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Effects of chronic administration of neuroleptics: Dyskinesias in monkeys
Pharmac. Ther. B, 1976. Vol. 2, pp. 167-171. Pergamon Press. Printed in Great Britain
Specialist Subject Editor: O. H O R N Y K I E W I C Z
EFFECTS
OF
NEUROLEPTICS:
CHRONIC
ADMINISTRATION
DYSKINESIAS G.
IN
OF
MONKEYS
PAULSON
Neurological Associates, 931 Chatham Lane, Columbus, Ohio 43221
THERE is m o r e data on the behavioral and neurologic effects of phenothiazines and b u t y r o p h e n o n e s on man than on any other primate. There is, however, some limited data available for m o n k e y s , and selected portions are reviewed here. In evaluating the effects of drugs on behavioral p h e n o m e n a in m o n k e y s it is wise to recognize the limitations in laboratory methods. There are m a r k e d differences b e t w e e n the b e h a v i o r of m o n k e y s in a confined e n v i r o n m e n t and the behavior of free and widely ranging bands of m o n k e y s . One almost certain w a y to produce stereotyped m o v e m e n t s in any primate is to go to the e x t r e m e of captivity, to produce isolation or sensory deprivation. In c h i m p a n z e e s that have been blinded there m a y be rhythmical rocking, aimless restlessness, picking at the body, gnawing or circling. Their m o v e m e n t s are reminiscent of those seen in severely-retarded or congenitally-blinded humans (Berkson and D a v e n p o r t , 1962; Rawls and Paulson, 1966) and portions of such behavior can be seen in any second-rate zoo. These, and almost all other, stereotyped m o v e m e n t s m a y be exaggerated at times of excitement or agitation. There can be a c o m p a r a b l e increase in m o v e m e n t s after injection of epinephrine or following the ingestion of a m p h e t a m i n e - t y p e drugs. T r e m o r s or jerks can follow the use of almost any psychotropic drug, either acutely or after withdrawal. In addition to the s t e r e o t y p e d or restless m o v e m e n t s that result f r o m isolation, various types of anatomical damage also lead to m o v e m e n t disorders. Though rarely occurring in the free state, cortical or subcortical lesions in several areas can serve to release pathological m o v e m e n t s (Goldstein et al., 1969; Poirier et al., 1966). Any ill m o n k e y can display a tremor, just as a febrile man can manifest shivering or a toxic tremor. Rhythmical t r e m o r can result f r o m a complex variety of lesions, including even lesions in the ansa peduncularis (Mettler, 1965). Other abnormalities of m o v e m e n t can be elicited f r o m lesions in the sub-cerebellar nuclei, red nucleus, and even from destruction of regions as rostral as portions of the caudate. Most efforts to produce t r e m o r have involved lesions in brain stem nuclei, cerebellum or in the p a t h w a y s originating f r o m the cerebellum (Carpenter, 1961). According to some reports, lesions in the caudate m a y produce a hypotonic or catatonic state; in other reported studies rhythmical or agitated behavior is noted. In fact within the caudate an anterior and ventral lesion m a y produce hyperkinesias (Liles and Davis, 1969), whereas a different lesion m a y lead to akinesia. As will be mentioned later, lesions and drugs, though m a r k e d l y complicating the a s s e s s m e n t of the effect of either the lesion or of the drug, m a y produce unexpected results. Combinations of drugs and lesions can even elicit totally unique behavior as well as behavioral p h e n o m e n a not previously o b s e r v e d in that animal. As has b e e n reviewed by Degkwitz, this can be particularly true with our favorite primate for investigation, man, but it is also true with species usually considered more primitive. F r o m o b s e r v a t i o n s of other creatures one can assume that conditioned responses are attenuated by phenothiazines, particularly if the drug is administered acutely. Stimuli will be less effective and responses will be less intense in animals which have received phenothiazines either acutely or chronically. Though there appears to be less certain evidence regarding effects of phenothiazines on the acquisition of responses or p e r m a n e n c e of learning, it is considered likely that since impaired vigilance results f r o m phenothiazine ingestion, learning would also be impaired b y this group of drugs. Any 167
