- Email: [email protected]
The effect of L-3, 4-dihydroxyphenylalanine and DL-5- -hydroxytryptophan on rigidity and tremor induced by reserpine, chlorpromazine and phenoxybenzamine
Life Sciences Vol . 3, pp. 351-380, 1984. Pergamon Press, Inc. Printed in the United States.
THE EFFECT OF L-3, 4-DIHYD,ROXYPHENYLALANINE AND DL-5-HYDROXYTRYPTOPHAN ON RIGIDITY AND TREMOR INDUCED BY RESERPINE, CHLORPROMAZINE AND PHENOXYBENZAMINE Björn-Erik Rooa and Göran Steg Departments of Pharmacology and Physiology University of Göteborg, Sweden (Received 12 March 1964) A syndrome of akinesia, rigidity and tremor can be induced in rats after administration of reserpinel' 2 . A technique giving access to the activity of single efferent axons and motor units without interfering with the induced motor phenomena was developed for an analysis of the muscle control in the reserpine syndrome 2 .
A decrease of y -fibre activity
and an increase of a-fibre activity was demonstrated simultaneously with the appearance of the motor phenomena after reserpine injection .
The
result showed that the a-moto-neurone hyperactivity of reserpine rigidity is not secondary to a hyperactivity of y -motor axons,
These motor fibres
serve as regulators of muscle spindle sensitivity and influence the a-moto neurones via the stretch reflex .
The spontaneous muscle contraction main-
taining the flexion posture of the rigid animal was shown to be due to a tonic activity of slowly contracting motor units2.
Using the same technique
we have extended the analysis to the motor disturbances caused by chlorpromazine and phenoxybenzamine and further studied the action of L-3, 4-dihydroxyphenylalanine (L-DOPA), DL-5-hydroxytryptophan (5-HTP), dopamine and 5-hydroxytryptamine (5-HT) on the drug induced condition . The distribution of the monoamines in the brain seems to be 351
352
L-DOPA AND 5-ATP ON RESERPINE RIGmITY
almost the same in all mammals3 , the brain stem, noradrenaline,
Vol. 3, No. 4
Noradrenaline is localized mainly to
The distribution of dopamine is not the same as that of The highest concentration$ are found in the corpus striatum
and only relatively small amounts in other brain atructures 3 ,
5-HT is
found in high concentrations in the hypothalamus, thalamus, caudate nucleus, putamen and the dorsal part of the medulla oblongata containing the floor of 4th ventricle4' 5, 6, 7 The inhibitory effect of reserpine on monoaminergic transmission mechanisms seems to depend on the blocking action of the drug on the function These of granules in the nerve terminal s granules serve as stores for monoamines and it is supposed that the amines must be taken up in the store to be able to fulfill their function as transmitters 9 .
After
administration of reserpine the levels of monoaminea in the brain decrease while the levels of acid monoamine metabolites increase 10,11,12,13 While reserpine appears to exert a presynaptic blocking action on the monoaminergic transmission, chlorpromazine is generally believed to act as a receptor blocking agent with effect on several receptors .
Phenoxybenzamine
on the other hand is known as a rather specific a-adrenergic receptor blocking agent, Methods The rigidity and tremor induced by reserpine, chlorpromazine and phenoxybenzamine is demonstrated in the calf muscle electromyogram (emg) shown in the figures at rest and at muscle stretch by dorsiflexion of the foot.
