Striatal monoamines and reserpine and chlorpromazine rigidity

Pharrnac. rher. B,

1976, Vol. 2, pp. 113-128. Pergamon Press.

Printed in Great Britain

Specialist Subject Editor: O. HORNYKIEWICZ

STRIATAL M O N O A M I N E S A N D R E S E R P I N E A N D C H L O R P R O M A Z I N E RIGIDITY I. JURNA lnstitat fi~r Pharmakologie und Toxikologie d. Univ. des Saarlandes, 665 Homburg (Saar), Germany

R E SE R PIN E RIGIDITY Shortly after having found clinical use as a tranquillizing agent, reserpine was reported to induce a Parkinson-like syndrome in man which includes rigidity (Flach, 1955; Kinross-Wright, 1955; Kline and Stanley, 1955). A similar disturbance of motor functions was observed in animals when reserpine was given in high doses, or in low doses for a long period (Windle and Cammermeyer, 1958; Glow, 1959; Steg, 1964; Carlsson, 1966). The changes in motor activity are largely attributed to a depletion by reserpine of monoamines from the storage sites in the central nervous system. This depletion is not a specific one as all monoamines (dopamine, norepinephrine and 5-hydroxytryptamine) are affected in different regions of the brain (Holzbauer and Vogt, 1956; Carlsson et al., 1957b, 1962; Fuxe, 1965; Carlsson, 1966). Of all brain structures, however, the basal ganglia have attracted special interest with respect to the extrapyramidal motor symptoms (Hornykiewicz, 1966). Examination of brains removed from Parkinson patients revealed a considerable loss of dopamine and 5-hydroxytryptamine in the caudate nucleus and putamen (Ehringer and Hornykiewicz, 1960; Bernheimer et al., 1961, 1963, 1965), and an extreme reduction of monoamines in the striatum of animals has been achieved by the administration of reserpine (Bertler, 1961; Carlsson et al., 1962; Carlsson, 1966; H/Skfelt, 1968). The motor symptoms in Parkinson's disease as well as those produced by reserpine in man and animals are attenuated or even abolished by systemically administered L-dopa (cf. Hornykiewicz, 1966). L-dopa is the immediate precursor in the biosynthesis of dopamine. Dopamine does not penetrate the blood-brain barrier, whereas L-dopa enters the brain where it is converted into dopamine and, to less extent, into norepinephrine (Carlsson et al., 1958; Carlsson, 1964a). It is well established that dopamine is the precursor in the formation of norepinephrine (Blaschko, 1959; Schiimann, 1960), but there is also a great number of indirect and direct evidence that dopamine serves as a neurotransmitter in the striatum (cf. the reviews of Carlsson, 1964b; Bertler and Rosengren, 1966; Hornykiewicz, 1966). To determine whether dopamine or norepinephrine is responsible for the therapeutical action of L-dopa in Parkinson patients, Birkmayer and Hornykiewicz (1962) applied dihydroxyphenylserine. This compound is transformed into norepinephrine without the intermediate formation of dopamine. The outcome of the test was negative, indicating that it is rather the lack of dopamine than of norepinephrine which gives rise to the extrapyramidal syndrome. How far 5-hydroxytryptamine is involved in this respect has not yet been established. 5-Hydroxytryptamine, like dopamine, does not penetrate the blood-brain barrier. Its precursor 5-hydroxytryptophan reaches the brain when systemically administered, but the results obtained with 5-hydroxytryptophan in Parkinson patients are contradictory (Birkmayer and Hornykiewicz, 1962; Cotzias et al., 1968, 1969a, b). Moreover, the compound failed to counteract reserpine hypokinesia and ptosis in rats, but potentiated the reserpine antagonism of L-dopa (Carlsson et al., 1957a). Reserpine rigidity, however, was found to be abolished by 5-hydroxytryptophan (Roos and Steg, 1964). Although this indicates that 5-hydroxytryptamine may be involved in extrapyramidal motor activity, attention has focused mainly on dopamine. JPTB., Vol. 2, No. I--H