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aspects of learning that hinge on m o t o r function can be limited by phenothiazines. Motor activity is usually diminished by acute administration of the phenothiazine, but paradoxical effects can be observed. As with barbiturates, agitation or excitement is more likely in the old or very young. P s y c h o m o t o r retardation is not peculiar, of course, to phenothiazines, and is noted following administration of m a n y centrally active drugs. In most experiments on learning or behavior it is difficult or impossible to selectively impair either registration of new information, the level of awareness of the environment, retention of information, or the retrieval of information. Phenothiazine m a y well affect all ( G o o d m a n and Gilman, 1965). It has been stated that, unlike the barbituarates, reserpine and chloropormazine will not produce m a j o r neurophysiologic or E E G changes, particularly in readings from sub-cortical areas (Domino, 1962). According to Monroe (Monroe et al., 1955), m o n k e y s receiving chlorpromazine and reserpine show no difference in E E G recordings f r o m the medial t e g m e n t u m as c o m p a r e d with records from sub-cortical or cortical areas. Seizures were not noted in these reports. The depth of sleep induced in these animals was sometimes quite shallow when c o m p a r e d to more normal sleep. Nevertheless, chlorpromazine has been used as an activating medication in electroencephalographic work by some clinicians and will sometimes elicit spikes or potentiate the chance for seizures in humans (Stewart, 1957). In one group of eighty patients receiving as high a level as 2000 mg/day of chlorpromazine, eight had seizures within 3 weeks after starting the drug (Paulson, personal observations). Chlorpromazine and other phenothiazines, in contrast to m a n y drugs with sedative action, do not serve as useful anticonvulsants and, indeed, tend to trigger seizure activity. Certain phenothiazines m a y be less likely than others to produce (Paulson and Buffaloe, 1964) seizures, but none are likely to inhibit seizures unless via an effect on emotional lability. Occasional patients do have reflex epilepsy triggered by emotional stress. It seems probable that seizures triggered b y startle might also be d a m p e n e d by phenothiazines. Although there has been much work regarding E E G changes following chlorpromazine administration in man, and the activation of slow w a v e s or spike activity can occur s e c o n d a r y to these drugs, there is little or no data available about such effects on monkeys. In view of the remarkable similarities in E E G development, effects should parallel. Cortical and thalamic studies of the effect of phenothiazines on subcortical structures are similarly limited. Chlorpromazine can decrease spontaneous firing in the caudate nucleus region. On the other hand, Adey and Dunlop (1960) have suggested that firing rates following sciatic stimulation are increased by phenothiazine. Though hypothalamic and basal ganglia responses to phenothiazines are quite prominent in the literature, one of the m a j o r effects of the phenothiazines appears to be on the reticular activating system of the brain stem. Massive doses of chlorpromazine can produce respiratory depression, and there m a y be a loss of the normal attenuation of the E E G arousal response when animals are on lower doses of chlorpromazine. Killam and Killam (1958) have suggested that chlorpromazine increases reticular activity and perhaps it is via this m e c h a n i s m that the E E G arousal response is blocked by phenothiazine. It should be recalled that E E G and behavioral arousal responses are not identical. The ),-efferent system is suppressed by phenothiazines, and the effect of phenothiazine is probably not localized solely either in the neuromuscular junction nor primarily in basal ganglia. The p h e n o m e n o n of tolerance and physical d e p e n d e n c y is an interesting one with regard to chlorpromazine, one that has not been investigated in monkeys. In general, it appears true that the medications are not addictive in either m o n k e y s or man. Monkeys given up to 3 0 m g / k g of chlorpromazine a day showed no obvious withdrawal s y m p t o m s when the drug was discontinued, either soon after the drug was administered or after chronic administration. We did not note any withdrawal s y m p t o m s when the drug was discontinued in our group of monkeys. Tolerance to the sedative effect develops slowly, however, and m a y require months. We have administered chlorpromazine to thirteen rhesus m a c a c u s by intranasal catheter. The dosage was a p p r o x i m a t e l y 30 mg/kg. In contrast to control animals and to
Effects of chronic administration of neuroleptics: dyskinesias in monkeys