The spontaneous and reflex activity of single motor axons was
recorded in the fine coccygeal ventral roots of laminectomized rats which were kept at a superficial level of nitrous oxide anaesthesia, not interfering with the rigidity and tremor, The action potentials were identified by their conduction velocity indicated by the conduction time between two pairs of recording electrodes attached to the ventral root 5-10 mm apart,
Each
Vol. 9, No . 4
L-DOPA AND 5-HTP ON RESERPINE RIGmITY
353
electrode pair was connected to one beam of a dual beam oscilloscope . As seen in the figures, the fast big amplitude a-fibre potentials have a short time lag, and the slow small y -potentials a long time lag between the proximal (upper beam) and the distal (lower beam) electrode pairs . The reflex recorded in the ventral root on dorsal root stimulation
s final
reflex) consisted of one early mono- and polysynaptic a-component and one late polysynaptic y -component 2 . All drugs were injected intravenously through a polyethylene catheter inserted into the lateral tail vein. Re salts In the untreated animals there was a spontaneous activity of the y -efferents (Fig . 1-5) . Caihol
The a-efferents were inactive at rest and respond~ranpirw 7o+~qkq bd lof L D~OP~~ OOn~q/lqbrf +O~n
afhr L-0OF14 ~N
~ff
10~u~o ~M~
_,
na IOOiwo
FIG . 1
Reserpine increased the a- and decreased the y -component of the reflex response to dorsal root stimulation s final reflex), abolished the spontaneous y -activity of , and induce rigs ity L-DOPA reversed all these changes or a period of approx, h; hour after which the animal returned to its previous reserpiaized state.
S54
L-DOPA AND 5-HTP ON RESERPINE RIGIDITY
Vol. 3, No. 4
ed only in short bursts when the animal was stimulated by puffs of air blown on the snout and head ( Tact, stim, , Fig . 3) .
The reflex response
to dorsal root stimulation contained a few or no single a-potentials and several y -fibre potentials (Fig . 1, 3, 4, 5),
The electromyogram
em
was
silent at rest and only showed a weak response at dorsiflexion of the foot stretch
(Fig, 1, 4 and 5) . After injection of reaerpine (Fig. 1, 4 and 5), chlorpromazine
(Fig, 2) and phenoxybenzamine (Fig . 3) the carra
ufta ehlorprom~inn Inj~olion
100 nnsc
IOOw~e
FIG 2 of Appearance rigidity and' disappearance of spontaneous y -activity after injection of 10 mg~kg chlorpromazine . was strongly reduced
of .
FIG 3 and a-efferent discharge bey fore and after injection of ?5 ~~kg phenoxybenzamine .
The threshold for activation of the a-efferenta
by tactile stimuli was lowered (Fig, 3), -efferent discharge appeared (Fig. 4) .
Sometimes a spontaneous aThe a-component of the spinal
reflex response to dorsal root stimulation was enhanced whereas the y -component was strongly reduced (Fig . 1, 3, 4, 5)',
Simultaneously a spon-
taneous electromyographic activity was recorded in the calf muscles (em at rest (Fig, 1, 4, 5),
Rigidity and tremor was palpated at doraiflexion of
Vol. 3, No. 4 the foot.
L-DOPA AND 5-ATP ON RESER.PINE ßIGiDITY
355
It was demonstrated as an increased and sometimes synchron-
ized electromyographic activity (stretc h) (Fig . 1-5) . 4Smin afterr Lv. injation of raurpi~ 3Ânq~kq brrf
coeMrol
lomin oftx W. Mfudon tS-F{TP 20omq/kq bnt
aff .r ~~ 5-HTPlrdudan
FIG. 4 Reserpine and 5-HTP effects on y - and a-efferents . CoMrol
26mb afNr lr In~bn afUr tnhwlon of dapo- afhr vpYaW :otlon of nwrpY» Tnp/kq brf ~M 20nglkp bA
~ff
IOOnwe
FIG, 5 The changea of y - and a-efferent activity after injection of reserpine and dopamine and after spinalization .
358
L-DOPA AND 5-HTP ON RESERPINE RIGmITY
Vol . 3, No. 4
Injection of L-DOPA reversed the reserpine effect (Fig . 1), spontaneous y -activity reappeared,
The
The reflex activation of the a-moto-
neurones at dorsal root stimulation was reduced to its pre-reserpine level, The y -component of the reflex reappeared .
Rigidity and tremor disappeared,
A similar effect was seen after injection of 5-HTP (Fig, 4),
The L-DOPA
effect had vanished completely 40 minutes after the injection .