1 13

114

I. JURNA RIGIDITY I N D U C E D BY C H L O R P R O M A Z I N E AND O T H E R TRANQUILLIZING AGENTS

Apart from reserpine, a number of other tranquillizing agents induce rigidity, tremor and akinesia in man and animals. It comprises drugs of different chemical structure, such as phenothiazines (chlorpromazine), butyrophenones (haloperidol) and benzoquinolizines (tetrabenazine) (cf. Friedman, 1964). Tetrabenazine, like reserpine, depletes monoamines from their storage sites, but its action differs in various details from that of reserpine, among which it is worth mentioning that the depletion of monoamines is much more pronounced in the central nervous system than in peripheral organs (Quinn et al., 1959; Pletscher et al., 1962; Dahlstr6m et al., 1965; Carlsson, 1966). Chlorpromazine and haloperidol are substances with a marked blocking effect on adrenergic alpha receptors (Gordon, 1967; Janssen, 1967). Strikingly enough, not all phenothiazines are likely to induce parkinsonism. Derivatives with a strong antihistaminic property, as promethazine, seem to be less dangerous in this respect than those with a strong sympatholytic action, as for instance triflupromazine, fluphenazine or chlorpromazine. Accordingly, chlorpromazine and haloperidol are assumed to produce rigidity not by depletion but by blocking the receptor sites for dopamine in the striatum (Carlsson and Lindqvist, 1963; And6n et al., 1964b; Roos, 1965; Da Prada and Pletscher, 1966; Van Rossum, 1966; Cools and Van Rossum, 1970; Cools, 1971). Recently, dopamine receptor blockade by chlorpromazine has been demonstrated by York (1972) in striatal neurones. Probably, also the rigidity following the administration of a pure adrenergic alpha receptor blocking agent, i.e. phenoxybenzamine (Roos and Steg, 1964) is due to dopamine receptor blockade.

UNILATERAL IMPAIRMENT OF DOPAMINERGIC TRANSMISSION Unilateral impairment of dopaminergic transmission in the striatum of rats results in an asymmetric motor disturbance: (1) When a lesion is placed rostrally to the substantia nigra of one side, interrupting the pathway of dopaminergic neurons in the substantia

A

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FIG. I. Effect of interference with dopaminergictransmission on the turning of the rat's head.

Striatal monoaminesand reserpine and chlorpromazinerigidity

115

nigra to the caudate nucleus and putamen (And6n et al., 1964a, 1966b), no changes in gross motor activity is observed. The absence of motor disturbance may be due to a lesion of neighboring structures. However, after an injection of reserpine, chlorpromazine or haloperidol to the operated animals, rigidity develops on the side opposite to the lesion; the head of the animal is turned to this side (Fig. IA; cf. Steg, 1966). After sucking away the corpus striatum on one side, systemic injection of reserpine and a-methyltyrosine evokes turning of the head to the unoperated side (Fig. 1A); subsequent administration of apomorphine, which has been suggested by Ernst (1967) to stimulate dopaminergic receptor sites in the brain, results in turning of the head to the operated side (Fig. IC; And6n et al., 1967). (2) Unilateral injection of chlorpromazine into the striatum evokes turning of the head to the same side, whereas similar injection of dopamine leads to turning of the head to the contralateral side (Fig. 1B and C; Ungerstedt et aL, 1969). (3) Unilateral injection of 6-hydroxydopamine into the substantia nigra or the striatum produces turning of the head to the side of the injection (Fig. ID; Ungerstedt, 1968). 6-Hydroxydopamine has been found to deplete peripheral organs of norepinephrine (Porter et al., 1963; Laverty et al. 1965) by way of selective, acute degeneration of sympathetic nerve terminals (Malmfors and Sachs, 1968; Thoenen and Tranzer, 1968; Tranzer and Thoenen, 1968). It interferes with the formation of dopamine in dopaminergic neurons (Uretsky and Iversen, 1970), and degeneration of dopaminergic neurons has been observed after an injection of 6-hydroxydopamine into the substantia nigra or the striatum (Ungerstedt, 1968).