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animals on L-dopa, effects were noted almost immediately. The animals m o v e d more slowly and were apathetic after an initial dose of even 5 mg/kg. The vigor of biting remained the same, but they were slow to arouse. It was impossible to begin at the final dose, because anorexia was severe and the animals failed to drink adequate fluids. The ultimate dosage was only reached after 2 months or more, but in a few animals could be reached in as little as 3 weeks. Dyskinesias did not occur for at least 3 months after chlorpromazine in any animal, and usually only at about 6 months. The e x t r e m e gnawing and tongue dyskinesias o b s e r v e d in immediate association with the medication L-dopa, administered intraperitoneally in large doses, was n e v e r observed with chlorpromazine. In two animals apparent torticollis was observed, but was very transitory. Nevertheless, at least six out of thirteen of the animals on chronic chlorpromazine eventually developed a dyskinesia. In three, the m o v e m e n t continued for a w e e k each time the drug was discontinued, but in none did it appear to be permanent. When dyskinesia was present it was most severe a p p r o x i m a t e l y 3 hrs after each dose. The variety of dyskinetic m o v e m e n t s were reminiscent of, if not identical to, the buccolingual form of tardive dyskinesias as described by Degkwitz, Crane and others. In some m o n k e y s the tongue appeared to writhe in the floor of the mouth; more often there was repetitive protrusion of the tongue with licking and mouthing. Some animals protruded the tongue only a few millimeters b e t w e e n the lips and held the tongue there for prolonged periods of time. Discontinuation of the drug for f r o m 1 to 3 weeks led to diminution or complete clearance of the dyskinesias. In no instance was the t e m p o r a r y discontinuance associated with any increase in the m o v e m e n t s nor did dyskinesia appear for the first time w h e n the medicine was discontinued. This is notable because it has been o b s e r v e d in humans that tardive dyskinesias m a y be noted for the first time when the dosage has been reduced. The dyskinesias while on chlorpromazine were so severe that several animals mutilated themselves prior to final sacrifice. Twelve animals received haloperidol in doses calculated to be comparable to that of the chlorpromazine. M a x i m u m dosage was 3 mg per animal and m o s t animals weighed b e t w e e n 4.5 and 5.5 kg. The initial lethargy noted with chlorpromazine was less obvious with this dosage of haloperidol, although this would also be a very large dose by weight in humans. Medication was discontinued for from 1 to 3 weeks on two separate occasions in each animal, without the a p p e a r a n c e of neurologic signs. Three of the group on chronic haloperidol received 10 mg of a m p h e t a m i n e without m a j o r effect, whereas a m p h e t a m i n e produces e x t r e m e agitation normally. Due to the fact that the a m p h e t a m i n e usually produced a m a j o r change in the m o n k e y s , and indeed this dose can be fatal, it is suggested that the haloperidol blocked the effect of the amphetamine. N o n e of the animals receiving haloperidol developed any type of dyskinesia while on that drug. Since tardive dyskinesia is a m a j o r public health problem, the fact that tardive dyskinesia did not result f r o m haloperidol but was present in a third of the animals after chlorpromazine is of clinical interest. Deneau and Crane (1969) noted, in m o n k e y s receiving high doses of chlorpromazine to study damage of lens and cornea, that in the seventeen m o n k e y s receiving 30 mg/kg of chlorpromazine there was moderate slowing of m o t o r activity, decreased vocalization and cessation of social interaction soon after the drugs were initiated. The investigators thought that these changes were related to the blood levels of chlorpromazine, in that several hours after the doses were administered the animals were tranquilized and after 4-6 hrs were maximally sedated. A few in this group of animals developed acute neurologic effects, specifically restlessness or dystonia, and one showed dramatic postural disorders followed by prostration and a tendency to bite himself. Six months after the study began, abnormal tongue m o v e m e n t s were noted in one m o n k e y , usually for only a few hours after the dose. The m o v e m e n t s were described as consisting of almost continuous forceful protrusion of the tongue. Other m o v e m e n t s were observed, including side-to-side m o v e m e n t s of the chin, rapid intermittent protrusion of the distal third of the tongue, plus rapid activity of the lips and cheeks. This m o n k e y a p p e a r e d unable to swallow food, and there were occasional