The
diminishing effect of 5-HTP 25 minutes after the injection is demonstrated by the reappearing rigidity and spontaneous a-efferent discharge and by the decreasing y -activity, Dopamine did not change the state induced by reserpine (Fig, 5), After removal of aupraspinal influence by apinalization in the upper lumbar region the rigidity and tremor was abolished and the increased a-motoneurone excitability was lowered (Fig, 5),
5-HT did not have any
effect on the spinal reflex mechanisms but abolished rigidity, Discussion Chlorpromazine and phenoxybenzamine induced the same motor and physiologic phenomena as reserpine .
The rigidity was accompanied by
a suppression of y -fibre activity and an increase of a-motoneurone excit ability,
A cessation of y -efferent activity after chlorpromazine injection has also been found in the intercollicular decerebrate cat 14 . The observation that L-DOPA, the precursor of dopamine, reverses the changes induced by reserpine is in agreement with the earlier finding in mice and rabbits of a complete elimination of the reserpine effects after L-DOPA injection l5 ,
The postulated dependence of reserpine
rigidity on a selective increase of a-motoneurone excitability2 during y -inactivity is confirmed by the finding that the abolishment of reserpine rigidity after L-DOPA injection is always accompanied by a reappearance of spontaneous y -efferent activity and a reduction of a-motoneurone excitability to the pre-reserpine level,
Vol. 3, No. 4
L-DOPA AND 5-HTP ON RESERPINE RIGmITY
357
This finding also establishes a connection between the neurophysiological mechanisms of extrapyramidal motor phenomena and monoamine action. Although 5-HTP, the precursor of 5-HT, has earlier been found unable to antagonize the akinesia of reaerpine treated animals l5 , it abolished the rigidity and tremor and reversed the reaerpine induced changes in y - and a-motoneurone excitability .
Whereas the rigidity and tremor are
demonstrated electromyographically, the akineaia does not manifest itself with the present electrophyaiological technique . Dopamine and 5-HT, injected intravenously, do not penetrate the blood-brain-barrier and reach only peripheral synapses . did not influence the spinal stretch reflex mechanisms .
These substances Our findings thus
indicate that peripheral sites of reaerpine action are negligible for the generation of extrapyramidal motor phenomena.
At spinalization of a
reserpinized rat the a-motoneurone reflex excitability was reduced and the rigidity abolished, which indicated the dependence of the reaerpine motor syndrome on aupraepinal mechanisms . Reserpine has widespread effects in the organism.
The peri-
pheral and spinal sites of action have been excluded as responsible for the generation of rigidity .
Some of its clinical actions may be ascribed to
brain structures which are not essential for the generation of rigidity . Therefore a complete agreement between the parkinsonian syndrome and the reaerpine induced state can not be expected. It has been shown that a-methyl-DOPA increases both rigidity and tremor in parkinaonian patients l6, a-Methyl-DOPA was also found to cause parkinaonism in a patient who had developed parkinsonian signs previously on reaerpine treatment l ~ .
The observation is of particular interest because
it has been shown that a-methyl-DOPA inhibits the synthesis of amines in vivo la.
This is likely to depend on inhibition of the enzymes hydroxylating 12, 19 The level of dopamine tyrosine and tryptophan on the aromatic ring9'
358
L-DOPA AND 5-HTP ON RE3ERPINE RIGmITY
Vol . 3, No. 4
in corpus striatum of parkinaonian patients is strongly reduced20 .
Pre-
liminary results suggest that a corresponding decrease occurs in the level of the acid metabolite of this amine, i. e . 3, 4-dihydroxyphenylacetic acid (DOPAC) 21 .
This suggests that the synthesis of dopamine is impaired in
parking oniam . L-DOPA injection markedly diminishes the akinesia of parkinsonian patients 22 .
Oral administration of this drug to parkinsonian patients was reported to reduce akinesia and rigidityl6, 23~ whereas 5-HTP mainly reduced the tremor and only to a lesser degree the rigidity23 .
L-DOPA
administration to patients pre-treated with reaerpine counteracted its sedative and akinetic effects 24.
Monoamine oxidase inhibitors have been used
with some success in treatment of parkinaonian patients 25 and pre-treatment with monoamine oxidase inhibitors strongly accentuated and prolonged the effect of L-DOPA25 .