DOPAMINERGIC AND CHOLINERGIC INTERACTION IN T H E NIGRO-STRIATAL SYSTEM Rigidity resulting from an impairment of dopaminergic transmission in the striatum can be explained in terms of a disturbed balance of dopaminergic and cholinergic interaction in the nigro-striatal system. Microelectrophoretic application of dopamine to caudate neurons inhibits the activity of most of the neurons tested, whereas similar application of acetylcholine activates the neurons (Bloom et al., 1965; Herz and Zieglg~insberger, 1966, 1968; McLennan and York, 1966, 1967). Depression of activity in caudate neurons was observed when stimulating the substantia nigra pars compacta or iontophoretically applying dopamine to these neurons (Connor, 1968, 1970). Moreover, electrical stimulation of pars compacta of the substantia nigra produces a release of dopamine from the caudate nucleus which is dependent on the stimulation intensity and frequency (Von Voigtlander and Moore, 1971a; Chiueh and Moore, 1973). Thus, dopamine released by nigral dopaminergic neurons obviously acts as an inhibitory, and acetylcholine as an excitatory, transmitter substance in the striatum. In accordance with this view Steg (1969), when recording from striatal neuron activated by microelectrophoretic application of glutamate, observed an increase in neuronal activity after systemic administration of reserpine or physostigmine (Fig. 2). The activatory effect of both these drugs was inhibited by L-dopa and atropine. The inhibitory dopaminergic neurons seem to operate on a neuronal feed-back (Corrodi et al., 1967a, b), to which contribute cholinergic neurons and neurons containing GABA. Accordingly, the firing rate of dopaminergic neurons has been found to be reduced by L-dopa, amphetamine and apomorphine, and to be increased by dopamine receptor blocking agents (Bunney et al., 1973a, b). However, which motor escape from the feed-back system is important for the maintenance of cholinergic rigidity has still to be found out.

A L P H A AND GAMMA MOTOR ACTIVITY In an attempt to determine which of the two final motor pathways--the ~- or the ),-motor route--is mainly involved in the rigidity produced by neuropleptic agents, Steg and co-workers (Steg, 1964; Roos and Steg, 1964; Arvidsson et al., 1966) developed a

116

I. JURNA

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FIG. 2A. Repeated microelectrode recordings from six cells in one vertical track during intraveous administration of reserpine and L-dopa. The ceils were activated by glutamate applied through the recording electrode. The changes of impulse frequency (vertical axis)

during successive drug injections (horizontal axis) are demonstrated. Reserpine increases and L-dopa decreases striatal cell activity (from Steg, 1969). B. The effects of physostigmine, L-dopa and atropine are demonstrated with the same techniques as in Fig. 2A. A spatial differentiation of the drug responses is seen. Physostigmine activates striatal cells which are later depressed by L-dopa and atropine (from Steg, 1969).

technique which allows to distinguish between a and y (or fusimotor) units in ventral root filaments not only by differences in the amplitude and shape of the potentials recorded, but also by the different conduction velocities of the potentials. The a - m o t o n e u r o n s innervate the skeletal muscle fibers. The y - m o t o n e u r o n s control the tone of the intrafusal muscle fibers and, via the muscle spindles and the afferent pathway, influence the activity of the a - m o t o n e u r o n s , a-Discharges consist of potentials of a sharp form with relatively high amplitude, whereas y-discharges are characterized by rounded potentials of low amplitude. The potentials are conducted in a - m o t o r axons at a higher speed than in y-axons. It was found that reserpine, chlorpromazine, haloperidol and phenoxybenzamine increase c~- and reduce y-motor activity in the rat (Fig. 3; Roos and Steg, 1964; Arvidsson et al., 1966). Before the administration of these drugs, a-activity was very low and 3,-activity high. Reserpine, chlorpromazine, etc., thus cause a shift from 7- to adominance in spinal motor activity. A similar result was obtained with tetrabenazine (Jurna et al., 1969) and a - m e t h y l - p - t y r o s i n e (Fig. 4). a - M e t h y l - p - t y r o s i n e is an inhibitor of tyrosine hydroxylase (Nagatsu et al., 1964; Udenfriend et al., 1965), which is responsible for the conversion of tyrosine into dopa. It does not interfere with the uptake of monoamines into neurons (Corrodi et al., 1966) and, therefore, reduces only the content of dopamine and norepinephrine, but not of 5-hydroxytryptamine in the central nervous system (And6n et al., 1966a). An increase in monosynaptic reflex amplitude has been reported by Stern and Ward (1962) to follow from an injection of chlorpromazine to cats with an intact neuraxis. Likewise, reserpine enhances monosynaptic mass reflexes in rats and, probably by way of reciprocal inhibition, reduces polysynaptic reflex activity (Grossmann et al., 1973). In