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s u d d e n s p a s m s o f t h e t o n g u e w i t h p r o t r u s i o n to t h e right. A t the s a m e t i m e , t h e r e m i g h t b e r o t a t i o n o f the n e c k , c l e n c h i n g o f t h e t o e s o r p o s t u r i n g o f t h e limbs. T h e a n i m a l which presented frequent episodes of acute dystonia recovered following biperiden. Dr. D e u e l (1969) n o t e d o n e o t h e r m o n k e y w i t h t r e m o r o f his h e a d ( 3 - 4 p e r sec), p l u s episodic rapid eye movements with occasional non-conjugate version. Retrocollis was a l s o o b s e r v e d briefly. It w a s t h o u g h t l i k e l y t h a t t h e r e w e r e t w o d i f f e r e n t p h e n o m e n a o b s e r v e d , o n e a p a r k i n s o n - l i k e h a b i t u s , w i t h r e t a r d a t i o n o f v o l u n t a r y a c t i v i t y , a n d in t h e o t h e r t h e r e w a s an a b n o r m a l d y s k i n e t i c m o v e m e n t o f t h e s k e l e t a l m u s c u l a t u r e as well as o f the t o n g u e . F r o m t h e s a m e g r o u p o f a n i m a l s o n c h l o r p r o m a z i n e , Dr. C a m m e r m e y e r (1969) n o t e d s o m e c h a n g e s n e u r o p a t h o l o g i c a l l y , c h a n g e s t h a t w e r e s i m i l a r to t h o s e s e e n w i t h r e s e r p i n e . In the o n e a n i m a l w h i c h w a s e v a l u a t e d in d e t a i l , it w a s t h o u g h t t h a t t h e c h a n g e s w e r e n o n - s p e c i f i c b u t n o t s e c o n d a r y to a r t i f a c t s . T h e m a j o r c h a n g e o b s e r v e d w a s an i n c r e a s e in fibrous a s t r o c y t e s , as c o m p a r e d w i t h a control macaque which had not received chlorpromazine. T h e r e h a v e b e e n no s t u d i e s o f a c o m b i n a t i o n o f s t r u c t u r a l l e s i o n s a n d d r u g s . S a x (personal communication) has recently reported marked increase of abnormal movem e n t s p r o d u c e d b y L - d o p a w h e n t h e d r u g is c o m b i n e d w i t h l e s i o n s in t h e c a u d a t e . S i n c e t a r d i v e d y s k i n e s i a is m o r e l i k e l y w h e n the p a t i e n t is o l d e r o r b r a i n d a m a g e d , s i m i l a r e f f e c t s m a y b e t r u e in m o n k e y s . In s u m m a r y , t h e r e is n o d o u b t t h a t c h r o n i c u s a g e o f p h e n o t h i a z i n e s l e a d s to n e u r o p h y s i o l o g i c e f f e c t s , p a r t i c u l a r l y p o t e n t i a t i o n of s e i z u r e a c t i v i t y w i t h s o m e c o m p o u n d s . E v e n less e q u i v o c a l , c h r o n i c d o s a g e w i t h c h l o r p r o m a z i n e in r h e s u s c a n p r o d u c e a c o m p l e x s i m i l a r to the t a r d i v e d y s k i n e s i a o f h u m a n s . T h i s o c c u r s m u c h l a t e r t h a n t h e a n t i c i p a t e d s e d a t i v e effect, a n d is p r o b a b l y d o s a g e r e l a t e d . It s e e m s p r o b a b l e t h a t at l e a s t o n e b u t y r o p h e n o n e , h a l o p e r i d o l , is r e l a t i v e l y less l i k e l y to p r o d u c e e x t r a p y r a m i d a l e f f e c t s in m o n k e y s .
REFERENCES ADEY, W. R. and DUNLOP, C. W. (1960) The action of certain cyclohexamines on the hippocampal system during approach performance in the cat. J. Pharmac. exp. Ther. 130: 418--426. BERKSON, G. and DAVENPORT,R. K. (1962) Stereotyped movements of mental defectives• I. Initial survey. Am. J. Merit. Deficiency 66: 849-852. CAMMERMEYER, J. (1969) Neuropathological study of rhesus chronically treated with chlorpromazine. In, Psychotropic Drugs and Dysfunctions of the Basal Ganglia. A Multidisciplinary Workshop. CRANE, GEORGE E. and GARDNER, RUSSEL JR. (eds.), U.S. Government Printing Office, Washington. CARPENTER, M. B. (1961) Brain stem and infratentorial neuraxis in experimental dyskinesia. Archs. Neurol. 5: 504-524. DENEAU, G. and CRANE, G. E. (1969) Dyskinesia in rhesus monkeys tested with high doses of chlorpromazine. In, Psychotropic Drugs and Dysfunctions of the Basal Ganglia. A Multidisciplinary Workshop. CRANE, GEORGE E. and GARDNER, RUSSELL JR. (eds.), U.S. Government Printing Office, Washington. DEUEL, R. K. (1969) Neurological examination of rhesus monkeys treated with high doses of chlorpromazine. In Psychotropic Drugs and Dysfunctions of the Basal Ganglia. A Multidisciplinary Workshop. CRANE GEORGE E. and GARDNER, RUSSELL JR. (eds.), U.S. Government Printing Office, Washington• DOMINO, E. F. (1962) Human pharmacology of tranquilizing drugs. Clin. Pharmac. Ther. 3: 599-664. GOLDSTEIN, M., BATTISTA, A. K., NAKATONI, S. and