The demonstrated abolishment of reaerpine in-
duced motor symptoms in the rat after L-DOPA injection is in good agreement with these clinical findings . The presented evidence seems to indicate that the rigidity induced by reaerpine has an origin similar to the parkinsonian rigidity, namely an inhibited transmission in the monoaminergic synapses in some regions of the brain.
This supports the assumption that the mechanisms revealed in
the electrophyaiological analysis of reaerpine rigidity are the same as those of parkinsonian rigidity .
The research supported in this document has been sponsored by AIR FORCE OFFICE OF SCIENTIFIC RESEARCH, OAR through the European Office of Aerospace Research, United States Air Force (Grant No. AF EOAR 64-30), the Swedish State Medical Research Council and by the Medical Faculty, University of Göteborg . For technical assistance we are indebted to Mias Ann-Christine Johnson . For generous gifts of drugs we want to thank the LEO Ltd, Hälaingborg, Sweden (chlorpromazine and phenoxybenzamine) and the Swedish Ciba, Stockholm, Sweden (reaerpine) . References 1,
P. GLOW, J . Neurol . NeurosurQ . Psychiat. T~, 11-32 (195 9)
Vol . 3, No. 4
L-DOPA AND 5-HTP ON RESERPINE RIGmITY
359
2.
G. STEG, Acta physiol. stand. 61, Suppl . 225 (1964)
3.
.~. BERTLER and E . ROSENGR.EN, Acta physiol. stand . 47, 350-361 (1959)
4.
fir. BERTLER, Acta physiol. scared, 51, 97-107 (1961)
5.
D, F . BOGDANSKI, H. WEISSBACH and S. UDENFRIEND, J . Neurochem, 1, 272-278 (1957)
6.
A. H. AMIN, T . B . B, CRAWFORD and J . H. GADDUM, J . Physiol . 126, 596-618 (1954)
7,
M . K. PAASONEN and M. VOGT, J . Physiol . 131, 617-626 (1956)
8.
.8r . BERTLER, Acta physiol, stand, 51, 75-83 (1961)
9.
A. CARLSSON, Symposium on "Binding Sites of Brain Biogenic Amines" held at Galesburg, Illinois, March 1963 ; to be published in Progress in Brain Research .
10 .
B. -E . RODS and B . WERDINIUS, Life Sciences 1 105-107 (1962)
11,
N. -E, ANDÉN, B. -E . RODS and B. WERDINIUS, Life Sciences 2, 319-325 (1963)
12,
B, -E . R00 .S, N. -E . ANDEN and B, WERDINIUS, Int . J . Neuropharmacol . (1964) . In press,
13 .
N. -E, ANDEN, B. -E . ROOS and B, WERDINIUS, Life Sciences 3, (1964) . In press .
14,
H. D, HENATSCH and D. INGVAR, Arch. Psychiat . Nervenkr . 1Q5, 77=93 (1956)
15.
A, CARLSSON, M . LINDQVIST and T . MAGNUSSON, Nature 180, 1200 (1957)
16 .
A. BARBEAU, T, L. SOURKES and G, F, MURPHY, In "Symposium Bel-Air, Monoamines et systéme nerveux central" (1961) PP" 247-262
17 .
B . M, GRODEN, Brit. Med . J.
1, 1001 (1963)
18 .
S. E. SMITH, Brit, J . Pharmacol. 15, 319-327 ( 196 0)
360
L-DOPA AND 5-HTP ON RESERPINE RIGmITY
Vol. 3, No. 4
1q.
B .-E . ROOS and B . WERDINIUS, Life Sciences . 2, q2-96 (1963)
20.
H. EHRINGER and O. HORNYKIEWICZ, ~ Klin: ~Vlrachr . 38 ; 1236-123q (1g60)
21 .
B . -E . RODS and E . ROSENGREN, Unpubl, o~serv.
22 .
W . BIRKMAYER and O. HORNYKIEWICZ, Wien.klin. Wachr . 73, 787-788 (1g61)
23 .
A. BARREAU, Canad . Med . Ass. J . 87, 802-807 (1962)
24.
R. DECKWITZ, R. FROWEIN, C. KULENKAMPFF and U . MORS, Klin. Wachr. 38, T20-123 (1960)
25 .