Striatal monoamines and reserpine and chlorpromazine rigidity

117

45mln ofter iv injection of reser~ne 7mg/kg

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FIG. 3. The reflex and spontaneous activity of a- and y-efferents recorded before and after reserpine injection. The electrode pairs attached to ventral root filament were placed 9 mm apart. The action potentials of ~t- and y-motor units are distinguished by the difference in conduction velocity and spike amplitude. The fast a-potentials show a short, and the slow y-potentials a long time lag between two pairs of recording electrodes. The dorsal root was stimulated with a single test pulse (T) and a conditioning pulse subthreshold for reflex activation and preceding the test pulse (C ÷ T). Stimulus artifacts indicated by arrows. Reserpine and reflex conditioning between stimulus artifact and first a-discharge. Reserpine decreases y-reflex activity as well as spontaneous ),-discharges (eft). The electromyogram (emg) shows phasic activity during quick stretch of the calf muscles before reserpine, and tonic activity during and after sustained muscle stretch after reserpine. Reflex activity was recorded with running beam on stationary film, spontaneous activity from ventral root filament and electromyogram with running beam on running film (from Steg, 1964).

e x p e r i m e n t s p e r f o r m e d on v e n t r a l r o o t f i l a m e n t s o f r a t s w i t h d r u g s i n d u c i n g r i g i d i t y it was observed that not only the number of a-reflex discharges had increased after drug a d m i n i s t r a t i o n , b u t t h a t also the i n t e r v a l b e t w e e n the s t i m u l u s eliciting reflex a c t i v i t y a n d t h e first a - r e f l e x d i s c h a r g e w a s r e d u c e d to a v a l u e 0 . 0 - 1 . 5 m s e c ; Fig. 5) w h i c h c o r r e s p o n d s w i t h t h e l a t e n c y in a m o n o s y n a p t i c reflex p a t h w a y . T h e effect on a - r e f l e x d i s c h a r g e o f r e s e r p i n e o r c h l o r p r o m a z i n e r e s e m b l e s t h e c o n d i t i o n i n g o f reflex a c t i v i t y p r o d u c e d b y a s h o r t t r a i n of e l e c t r i c a l p u l s e s a p p l i e d e i t h e r to the s a m e d o r s a l r o o t to w h i c h t h e t e s t s t i m u l u s is a p p l i e d (Fig. 3) o r to o n e of t h e d o r s o l a t e r a l f u n i c u l i of t h e spinal c o r d . T h e r e f o r e , it m a y b e a s s u m e d t h a t i m p a i r m e n t o f d o p a m i n e r g i c t r a n s m i s s i o n s e t s off a d e s c e n d i n g b a r r a g e o f i m p u l s e s w h i c h f a c i l i t a t e s m o t o n e u r o n s that, u n d e r n o r m a l c o n d i t i o n s , will b e s t i m u l a t e d s u b l i m i n a l l y b y m o n o s y n a p t i c a c t i v a t i o n . S i n c e r e s e r p i n e r i g i d i t y is a l w a y s p r e s e n t d u r i n g r e d u c e d f u s i m o t o r a c t i v i t y and p e r s i s t s a f t e r d e a f f e r e n t a t i o n , it m a y b e c l a s s i f i e d as an a l p h a r i g i d i t y (Steg, 1966). T h i s is in c o n t r a s t to t h e r i g i d i t y r e s u l t i n g f r o m i n t e r c o l l i c u l a r d e c e r e b r a t i o n w h i c h is d u e to y - h y p e r a c t i v i t y a n d , t h e r e f o r e , is a b o l i s h e d b y c u t t i n g the d o r s a l r o o t s ( G r a n i t , 1955). It s h o u l d b e n o t i c e d t h a t , d e s p i t e t h e o b v i o u s s i m i l a r i t y o f b i o c h e m i c a l c a u s e s of the r i g i d i t y in P a r k i n s o n ' s d i s e a s e a n d r e s e r p i n e r i g i d i t y in a n i m a l s , it is still an o p e n q u e s t i o n w h e t h e r P a r k i n s o n r i g i d i t y is m a i n t a i n e d b y t h e a - or t h e y - m o t o r s y s t e m (cf. C a l n e , 1970).