ANAGNOSTE, B. (1969) Drug-induced relief of tremor in monkeys with mesencephalic lesion. Nature Lond. 224: 382-384. GOODMAN, LOUIS S. and GILMAN ALFRED (eds.) (1965) The Pharmacological Basis of Therapeutics. Macmillan. KILLAM, K. F. and KILLAM, E. K. (1958) Drug action on pathways involving the reticular formation. In, Reticular Formation of the Brain, JASPER, H. H., PROCTOR, L. D., KNIGHTON, S. S., NOSHAY, W. C. and COSTELLO, R. T. (eds.) Little, Brown, Boston. LILES, S. L. and DAVIS, G. D. (1969) Permanent athetoid and choreiform movements after small caudate lesions in the cat. In, Psychotropic Drugs and Dysfunctions of the Basal Ganglia. A Multidisciplinary Workshop. CRANE GEORGE E. and GARDNER, RUSSELL JR. (eds.), U.S. Government Printing Office, Washington. METTLER, F. A. (1965) Syndrome of the ansa peduncularis. J. Nerv. Merit. Dis. 140: 17-25. MONROE, R. R., HEATH, R. G., MICKLE, W. A. and MILLER, W. (1955) A comparison of cortical and subcortical brain waves in normal, barbiturate, reserpine and chlorpromazine sleep. Ann. N.Y. Acad. Sci. 61: 1PAULSON, G. W. and BUFFALOE,W. (1964) Use of thioridazine hydrochloride in epilepsy. Dis. Nerv. Sys. 25: 243.
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POIRIER, L. J., SOURKES, T. L., BOUVIER, G., BOUCHER, R. and CARABIN, S. (1966) Striated amines, experimental tremor and the effect of harmaline in the monkey. Brain 89: 37-52. RAWLS, R. and PAULSON, G. (1966) Retrolental fibroplasia in North Carolina. N. Carolina Med. J. 27: 420-426. STEWART, L. F. (1957) Chlorpromazine: Use to activate electroencephalographic seizure patterns. EEG clin. Neurophysiol. 9: 427-440.
Specialist Subject Editor: O. H O R N Y K I E W I C Z
EFFECTS
OF
NEUROLEPTICS:
CHRONIC
ADMINISTRATION
DYSKINESIAS G.
IN
OF
MONKEYS
PAULSON
Neurological Associates, 931 Chatham Lane, Columbus, Ohio 43221
THERE is m o r e data on the behavioral and neurologic effects of phenothiazines and b u t y r o p h e n o n e s on man than on any other primate. There is, however, some limited data available for m o n k e y s , and selected portions are reviewed here. In evaluating the effects of drugs on behavioral p h e n o m e n a in m o n k e y s it is wise to recognize the limitations in laboratory methods. There are m a r k e d differences b e t w e e n the b e h a v i o r of m o n k e y s in a confined e n v i r o n m e n t and the behavior of free and widely ranging bands of m o n k e y s . One almost certain w a y to produce stereotyped m o v e m e n t s in any primate is to go to the e x t r e m e of captivity, to produce isolation or sensory deprivation. In c h i m p a n z e e s that have been blinded there m a y be rhythmical rocking, aimless restlessness, picking at the body, gnawing or circling. Their m o v e m e n t s are reminiscent of those seen in severely-retarded or congenitally-blinded humans (Berkson and D a v e n p o r t , 1962; Rawls and Paulson, 1966) and portions of such behavior can be seen in any second-rate zoo. These, and almost all other, stereotyped m o v e m e n t s m a y be exaggerated at times of excitement or agitation. There can be a c o m p a r a b l e increase in m o v e m e n t s after injection of epinephrine or following the ingestion of a m p h e t a m i n e - t y p e drugs. T r e m o r s or jerks can follow the use of almost any psychotropic drug, either acutely or after withdrawal. In addition to the s t e r e o t y p e d or restless m o v e m e n t s that result f r o m isolation, various types of anatomical damage also lead to m o v e m e n t disorders. Though rarely occurring in the free state, cortical or subcortical lesions in several areas can serve to release pathological m o v e m e n t s (Goldstein et al., 1969; Poirier et al., 1966). Any ill m o n k e y can display a tremor, just as a febrile man can manifest shivering or a toxic tremor. Rhythmical t r e m o r can result f r o m a complex variety of lesions, including even lesions in the ansa peduncularis (Mettler, 1965). Other abnormalities of m o v e m e n t can be elicited f r o m lesions in the sub-cerebellar nuclei, red nucleus, and even from destruction of regions as rostral as portions of the caudate. Most efforts to produce t r e m o r have involved lesions in brain stem nuclei, cerebellum or in the p a t h w a y s originating f r o m the cerebellum (Carpenter, 1961). According to some reports, lesions in the caudate m a y produce a hypotonic or catatonic state; in other reported studies rhythmical or agitated behavior is noted. In fact within the caudate an anterior and ventral lesion m a y produce hyperkinesias (Liles and Davis, 1969), whereas a different lesion m a y