W . BIRKMAYER and O. HORNYKIEWICZ, Arch. Psychiat . Nervenkr . 203, 560-574 (1962)
THE EFFECT OF L-3, 4-DIHYD,ROXYPHENYLALANINE AND DL-5-HYDROXYTRYPTOPHAN ON RIGIDITY AND TREMOR INDUCED BY RESERPINE, CHLORPROMAZINE AND PHENOXYBENZAMINE Björn-Erik Rooa and Göran Steg Departments of Pharmacology and Physiology University of Göteborg, Sweden (Received 12 March 1964) A syndrome of akinesia, rigidity and tremor can be induced in rats after administration of reserpinel' 2 . A technique giving access to the activity of single efferent axons and motor units without interfering with the induced motor phenomena was developed for an analysis of the muscle control in the reserpine syndrome 2 .
A decrease of y -fibre activity
and an increase of a-fibre activity was demonstrated simultaneously with the appearance of the motor phenomena after reserpine injection .
The
result showed that the a-moto-neurone hyperactivity of reserpine rigidity is not secondary to a hyperactivity of y -motor axons,
These motor fibres
serve as regulators of muscle spindle sensitivity and influence the a-moto neurones via the stretch reflex .
The spontaneous muscle contraction main-
taining the flexion posture of the rigid animal was shown to be due to a tonic activity of slowly contracting motor units2.
Using the same technique
we have extended the analysis to the motor disturbances caused by chlorpromazine and phenoxybenzamine and further studied the action of L-3, 4-dihydroxyphenylalanine (L-DOPA), DL-5-hydroxytryptophan (5-HTP), dopamine and 5-hydroxytryptamine (5-HT) on the drug induced condition . The distribution of the monoamines in the brain seems to be 351
352
L-DOPA AND 5-ATP ON RESERPINE RIGmITY
almost the same in all mammals3 , the brain stem, noradrenaline,
Vol. 3, No. 4
Noradrenaline is localized mainly to
The distribution of dopamine is not the same as that of The highest concentration$ are found in the corpus striatum
and only relatively small amounts in other brain atructures 3 ,
5-HT is
found in high concentrations in the hypothalamus, thalamus, caudate nucleus, putamen and the dorsal part of the medulla oblongata containing the floor of 4th ventricle4' 5, 6, 7 The inhibitory effect of reserpine on monoaminergic transmission mechanisms seems to depend on the blocking action of the drug on the function These of granules in the nerve terminal s granules serve as stores for monoamines and it is supposed that the amines must be taken up in the store to be able to fulfill their function as transmitters 9 .
After
administration of reserpine the levels of monoaminea in the brain decrease while the levels of acid monoamine metabolites increase 10,11,12,13 While reserpine appears to exert a presynaptic blocking action on the monoaminergic transmission, chlorpromazine is generally believed to act as a receptor blocking agent with effect on several receptors .
Phenoxybenzamine
on the other hand is known as a rather specific a-adrenergic receptor blocking agent, Methods The rigidity and tremor induced by reserpine, chlorpromazine and phenoxybenzamine is demonstrated in the calf muscle electromyogram (emg) shown in the figures at rest and at muscle stretch by dorsiflexion of the foot.
The spontaneous and reflex activity of single motor axons was
recorded in the fine coccygeal ventral roots of laminectomized rats which were kept at a superficial level of nitrous oxide anaesthesia, not interfering with the rigidity and tremor, The action potentials were identified by their conduction velocity indicated by the conduction time between two pairs of recording electrodes attached to the ventral root 5-10 mm apart,
Each
Vol. 9, No . 4
L-DOPA AND 5-HTP ON RESERPINE RIGmITY
353
electrode pair was connected to one beam of a dual beam oscilloscope . As seen in the figures, the fast big amplitude a-fibre potentials have a short time lag, and the slow small y -potentials a long time lag between the proximal (upper beam) and the distal (lower beam) electrode pairs . The reflex recorded in the ventral root on dorsal root stimulation
s final
reflex) consisted of one early mono- and polysynaptic a-component and one late polysynaptic y -component 2 . All drugs were injected intravenously through a polyethylene catheter inserted into the lateral tail vein. Re salts In the untreated animals there was a spontaneous activity of the y -efferents (Fig . 1-5) . Caihol
The a-efferents were inactive at rest and respond~ranpirw 7o+~qkq bd lof L D~OP~~ OOn~q/lqbrf +O~n
afhr L-0OF14 ~N
~ff
10~u~o ~M~
_,
na IOOiwo
FIG . 1
Reserpine increased the a- and decreased the y -component of the reflex response to dorsal root stimulation s final reflex), abolished the spontaneous y -activity of , and induce rigs ity L-DOPA reversed all these changes or a period of approx, h; hour after which the animal returned to its previous reserpiaized state.