118

I. JURNA

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FIG. 4. The effect of a - m e t h y l - p - t y r o s i n e and dopa on spinal motor activity. Upper row of recordings: reflex discharge led off with two pairs of recording electrodes from vental root filament S,. U p p e r tracing: electrode pair proximal to spinal cord. Lower tracing: electrode pair distal to spinal cord. The distance between the two pairs of electrodes was 4 mm. Reflex activity was elicited by electrical stimulation of corresponding dorsal root with single rectangular pulses of supramaximal strength and 0.5 msec duration. An a - and a y-discharge are indicated by arrows. L o w e r row of recordings: electromyogram led off from right (upper tracing) and left (lower tracing) triceps surae muscle without and during stretch. First column: recordings made 12 hr after intraperitoneal injection of a - m e t h y l - p - t y r o s i n e 500 mg/kg, showing high a - and low y-reflex activity, and tonic activity in the electromyogram. Second and third column: recordings made 30 and 45 rain after intravenous injection of L-dopa I00 mg/kg, showing reduced a - and increased ",/-reflex activity, and phasic activity in the electromyogram during quick muscle stretch. The diagram presents the m e a n values of c~- and y-reflex discharges calculated from fifteen recordings made before and at 30 and 45 rain after dopa. Ordinate: n u m b e r of a-reflex discharges per sweep; abscissa: n u m b e r of y-discharges per sweep (from Jurna et al., 1972). %

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FIG. 5. Distribution of the interval between stimulus artifact and first a-reflex discharge before and after reserpine (A) or tetrabenazine (B). The interval is plotted in msec against the f r e q u e n c y of distribution in per cent of the total n u m b e r of determinations (n). A: The control values (n = 2202) are represented by the faint lined-shaded area, the values obtained 30 min after intravenous injection of reserpine 10 mg/kg (n = 1414) by h e a v y lined area. B: The control values (n = 1752) are represented by the faint lined-shaded area, the values obtained 30 min after intravenous injection of tetrabenazine 50 mg/kg (n = 491) by h e a v y lined area (from Jurna and Lanzer, 1969; Jurna, et al., 1969).

Striatal monoamines and reserpine and chlorpromazine rigidity LESIONS ELIMINATING

119

RESERPINE RIGIDITY

Reserpine rigidity is abolished when the striatum on both sides is sucked off or when the dorsolateral funiculi of the spinal cord are transected a b o v e the level of the m o t o n e u r o n s supplying the muscles from which the e l e c t r o m y o g r a m signalling rigidity is recorded (Arvidsson et al., 1967). It remains unchanged after decortication, ablation of the cerebellum, destruction of the vestibular and red nuclei and after p y r a m i d e c t o m y (Fig. 6). These results are identical with those obtained in experiments on physostig-

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FIG. 6. The effect of lesions in the central nervous system of the rat on electromyographical hyperactivity (rigidity) caused by reserpine. Note the decrease of activity only after lesion of the striatum and the dorsolateral funicles (indicated by black structures in the schematical drawing). Ineffective lesions are marked by hatched structures (from Arvidsson et al., 1967).

mine rigidity. As has been discussed elsewhere, a shift in the balance between cholinergic and dopaminergic transmission in the striatum towards cholinergic dominance leads to hyperactivity of the c~-motor system and thus to rigidity. Simultaneously, the activity of the ~/-motor system is depressed. The change in spinal m o t o r activity is probably produced by an increased impulse output along a descending p a t h w a y in the dorsolateral funiculi (Jurna and Theres, 1969). Depression of y - m o t o r activity has been o b s e r v e d after the administration of chlorpromazine or intercollicularly decerebrate cats (Henatsch and Ingvar, 1956). This effect is responsible for the elimination of decerebrate rigidity and has been interpreted in terms of an action of the drug on the reticular formation. This does not invalidate the hypothesis that reserpine or chlorpromazine rigidity is operated from the striatal system, but it raises the question whether, in the rat, depression of the 3,-motor system is brought about by the striatum.