lead to akinesia. As will be mentioned later, lesions and drugs, though m a r k e d l y complicating the a s s e s s m e n t of the effect of either the lesion or of the drug, m a y produce unexpected results. Combinations of drugs and lesions can even elicit totally unique behavior as well as behavioral p h e n o m e n a not previously o b s e r v e d in that animal. As has b e e n reviewed by Degkwitz, this can be particularly true with our favorite primate for investigation, man, but it is also true with species usually considered more primitive. F r o m o b s e r v a t i o n s of other creatures one can assume that conditioned responses are attenuated by phenothiazines, particularly if the drug is administered acutely. Stimuli will be less effective and responses will be less intense in animals which have received phenothiazines either acutely or chronically. Though there appears to be less certain evidence regarding effects of phenothiazines on the acquisition of responses or p e r m a n e n c e of learning, it is considered likely that since impaired vigilance results f r o m phenothiazine ingestion, learning would also be impaired b y this group of drugs. Any 167
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aspects of learning that hinge on m o t o r function can be limited by phenothiazines. Motor activity is usually diminished by acute administration of the phenothiazine, but paradoxical effects can be observed. As with barbiturates, agitation or excitement is more likely in the old or very young. P s y c h o m o t o r retardation is not peculiar, of course, to phenothiazines, and is noted following administration of m a n y centrally active drugs. In most experiments on learning or behavior it is difficult or impossible to selectively impair either registration of new information, the level of awareness of the environment, retention of information, or the retrieval of information. Phenothiazine m a y well affect all ( G o o d m a n and Gilman, 1965). It has been stated that, unlike the barbituarates, reserpine and chloropormazine will not produce m a j o r neurophysiologic or E E G changes, particularly in readings from sub-cortical areas (Domino, 1962). According to Monroe (Monroe et al., 1955), m o n k e y s receiving chlorpromazine and reserpine show no difference in E E G recordings f r o m the medial t e g m e n t u m as c o m p a r e d with records from sub-cortical or cortical areas. Seizures were not noted in these reports. The depth of sleep induced in these animals was sometimes quite shallow when c o m p a r e d to more normal sleep. Nevertheless, chlorpromazine has been used as an activating medication in electroencephalographic work by some clinicians and will sometimes elicit spikes or potentiate the chance for seizures in humans (Stewart, 1957). In one group of eighty patients receiving as high a level as 2000 mg/day of chlorpromazine, eight had seizures within 3 weeks after starting the drug (Paulson, personal observations). Chlorpromazine and other phenothiazines, in contrast to m a n y drugs with sedative action, do not serve as useful anticonvulsants and, indeed, tend to trigger seizure activity. Certain phenothiazines m a y be less likely than others to produce (Paulson and Buffaloe, 1964) seizures, but none are likely to inhibit seizures unless via an effect on emotional lability. Occasional patients do have reflex epilepsy triggered by emotional stress. It seems probable that seizures triggered b y startle might also be d a m p e n e d by phenothiazines. Although there has been much work regarding E E G changes following chlorpromazine administration in man, and the activation of slow w a v e s or spike activity can occur s e c o n d a r y to these drugs, there is little or no data available about such effects on monkeys. In view of the remarkable similarities in E E G development, effects should parallel. Cortical and thalamic studies of the effect of phenothiazines on subcortical structures are similarly limited. Chlorpromazine can decrease spontaneous firing in the caudate nucleus region. On the other hand, Adey and Dunlop (1960) have suggested that firing rates following sciatic stimulation are increased by phenothiazine. Though hypothalamic and basal ganglia responses to phenothiazines are quite prominent in the literature, one of the m a j o r effects of the phenothiazines appears to be on the reticular activating system of the brain stem. Massive doses of chlorpromazine can produce respiratory depression, and there m a y be a loss of the normal attenuation of the E E G arousal response when animals are on lower doses of chlorpromazine. Killam and Killam (1958) have