylating enzyme, two possibilities should be considered (see Fig 2). First,
dopamine molecules, formed from exogenous dopa
in as yet biochemically unidentified striatal interneurons or efferents, could reach and activate dopaminergic receptors localized on other such neurons
which do not contain decarboxylase. An interesting alternative is that one or more of these neuronal
elements could contain both dopa decarboxylase
activity and postsynaptic dopaminergic receptors. Therefore, a given interneuron (or efferent)
might be able to both form dopamine from exogenous dopa and, via dopaminergic receptors localized
on the same neuron, respond physiologically to the
released dopamine (see Fig 2).
Such mechanisms might participate in producing
L-dopa’s therapeutic efficacy and also the side effects
associated with its chronic administration. For instance, one of the major problems emerging during
long-term dopa therapy is a declining responsiveness to the drug [15, 21, 231. This phenomenon is
probably not due to continuous degeneration of
dopaminergic neurons [2 31. There is evidence that
other neuronal systems besides the nigrostriatal
tracts, including striatal interneurons and efferents,
may also degenerate in Parkinson disease [40].Reductions in glutamic acid decarboxylase, choline
acetyltransferase, and acetylcholinesterase activities
have been demonstrated in parkinsonian striata, indicating possible loss of GABAergic and cholinergic
neurons [30, 33, 39,401. Consequently, gradual decreases in dopa’s therapeutic potency may be due, in
part, to progressive disappearance of postsynaptic
dopaminergic receptors localized on target neurons
for nigrostriatal terminals [39].However, degeneration of decarboxylase-containing striatal interneurons
(or efferents), with resultant decreases in the fraction
of enzymatic activity that is crucial for adequate decarboxylation of exogenous dopa in these patients,
could represent an equally important mechanism.
Further characterization of dopamine synthesis from
L-dopa within nonaminergic striatal neurons may lead
to a better understanding of dopa’s mechanisms of
action and perhaps to the development of new therapeutic strategies for parkinsonism.
Supported in part by the National Institutes of Health and the
American Parkinson’s Disease Association.
1. Agid Y , Javoy F, Glowinski J: Hyperactivity of remaining
doparninergic neurons after partial destruction of the nigrostriatal dopaminergic system in the rat. Nature 245:15&151,
Annals of Neurology
2. Barbeau A: L-DOPA therapy in Parkinson’s disease: a critical
review of nine years’ experience. Can Med Assoc J 101:791800, 1969
3. Bernheimer H, Birkmayer W, Hornykiewicz 0, et al: Brain
dopamine and syndromes of Parkinson and Huntington: clinical, morphological and neurochemical correlations. J Neurol
Sci 20:415-455, 1973
4. Bertler A, Falck B, Owman C, et al: The localization of
monoaminergic blood-brain barrier mechanisms. Pharmacol
Rev 18:369-385, 1966
5. Birkmayer W, Hornykiewicz 0: Der L-Dioxyphenylalanin
(=L-DOPA)-effekt bei der Parkinson-Akinese. Wien Klin
Wochenschr 73:787-788, 1961
6. Bunney BS, Aghajanian GK, Roth RH: L-DOPA, amphetamine and apomorphine: comparison of effects on the
firing rate of rat dopaminergic neurons. Nature 245:123-125,
7. Bunney BS, Walters JR, Roth RH, et al: Dopaminergic neurons: effect of antipsychotic drugs and amphetamine on single
cell activity. J Pharmacol Exp Ther 185:560-571, 1973
8. Calne DB: Developments in the pharmacology and therapeutics of parkinsonism. Ann Neurol 1:111-119, 1977
9. Calne DB, Stern GM, Laurence DR, et al: I--DOPA in postencephalitic parkinsonism. Lancet 1:744-747, 1969
10. Cotzias GC, Papavisiliou PS, Gellene R: Modification of parkinsonism. Chronic treatment with L-DOPA. N E n d J Med
280~337-345, 1969
11. Dairman W, Christenson J, Udenfriend S: Characterization of
DOPA decarboxylase. In Usdin E, Snyder S (eds): Frontiers in
Catecholamine Research. New York, Pergarnon, 1973, pp
12. Duvoisin RC, Lob-Antunes J, Yahr MD: Response of patients with postencephalitic parkinsonism to levodopa. J
Neurol Neurosurg Psychiatry 35:487-495, 1972
13 Duvoisin RC, Mytilineou C: Where is L-DOPA decarboxylated in the striatum after 6-hydroxydopamine nigrotomy?
Brain Res 152:369-373, 1978
14. Everett GM, Borcherding JW:
L-DOPA: effect on concentration of doparnine, norepinephrine and serotonin in brains of
mice. Science 168:849-850, 1970
15. Fahn S, Calne DB: Considerations in the management of parkinsonism. Neurology 28:5-7, 1978
16. Fields JZ, Reisine TD, Yamamura HI: Loss of striatal
dopaminergic receptors after intrastriatal kainic acid injection.