DRUGS STIMULATING DOPAMINERGIC TRANSMISSION Rigidity as well as the changes in spinal m o t o r activity produced by reserpine and other neuroleptic drugs are eliminated by drugs which stimulate noradrenergic or dopaminergic transmission. An intravenous injection of L-dopa (Fig. 7), m e t h a m phetamine or propylhexedrine to reserpinized rats depresses s - h y p e r a c t i v i t y and increases y-activity; the tonic activity in the e l e c t r o m y o g r a m disappears so that only phasic activity can be elicited by quick stretch of the muscles as before the administra-

120

I. JURNA 45rain after iv rejection

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I00 msec FIG. 7. Reserpine increased the c~- and decreased the "y-component of the reflex response to dorsal stimulation (spinal reflex), abolished the spontaneous y-activity (eft), and induced rigidity (emg). L-dopa reversed all these changes for a period of approx. ½hr after which the animal returned to its previous reserpinized state (from Roos and Steg, 1964).

tion of reserpine (Roos and Steg, 1964; Arvidsson et al., 1966; Jurna and Lanzer, 1969). A similar effect is obtained with apomorphine (2 mg/kg i.v.; Jurna and Nell, unpublished results), which is most probably due to the direct action of the drug on dopaminergic receptors in the striatum (Ernst, 1967; And6n et al., 1967). Systemic administration of dopamine, which does not penetrate the blood-brain barrier, has no effect on rigidity (Steg, 1966). Methamphetamine and its hydrogenated derivative propylhexedrine are, CONTROL

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FIG. 8. Effect of reserpine 10 mg/kg and amantadine hydrochloride 50 mg/kg on alpha and gamma reflex discharges. Reflex activity was recorded with two pairs of electrodes from a filament isolated from ventral root S,. Upper tracings: recordings made with pair of electrodes proximal to spinal cord. Lower tracings: recordings made with pair of electrodes distal to spinal cord. The diagrams give the distribution of the interval between stimulus artifact and the first c~-reflex discharge. The interval is plotted in msec against the frequency of distribution in per cent of the total number of determinations (n). The control values (n = 330) are represented in the left-hand diagram by the heavy lined area. The values obtained 30 rain after reserpine (n = 130) are represented in both diagrams by the faint lined-shaded area. The values obtained 30 min after amantadine (n = 154) are represented in the right hand diagram by the heavy lined area (from Jurna et al., 1972).

Striatal monoamines and reserpine and chlorpromazine rigidity

121

like amphetamine, sympathomimetic agents acting by a release of norepinephrine from sympathetic nerve terminals (for a general survey of literature cf. Muscholl, 1966; with respect to propylhexedrine cf. Marsh, 1948; Siegmund et al., 1948; Marsh and Herring, 1949; Lands and Grant, 1952). In all probability, amphetamine acts presynaptically also in the brain by releasing dopamine from, or by inhibiting its uptake into the presynaptic terminals (Carlsson and Waldeck, 1966; Carlsson et al., 1966; Glowinski and Axelrod, 1966; Glowinski et al., 1966; McKenzie and Szerb, 1968; Besson et al., 1969, 1971; Coyle and Snyder, 1969; Chiueh and Moore, 1973). Its motor effects are abolished by reserpine and/or an impairment of catecholamine synthesis (Weisman et al., 1966; Ernst, 1967; And6n et al., 1967; Hanson, 1967). It may be assumed that methamphetamine and propylhexedrine act in a similar way as amphetamine. L-Dopa and methamphetamine also abolish the rigidity produced by tetrabenazine (Jurna et al., 1969), and L-dopa eliminates the rigidity resulting from the administration of ct-methyl-p-tyrosine (Fig. 4). Moreover, the anti-viral agent amantadine antagonizes the effect of reserpine on a- and y-motor activity (Fig. 8; Jurna et al., 1972a). This action can be attributed either to an increased synthesis or release of dopamine in the striatum, or to a reduced uptake of dopamine into dopaminergic terminals (Scatton et al., 1970; Von Voigtlander and Moore, 1971b, c; Baldessarini et al., 1972; Heimans et al., 1972). CHOLINOLYTIC AGENTS The changes in spinal motor control underlying reserpine and physostigmine rigidity are identical (Arvidsson et al., 1966), as must have been expected on the ground of the CONT ROL

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FIG. 9. The effect of reserpine and atropine on a - and 3,-motor discharges. Upper row of records: reflex discharge led off from ventral root filament following stimulation of corresponding dorsal root with single pulses. Middle row of records: spontaneous discharges in ventral root filament. These recordings were made with two pairs of electrodes; running beam on stationary film. Lower row of records: electromyogram led off from calf muscles; running beam on running film. The recordings of the middle and right column were taken 30rain after intravenous injection of reserpine 10 mg/kg and 30 rain after intravenous injection of atropine 5 mg/kg. About fifteen similar recordings of a - and ),-reflex discharges were made during each period, the number of discharges was counted, and the mean values of the control period (Con) after reserpine (Res) and after atropine (At) are presented in the diagram (from Jurna and Lanzer, 1969).