suggested that chlorpromazine increases reticular activity and perhaps it is via this m e c h a n i s m that the E E G arousal response is blocked by phenothiazine. It should be recalled that E E G and behavioral arousal responses are not identical. The ),-efferent system is suppressed by phenothiazines, and the effect of phenothiazine is probably not localized solely either in the neuromuscular junction nor primarily in basal ganglia. The p h e n o m e n o n of tolerance and physical d e p e n d e n c y is an interesting one with regard to chlorpromazine, one that has not been investigated in monkeys. In general, it appears true that the medications are not addictive in either m o n k e y s or man. Monkeys given up to 3 0 m g / k g of chlorpromazine a day showed no obvious withdrawal s y m p t o m s when the drug was discontinued, either soon after the drug was administered or after chronic administration. We did not note any withdrawal s y m p t o m s when the drug was discontinued in our group of monkeys. Tolerance to the sedative effect develops slowly, however, and m a y require months. We have administered chlorpromazine to thirteen rhesus m a c a c u s by intranasal catheter. The dosage was a p p r o x i m a t e l y 30 mg/kg. In contrast to control animals and to
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animals on L-dopa, effects were noted almost immediately. The animals m o v e d more slowly and were apathetic after an initial dose of even 5 mg/kg. The vigor of biting remained the same, but they were slow to arouse. It was impossible to begin at the final dose, because anorexia was severe and the animals failed to drink adequate fluids. The ultimate dosage was only reached after 2 months or more, but in a few animals could be reached in as little as 3 weeks. Dyskinesias did not occur for at least 3 months after chlorpromazine in any animal, and usually only at about 6 months. The e x t r e m e gnawing and tongue dyskinesias o b s e r v e d in immediate association with the medication L-dopa, administered intraperitoneally in large doses, was n e v e r observed with chlorpromazine. In two animals apparent torticollis was observed, but was very transitory. Nevertheless, at least six out of thirteen of the animals on chronic chlorpromazine eventually developed a dyskinesia. In three, the m o v e m e n t continued for a w e e k each time the drug was discontinued, but in none did it appear to be permanent. When dyskinesia was present it was most severe a p p r o x i m a t e l y 3 hrs after each dose. The variety of dyskinetic m o v e m e n t s were reminiscent of, if not identical to, the buccolingual form of tardive dyskinesias as described by Degkwitz, Crane and others. In some m o n k e y s the tongue appeared to writhe in the floor of the mouth; more often there was repetitive protrusion of the tongue with licking and mouthing. Some animals protruded the tongue only a few millimeters b e t w e e n the lips and held the tongue there for prolonged periods of time. Discontinuation of the drug for f r o m 1 to 3 weeks led to diminution or complete clearance of the dyskinesias. In no instance was the t e m p o r a r y discontinuance associated with any increase in the m o v e m e n t s nor did dyskinesia appear for the first time w h e n the medicine was discontinued. This is notable because it has been o b s e r v e d in humans that tardive dyskinesias m a y be noted for the first time when the dosage has been reduced. The dyskinesias while on chlorpromazine were so severe that several animals mutilated themselves prior to final sacrifice. Twelve animals received haloperidol in doses calculated to be comparable to that of the chlorpromazine. M a x i m u m dosage was 3 mg per animal and m o s t animals weighed b e t w e e n 4.5 and 5.5 kg. The initial lethargy noted with chlorpromazine was less obvious with this dosage of haloperidol, although this would also be a very large dose by weight in humans. Medication was discontinued for from 1 to 3 weeks on two separate occasions in each animal, without the a p p e a r a n c e of neurologic signs. Three of the group on chronic haloperidol received 10 mg of a m p h e t a m i n e without m a j o r effect, whereas a m p h e t a m i n e produces e x t r e m e agitation normally. Due to the fact that the a m p h e t a m i n e usually produced a m a j o r change in the m o n k e y s , and indeed this dose can be fatal, it is suggested that the haloperidol blocked the effect of the amphetamine. N o n e of the animals receiving haloperidol developed any type of dyskinesia while on that drug. Since tardive dyskinesia is a m a j o r public health