S54
L-DOPA AND 5-HTP ON RESERPINE RIGIDITY
Vol. 3, No. 4
ed only in short bursts when the animal was stimulated by puffs of air blown on the snout and head ( Tact, stim, , Fig . 3) .
The reflex response
to dorsal root stimulation contained a few or no single a-potentials and several y -fibre potentials (Fig . 1, 3, 4, 5),
The electromyogram
em
was
silent at rest and only showed a weak response at dorsiflexion of the foot stretch
(Fig, 1, 4 and 5) . After injection of reaerpine (Fig. 1, 4 and 5), chlorpromazine
(Fig, 2) and phenoxybenzamine (Fig . 3) the carra
ufta ehlorprom~inn Inj~olion
100 nnsc
IOOw~e
FIG 2 of Appearance rigidity and' disappearance of spontaneous y -activity after injection of 10 mg~kg chlorpromazine . was strongly reduced
of .
FIG 3 and a-efferent discharge bey fore and after injection of ?5 ~~kg phenoxybenzamine .
The threshold for activation of the a-efferenta
by tactile stimuli was lowered (Fig, 3), -efferent discharge appeared (Fig. 4) .
Sometimes a spontaneous aThe a-component of the spinal
reflex response to dorsal root stimulation was enhanced whereas the y -component was strongly reduced (Fig . 1, 3, 4, 5)',
Simultaneously a spon-
taneous electromyographic activity was recorded in the calf muscles (em at rest (Fig, 1, 4, 5),
Rigidity and tremor was palpated at doraiflexion of
Vol. 3, No. 4 the foot.
L-DOPA AND 5-ATP ON RESER.PINE ßIGiDITY
355
It was demonstrated as an increased and sometimes synchron-
ized electromyographic activity (stretc h) (Fig . 1-5) . 4Smin afterr Lv. injation of raurpi~ 3Ânq~kq brrf
coeMrol
lomin oftx W. Mfudon tS-F{TP 20omq/kq bnt
aff .r ~~ 5-HTPlrdudan
FIG. 4 Reserpine and 5-HTP effects on y - and a-efferents . CoMrol
26mb afNr lr In~bn afUr tnhwlon of dapo- afhr vpYaW :otlon of nwrpY» Tnp/kq brf ~M 20nglkp bA
~ff
IOOnwe
FIG, 5 The changea of y - and a-efferent activity after injection of reserpine and dopamine and after spinalization .
358
L-DOPA AND 5-HTP ON RESERPINE RIGmITY
Vol . 3, No. 4
Injection of L-DOPA reversed the reserpine effect (Fig . 1), spontaneous y -activity reappeared,
The
The reflex activation of the a-moto-
neurones at dorsal root stimulation was reduced to its pre-reserpine level, The y -component of the reflex reappeared .
Rigidity and tremor disappeared,
A similar effect was seen after injection of 5-HTP (Fig, 4),
The L-DOPA
effect had vanished completely 40 minutes after the injection .
The
diminishing effect of 5-HTP 25 minutes after the injection is demonstrated by the reappearing rigidity and spontaneous a-efferent discharge and by the decreasing y -activity, Dopamine did not change the state induced by reserpine (Fig, 5), After removal of aupraspinal influence by apinalization in the upper lumbar region the rigidity and tremor was abolished and the increased a-motoneurone excitability was lowered (Fig, 5),
5-HT did not have any
effect on the spinal reflex mechanisms but abolished rigidity, Discussion Chlorpromazine and phenoxybenzamine induced the same motor and physiologic phenomena as reserpine .