122

I. J U R N A

hypothesis that this type of rigidity is due to cholinergic dominance in cholinergic-dopaminergic interaction in the nigro-striatal system. Accordingly, L-dopa or methamphetamine depress physostigmine rigidity (Jurna et al., 1969) and, conversely, cholinolytic agents antagonize the disturbance of spinal motor activity induced by drugs impairing dopaminergic transmission. Thus, the effect of reserpine, tetrabenazine and a-methyl-p-tyrosine is abolished by atropine (Fig. 9) or by biperiden and trihexyphenidyl (Arvidsson et al., 1966; Jurna and Lanzer, 1969; Jurna et al., 1969, t972b). Biperiden and trihexyphenidyl are anti-Parkinson agents with marked cholinolytic properties. Arvidsson et al. (1966) succeeded in inhibiting the effect of reserpine on motor activity by pretreatment with atropine, but found it difficult to demonstrate an antagonizing action when atropine was injected after reserpine. This result has in its essence been confirmed by Jurna and Lanzer (1969), who found that atropine given after reserpine reduced only moderately, though significantly, the number of a-reflex discharges, whereas an injection of the same dose of atropine made 30 rain before the administration of reserpine completely blocked the effect of reserpine. It is difficult to decide what the reasons for the difference in the effectiveness of atropine against reserpine are. Although atropine inhibits the effect of microelectrophoretically applied acetylcholine on striatal neurons (McLennan and York, 1966), the reserpine antagonism may be due only in part to receptor block. Atropine in very high doses (50-400 mg/kg) has been reported to reduce the acetylcholine concentration in the brain (Giarman and Pepeu, 1962); Cox and Potkonjak (1969) found the whole brain concentration of acetylcholine markedly reduced by atropine in a dose of 40 mg/kg, whereas atropine 5 mg/kg caused only a slight reduction. Unfortunately, these authors did not extend their determinations beyond a period of 30 min after atropine administration so that it remains an open question whether a further fall in acetylcholine concentration had occurred. If this were the case, changes in the amount of acetylcholine available for transmission at different times after an injection of atropine could account for the different action of the drug when given before and after reserpine. C[ A

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Striatal monoamines and reserpine and chlorpromazine rigidity

123

1/, 12

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FIG. 1I. The effect of reserpine, L-dopa and atropine on a- and "),-reflex discharges after electrocoagulation of both substantiae nigrae. Ordinates: number of a- or 11-reflex discharges. Abscissae: time after the injection of the drugs. The moment of intravenous injection of reserpine (10 mg/kg), L-dopa (100 mg/kg) and atropine (5 mg/kg) is indicated by arrows and vertical bars. Each point of the curves represent the mean of six determinations (= six experiments). The thin vertical lines in these points give the standard deviation. Filled circles and unbroken lines: c~-discharges; open circles and broken lines: 11-discharges. The experiments were performed 24-28 days after electrocoagulation. Note that before the injection of L-dopa or atropine a -reflex activity is higher than ),-reflex activity (from Jurna et al., 1972).

THE

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T h e i m p o r t a n c e in r e s e r p i n e r i g i d i t y o f t h e n i g r o - s t r i a t a l s y s t e m as t h e site o f a d i s t u r b e d i n t e r a c t i o n b e t w e e n d o p a m i n e r g i c a n d c h o l i n e r g i c t r a n s m i s s i o n is s t r e s s e d b y t h e r e s u l t s o b t a i n e d in e x p e r i m e n t s w i t h s u b s t a n t i a n i g r a l e s i o n s ( J u r n a e t al., 1972b). A f t e r b i l a t e r a l e l e c t r o c o a g u l a t i o n o f t h e s u b s t a n t i a n i g r a in r a t s , a - r e f l e x a c t i v i t y w a s f o u n d to b e i n c r e a s e d , t h e l a t e n c y b e t w e e n s t i m u l a t i o n a n d t h e first a - d i s c h a r g e w a s reduced and y-motor activity depressed. Atropine normalized a- and y-reflex activity ( F i g s . 10A a n d 11), e l i m i n a t e d t o n i c a c t i v i t y in t h e e l e c t r o m y o g r a m (Fig. 11) a n d i n c r e a s e d t h e r e f l e x l a t e n c y (Fig. 12).