Life Sci 23;569-574, 1978
17 Hefti F, Melamed E, Wurtman RJ: Partial lesions of the
dopaminergic nigrostriatal system in rat brain: biochemical
characterization. Brain Res 195: 123-127, 1980
18. Hokfelt T, Fuxe K, Goldstein M Immunohistochemical localization of aromatic L-amino acid decarboxylase (dopa decarboxylase) in central dopamine and 5-hydroxytryptamine
nerve cell bodies in the rat brain. Brain Res 53:175-180,
19. Hong JS, Yang HYT, Costa E: On the localization of
methionine enkephdin neurons in rat striatum. Neuropharmacology 16:451-453, 1977
20 Hornykiewicz 0: The mechanisms of action of L-DOPA in
Parkinson’s disease. Life Sci 15:1249-1259, 1974
21 Hunter KR, Shaw KM, Laurence DR, et al: Sustained
levcdopa therapy in parkinsonism. Lancet 2:929-931, 1973
22. Langelier P, Roberge AG, Boucher R, et al: Effects of
chronically administered L-DOPA in normal and lesioned
cats. J Pharmacol Exp Ther 187:15-26, 1973
23. Lesser RP, Fahn S, Snider SR, et al: Analysis of the clinical
problems in parkinsonism and the complications of long-term
levodopa therapy. Neurology 29:1253-1260, 1979
24. Lloyd KG, Davidson L, Hornykiewicz 0:The neurochemistry
Vol 8 No 6 December 1980
of Parkinson's disease: effect of L-DOPA therapy. J Phar-
3 1.
macol Exp Ther 195:453-464, 1975
Lloyd KG, Hornykiewicz 0: Parkinson's disease: activity of
L-DOPA decarboxylase in discrete brain regions. Science
170:12 12-1213, 1970
Mars H: Modification of levodopa effect by systemic decarboxylase inhibition. Arch Neurol 28:91-95, 1973
Marsden CD, Parkes JD: Success and problems of long-term
levodopa therapy in Parkinson's disease. Lancet 1:345-349,
McDowell FH, Sweet RD: The "on-off" phenomenon. In
Birkmayer W, Hornykiewicz 0 (eds): Advances in Parkinsonism. Basel, Editiones Roche, 1976, pp 603-612
McGeer EG, Fibiger HC, McGeer PL, et al: Temporal
changes in amine synthesizing enzymes of rat extrapyramidal
structures after hemitransections or 6-OH-DA administration. Brain Res 523289-300, 1973
McGeer PL, McGeer EG: Cholinergic enzyme systems in
Parkinson's disease. Arch Neurol 25:265-268, 197 1
McGeer PL, McGeer EG: Duplication of biochemical changes
of Huntington's chorea by intrastriatal injections of glutamic
and kainic acids. Nature 263:517-519, 1976
McGeer PL, McGeer EG, Hattori T: Transmitters in the basal
ganglia. In Fonnum F (ed): Amino Acids as Chemical Transmitters. New York, Plenum, 1978, pp 123-141
McGeer PL, McGeer EG, Wada JA: Glutamic acid decarboxylase in Parkinson's disease and epilepsy. Neurology
(Minneap) 2 1:1000- 1007, 197 1
Melamed E, Hefti F, Liebman J, et al: Serotonergic neurons
are not involved in action of L-DOPA in parkinson's disease.
Nature 283:772-774, 1980
Melamed E, Hefti F, Wurtman RJ: Diminished decarboxylation of L-DOPA in rat striaturn after intrastriatal injections of
kainic acid. Neuropharmacology 19:409-411, 1980
Ng LKY, Chase TN, Colburn RW, et al: L-DOPA in parkinsonism: a possible mechanism of action. Neurology 22:688696, 1972
37. Oldendorf WH: Brain uptake of radiolabeled amino acids,
amines and hexoses after arterial injection. Am J Physiol
221: 1629-1639, 1971
38. Pardridge WM: Regulation of amino acid availability to the
brain. In Wunman RJ, Wurtman JJ (eds): Nutrition and the
Brain. New York, Plenum, 1977, vol 1, pp 141-203
39. Reisine TD, Fields JZ, Yamaniura HI: Neurotransmitter receptor alterations in Parkinson's disease. Life Sci 21:335-344,
40. Rinne U K Recent advances in research on parkinsonism.
Acta Neurol Scand 57:suppl 67:77-113, 1978
41. Rmne UK, Sonninen V, Hyyppa M: Effect of L-DOPA on
brain monomines and their metabolites in Parkinson's disease. fife Sci 10:549-557, 1971
42. Sandler M: How does L-DOPA work in parkinsonism? Lancet
11784-785, 1971
43. Schwarcz R, Coyle JT: Striatal lesions with kainic acid:
neurochemical characteristics. Brain Res 127:235-249, 1977
44. Swanson LW, Harunan BK: The central adrenergic system.
An immunofluorescence smdy of the location of cell bodies
and their efferent connections in the rat utilizing dopaminebeta-hydroxylase as a marker. J Comp Neurol 163:467-505,
45. Ungerstedt U: Postsynaptic supersensitivity aftcr 6-hydroxydopamine induced degeneration of the nigrostriatal
dopamine system. Acta Physiol Scand [Suppl] 367:69-93,
197 1
46. Vogt M: Drug-induced changes in brain dopamine and their
relation to parkinsonism. Sci Basis Med Annu Rev 16:276291, 1970
47. Yahr MD, Duvoisin RC, Mendoza MR, et al: Modification of
L-dopa therapy of parkinsonism by alpha-methyldopa hydrazine (MK-486). Trans Am Neurol Assoc 96:55-58,
48. Yahr MD, Duvoisin RC, Shear MJ: Treatment of parkinsonism with levodopa. Arch Neurol 2 1:343-354,
Hypothesis: Melamed et al: Dopa Metabolism in Parkinsonism
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