problem, the fact that tardive dyskinesia did not result f r o m haloperidol but was present in a third of the animals after chlorpromazine is of clinical interest. Deneau and Crane (1969) noted, in m o n k e y s receiving high doses of chlorpromazine to study damage of lens and cornea, that in the seventeen m o n k e y s receiving 30 mg/kg of chlorpromazine there was moderate slowing of m o t o r activity, decreased vocalization and cessation of social interaction soon after the drugs were initiated. The investigators thought that these changes were related to the blood levels of chlorpromazine, in that several hours after the doses were administered the animals were tranquilized and after 4-6 hrs were maximally sedated. A few in this group of animals developed acute neurologic effects, specifically restlessness or dystonia, and one showed dramatic postural disorders followed by prostration and a tendency to bite himself. Six months after the study began, abnormal tongue m o v e m e n t s were noted in one m o n k e y , usually for only a few hours after the dose. The m o v e m e n t s were described as consisting of almost continuous forceful protrusion of the tongue. Other m o v e m e n t s were observed, including side-to-side m o v e m e n t s of the chin, rapid intermittent protrusion of the distal third of the tongue, plus rapid activity of the lips and cheeks. This m o n k e y a p p e a r e d unable to swallow food, and there were occasional
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s u d d e n s p a s m s o f t h e t o n g u e w i t h p r o t r u s i o n to t h e right. A t the s a m e t i m e , t h e r e m i g h t b e r o t a t i o n o f the n e c k , c l e n c h i n g o f t h e t o e s o r p o s t u r i n g o f t h e limbs. T h e a n i m a l which presented frequent episodes of acute dystonia recovered following biperiden. Dr. D e u e l (1969) n o t e d o n e o t h e r m o n k e y w i t h t r e m o r o f his h e a d ( 3 - 4 p e r sec), p l u s episodic rapid eye movements with occasional non-conjugate version. Retrocollis was a l s o o b s e r v e d briefly. It w a s t h o u g h t l i k e l y t h a t t h e r e w e r e t w o d i f f e r e n t p h e n o m e n a o b s e r v e d , o n e a p a r k i n s o n - l i k e h a b i t u s , w i t h r e t a r d a t i o n o f v o l u n t a r y a c t i v i t y , a n d in t h e o t h e r t h e r e w a s an a b n o r m a l d y s k i n e t i c m o v e m e n t o f t h e s k e l e t a l m u s c u l a t u r e as well as o f the t o n g u e . F r o m t h e s a m e g r o u p o f a n i m a l s o n c h l o r p r o m a z i n e , Dr. C a m m e r m e y e r (1969) n o t e d s o m e c h a n g e s n e u r o p a t h o l o g i c a l l y , c h a n g e s t h a t w e r e s i m i l a r to t h o s e s e e n w i t h r e s e r p i n e . In the o n e a n i m a l w h i c h w a s e v a l u a t e d in d e t a i l , it w a s t h o u g h t t h a t t h e c h a n g e s w e r e n o n - s p e c i f i c b u t n o t s e c o n d a r y to a r t i f a c t s . T h e m a j o r c h a n g e o b s e r v e d w a s an i n c r e a s e in fibrous a s t r o c y t e s , as c o m p a r e d w i t h a control macaque which had not received chlorpromazine. T h e r e h a v e b e e n no s t u d i e s o f a c o m b i n a t i o n o f s t r u c t u r a l l e s i o n s a n d d r u g s . S a x (personal communication) has recently reported marked increase of abnormal movem e n t s p r o d u c e d b y L - d o p a w h e n t h e d r u g is c o m b i n e d w i t h l e s i o n s in t h e c a u d a t e . S i n c e t a r d i v e d y s k i n e s i a is m o r e l i k e l y w h e n the p a t i e n t is o l d e r o r b r a i n d a m a g e d , s i m i l a r e f f e c t s m a y b e t r u e in m o n k e y s . In s u m m a r y , t h e r e is n o d o u b t t h a t c h r o n i c u s a g e o f p h e n o t h i a z i n e s l e a d s to n e u r o p h y s i o l o g i c e f f e c t s , p a r t i c u l a r l y p o t e n t i a t i o n of s e i z u r e a c t i v i t y w i t h s o m e c o m p o u n d s . E v e n less e q u i v o c a l , c h r o n i c d o s a g e w i t h c h l o r p r o m a z i n e in r h e s u s c a n p r o d u c e a c o m p l e x s i m i l a r to the t a r d i v e d y s k i n e s i a o f h u m a n s . T h i s o c c u r s m u c h l a t e r t h a n t h e a n t i c i p a t e d s e d a t i v e effect, a n d is p r o b a b l y d o s a g e r e l a t e d . It s e e m s p r o b a b l e t h a t at l e a s t o n e b u t y r o p h e n o n e , h a l o p e r i d o l , is r e l a t i v e l y less l i k e l y to p r o d u c e e x t r a p y r a m i d a l e f f e c t s in m o n k e y s .
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