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124

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FIG. 14. Effect of microinjection of 6-hydroxydopamine into both substantiae nigrae, and of intravenous injection of L-dopa, methamphetamine, amantadine, and atropine on the distribution of the interval between stimulus artifact and the first a -reflex discharge. The interval is plotted in msec against the frequency of distribution in percent of the total number of determinations (n). All values obtained in the experiments performed 5-7 days after microinjection of 6hydroxydopamine (6-OH-DA) 8/~g in 4/~1 into both substantiae nigrae are presented in the four diagrams by the heavy lined area (n = 268). The values obtained 45 rain after the injection of L-dopa 10 mglkg (n = 144), 45 rain after the injection of methamphetamine 2 mg/kg (n = 79), and 45 rain after the injection of amantadine 50 mg/kg (n = 71) are presented by the faint lined-shaded areas (from Jurna et al., 1972).

Striatal monoamines and reserpine and chlorpromazine rigidity

125

L-Dopa was tested in these p r e p a r a t i o n s after a n a d d i t i o n a l a d m i n i s t r a t i o n of r e s e r p i n e , w h i c h was m a d e to v e r i f y w h e t h e r the effect of the l e s i o n s was m a x i m a l . R e s e r p i n e i n c r e a s e d a - r e f l e x d i s c h a r g e s slightly b u t not significantly. L-Dopa r e d u c e d a - a c t i v i t y a n d i n c r e a s e d the l a t e n c y of reflex d i s c h a r g e s (Fig. 11). This might i n d i c a t e that the l e s i o n s were i n c o m p l e t e . A n a t t e m p t was t h e r e f o r e m a d e to p r o d u c e selective d e g e n e r a t i o n of d o p a m i n e r g i c n e u r o n s s e n d i n g their a x o n s to the s t r i a t u m , b y m i c r o i n j e c t i o n of 6 - h y d r o x y d o p a m i n e into the s u b s t a n t i a nigra of b o t h sides. T h e c h a n g e s in spinal m o t o r a c t i v i t y o b s e r v e d f r o m 5 days after the m i c r o i n j e c t i o n o n w a r d s were the s a m e as if r e s e r p i n e had b e e n g i v e n (Figs. 10B, 13 and 14), a n d could be a b o l i s h e d b y an i n t r a v e n o u s i n j e c t i o n of a t r o p i n e (Fig. 10B). L-Dopa, m e t h a m p h e t a m i n e a n d a m a n t a d i n e , h o w e v e r , did n o t n o r m a l i z e spinal m o t o r a c t i v i t y (Figs. 13 a n d 14), p r o b a b l y b e c a u s e the s u b s t r a t e for a f a c i l i t a t i o n of d o p a m i n e r g i c t r a n s m i s s i o n b y these drugs, i.e. the storage sites a n d the e n z y m e f o r m i n g d o p a m i n e f r o m L-dopa, had d i s a p p e a r e d t o g e t h e r with a d o p a m i n e r g i c n e u r o n s .

FINAL REMARKS T h e data at p r e s e n t a v a i l a b l e s t r o n g l y suggest that the rigidity p r o d u c e d b y r e s e r p i n e or c h l o r p r o m a z i n e r e s u l t s f r o m a n i m p a i r m e n t of d o p a m i n e r g i c t r a n s m i s s i o n in the striatum. R e s e r p i n e rigidity r e s e m b l e s the rigidity in P a r k i n s o n ' s disease, for w h i c h B a r b e a u (1962) has a d v a n c e d the h y p o t h e s i s that it is due to a d i s e q u i l i b r i u m b e t w e e n a n t a g o n i s t i c m o n o a m i n e r g i c a n d c h o l i n e r g i c n e u r o n s y s t e m s . It p r o v i d e s a m o d e l for the t e s t i n g of a n t i - P a r k i n s o n drugs.

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