The rigidity was accompanied by
a suppression of y -fibre activity and an increase of a-motoneurone excit ability,
A cessation of y -efferent activity after chlorpromazine injection has also been found in the intercollicular decerebrate cat 14 . The observation that L-DOPA, the precursor of dopamine, reverses the changes induced by reserpine is in agreement with the earlier finding in mice and rabbits of a complete elimination of the reserpine effects after L-DOPA injection l5 ,
The postulated dependence of reserpine
rigidity on a selective increase of a-motoneurone excitability2 during y -inactivity is confirmed by the finding that the abolishment of reserpine rigidity after L-DOPA injection is always accompanied by a reappearance of spontaneous y -efferent activity and a reduction of a-motoneurone excitability to the pre-reserpine level,
Vol. 3, No. 4
L-DOPA AND 5-HTP ON RESERPINE RIGmITY
357
This finding also establishes a connection between the neurophysiological mechanisms of extrapyramidal motor phenomena and monoamine action. Although 5-HTP, the precursor of 5-HT, has earlier been found unable to antagonize the akinesia of reaerpine treated animals l5 , it abolished the rigidity and tremor and reversed the reaerpine induced changes in y - and a-motoneurone excitability .
Whereas the rigidity and tremor are
demonstrated electromyographically, the akineaia does not manifest itself with the present electrophyaiological technique . Dopamine and 5-HT, injected intravenously, do not penetrate the blood-brain-barrier and reach only peripheral synapses . did not influence the spinal stretch reflex mechanisms .
These substances Our findings thus
indicate that peripheral sites of reaerpine action are negligible for the generation of extrapyramidal motor phenomena.
At spinalization of a
reserpinized rat the a-motoneurone reflex excitability was reduced and the rigidity abolished, which indicated the dependence of the reaerpine motor syndrome on aupraepinal mechanisms . Reserpine has widespread effects in the organism.
The peri-
pheral and spinal sites of action have been excluded as responsible for the generation of rigidity .
Some of its clinical actions may be ascribed to
brain structures which are not essential for the generation of rigidity . Therefore a complete agreement between the parkinsonian syndrome and the reaerpine induced state can not be expected. It has been shown that a-methyl-DOPA increases both rigidity and tremor in parkinaonian patients l6, a-Methyl-DOPA was also found to cause parkinaonism in a patient who had developed parkinsonian signs previously on reaerpine treatment l ~ .
The observation is of particular interest because
it has been shown that a-methyl-DOPA inhibits the synthesis of amines in vivo la.
This is likely to depend on inhibition of the enzymes hydroxylating 12, 19 The level of dopamine tyrosine and tryptophan on the aromatic ring9'
358
L-DOPA AND 5-HTP ON RE3ERPINE RIGmITY
Vol . 3, No. 4
in corpus striatum of parkinaonian patients is strongly reduced20 .
Pre-
liminary results suggest that a corresponding decrease occurs in the level of the acid metabolite of this amine, i. e . 3, 4-dihydroxyphenylacetic acid (DOPAC) 21 .
This suggests that the synthesis of dopamine is impaired in
parking oniam . L-DOPA injection markedly diminishes the akinesia of parkinsonian patients 22 .
Oral administration of this drug to parkinsonian patients was reported to reduce akinesia and rigidityl6, 23~ whereas 5-HTP mainly reduced the tremor and only to a lesser degree the rigidity23 .
L-DOPA
administration to patients pre-treated with reaerpine counteracted its sedative and akinetic effects 24.
Monoamine oxidase inhibitors have been used
with some success in treatment of parkinaonian patients 25 and pre-treatment with monoamine oxidase inhibitors strongly accentuated and prolonged the effect of L-DOPA25 .
The demonstrated abolishment of reaerpine in-
duced motor symptoms in the rat after L-DOPA injection is in good agreement with these clinical findings . The presented evidence seems to indicate that the rigidity induced by reaerpine has an origin similar to the parkinsonian rigidity, namely an inhibited transmission in the monoaminergic synapses in some regions of the brain.
This supports the assumption that the mechanisms revealed in
the electrophyaiological analysis of reaerpine rigidity are the same as those of parkinsonian rigidity .
The research supported in this document has been sponsored by AIR FORCE OFFICE OF SCIENTIFIC RESEARCH, OAR through the European Office of Aerospace Research, United States Air Force (Grant No. AF EOAR 64-30), the Swedish State Medical Research Council and by the Medical Faculty, University of Göteborg . For technical assistance we are indebted to Mias Ann-Christine Johnson . For generous gifts of drugs we want to thank the LEO Ltd, Hälaingborg, Sweden (chlorpromazine and phenoxybenzamine) and the Swedish Ciba, Stockholm, Sweden (reaerpine) . References 1,
P. GLOW, J . Neurol . NeurosurQ . Psychiat. T~, 11-32 (195 9)
Vol . 3, No. 4
L-DOPA AND 5-HTP ON RESERPINE RIGmITY
359
2.
G. STEG, Acta physiol. stand. 61, Suppl . 225 (1964)
3.
.~. BERTLER and E . ROSENGR.EN, Acta physiol. stand . 47, 350-361 (1959)
4.
fir. BERTLER, Acta physiol. scared, 51, 97-107 (1961)
5.
D, F . BOGDANSKI, H. WEISSBACH and S. UDENFRIEND, J . Neurochem, 1, 272-278 (1957)
6.
A. H. AMIN, T . B . B, CRAWFORD and J . H. GADDUM, J . Physiol . 126, 596-618 (1954)
7,
M . K. PAASONEN and M. VOGT, J . Physiol . 131, 617-626 (1956)
8.
.8r . BERTLER, Acta physiol, stand, 51, 75-83 (1961)
9.
A. CARLSSON, Symposium on "Binding Sites of Brain Biogenic Amines" held at Galesburg, Illinois, March 1963 ; to be published in Progress in Brain Research .
10 .
B. -E . RODS and B . WERDINIUS, Life Sciences 1 105-107 (1962)
11,
N. -E, ANDÉN, B. -E . RODS and B. WERDINIUS, Life Sciences 2, 319-325 (1963)
12,
B, -E . R00 .S, N. -E . ANDEN and B, WERDINIUS, Int . J . Neuropharmacol . (1964) . In press,
13 .
N. -E, ANDEN, B. -E . ROOS and B, WERDINIUS, Life Sciences 3, (1964) . In press .
14,
H. D, HENATSCH and D. INGVAR, Arch. Psychiat . Nervenkr . 1Q5, 77=93 (1956)
15.
A, CARLSSON, M . LINDQVIST and T . MAGNUSSON, Nature 180, 1200 (1957)
16 .
A. BARBEAU, T, L. SOURKES and G, F, MURPHY, In "Symposium Bel-Air, Monoamines et systéme nerveux central" (1961) PP" 247-262
17 .
B . M, GRODEN, Brit. Med . J.
1, 1001 (1963)
18 .
S. E. SMITH, Brit, J . Pharmacol. 15, 319-327 ( 196 0)
360
L-DOPA AND 5-HTP ON RESERPINE RIGmITY
Vol. 3, No. 4
1q.
B .-E . ROOS and B . WERDINIUS, Life Sciences . 2, q2-96 (1963)
20.
H. EHRINGER and O. HORNYKIEWICZ, ~ Klin: ~Vlrachr . 38 ; 1236-123q (1g60)
21 .
B . -E . RODS and E . ROSENGREN, Unpubl, o~serv.
22 .
W . BIRKMAYER and O. HORNYKIEWICZ, Wien.klin. Wachr . 73, 787-788 (1g61)
23 .
A. BARREAU, Canad . Med . Ass. J . 87, 802-807 (1962)
24.
R. DECKWITZ, R. FROWEIN, C. KULENKAMPFF and U . MORS, Klin. Wachr. 38, T20-123 (1960)
25 .
W . BIRKMAYER and O. HORNYKIEWICZ, Arch. Psychiat . Nervenkr . 203, 560-574 (1962)