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Can neuroleptics influence the function of the brain hemispheres asymmetrically?
Neuropharmacology Vol. 23, No. 1, pp. 79-82, 1984 Printed in Great Britain. All rights reserved
0028-3908184 $3.00+ 0.00 Copyright 0 1984Pergamon Press Ltd
CAN NEUROLEPTICS INFLUENCE THE FUNCTION OF THE BRAIN HEMISPHERES ASYMMETRICALLY? J. FRITZE Neurologische Klinik, Knappschafts-Krankenhaus Bochum-Langendreer, D-4630 Bochum 7, FRG
Universititsklinik,
(Accepted 7 June 1983) Summary-A long-term intracarotid tube was implanted in 32 rats. Intracarotid injection of 4 different neuroleptics (haloperidol, cis- and tmns-flupenthixol, clopenthixol and reserpine) elicited a typical posture with abduction of the limbs on one side and and adduction on the other. Only the neuroleptically-active &-isomers of flupenthixol and clopenthixol provoked this dystonic reaction. The posture spontaneously vanished after 24 hr and could be antagonized with the anticholinergic biperiden. Sham injections of Ringer’s solution and isotonic glucose proved to be behaviourally inert. These results indicate an asymmetric distribution of the drugs in this experimental procedure. Their implications concerning drug-induced and spontaneous dystonias as well as psythopathology are discussed. Key words: neuroleptics, dystonia, schizophrenia, laterality.
as well as the extrapyramidal, effects of neuroleptics are ascribed to their antagonistic competition with the neurotransmitter dopamine at its receptor sites (Seeman, Lee, Chau-Wong and Wong, 1976; Snyder, Banerjee, Yamamura and Greenberg, 1974; Snyder, 1981). Psychophysiological investigations indicate an abnormal brain asymmetry to be involved in the pathogenesis of schizophrenia (for review see Wexler, 1980). This abnormal asymmetry has been found to be reversed with treatment with neuroleptics (Wexler and Heninger, 1979). Otherwise, Tomer, Mintz and Myslobodski (1982) have argued that at least some of the psychophysiological parameters found to indicate abnormal brain asymmetry in schizophrenia might be the consequence of treatment with neuroleptics rather than inherent to psychosis. Long-term treatment with neuroleptics may cause tardive dyskinesia (TD) which is ascribed to supersensitivity of dopamine receptors (Baldessarini, 1980; Klawans, Goetz and Perlik, 1980). Waziri (1980) postulated the asymmetric phenomena in tardive dyskinesia to be due to asymmetric supersensitivity of dopamine receptors which might be the consequence of a difference of blood supply and thus drug supply between the hemispheres. A (even interhemispherically) differential blood supply, depending on regional neuronal activity, is well documented (Dabbs and Choo, 1980; Deshmukh and Meyer, 1978; Lassen, Ingvar and Skinhoj, 1978). The scope of the present investigation was to find an animal system in which Waziri’s (1980) hypothesis of a functionally-relevant interhemispheric gradient of neuroleptics could be tested. Wada (1949), introduced the method of intracarotid administration of sodium amytal to determine the side of speech dom-
inance. Terzian (1964), demonstrated specific effects on mood in humans depending on the side of injection of sodium amytal. Thus, this procedure appeared to be promising for application to neuroleptics.
The antipsychotic,
METHODS Thirty-two male Wistar rats, weighing 250-400 g were used. They were maintained 2 per cage with a 12 hr light-dark cycle and free access to food and
water. Room temperaturp was kept constant at 25°C. After being operated on, the rats had to be maintained singly in order to prevent them from destroying the plaster fixation of the outer part of their intracarotid tube. Rats were tested for laterality of motor behaviour before and after the operation as well as under the influence of drugs, using observation of spontaneous behaviour in the open field (2 x 2m), the tail suspension test (Myslobodski and Braun, 1980), and an additional simple method where the animal was suspended at its centre of gravity by one finger of each hand and then let suddenly fall from a height of about 10 cm. The o’ ;ation was performed under pentobarbit 2 anaesthesia (30 mg/kg). After a median ventrai ncision of the neck, the a. carotis communis was prepared and carefully separated from n. vagus. As the polyethylene tube would obliterate the artery completely (outer diameter 0.6 mm) the latter was tied up on the heart side of the planned incision. Thus, severe bleeding was avoided. Surgical silk (size zero) was used. Another 2 threads were laid, the cranial one for avoiding bleeding by cautiously pulling and the other for tieing up the tube after its implantation. The artery was incised by ophthalmological scissors. After the tube had been implanted it 79
80
J. FRITZE Table I. Synopsis of the effects of intracarotid
injection of various neuroleptics
Posture Duration -.__ Drug------_._-~.Haloperidoi Cis-flupcnthixol Trans-flupenthixol Cis-clopenthixol ~r~~s-cIo~nthixol Reserpine Ringer’s solution
Abduction ipsilateral IO/IO (5/5r t- S/51) 5/14 (4/5r + l/91) 0 5/s (31% + 2131) 0 518 (2/3r + 3jSl) 0
Exit under ipsilateral abduction and torsion
posture
Antagonism of posture by ~____ biperiden
24 hr
+
0
5114 (1/5r+4/91) 0
24hr
+
218 (1/5r + l/31)
24hr
i-
0 40 hr
O?
2/14 (2/90 2114 Q/91) l/8 (ll5r) 0 I/S (1/3r) 0
Of
Contralateral _____~_ 0
2;8 (2151) 0
0
0
Contralateral seizures --_-. -. 4;10 0 0 0 0 0 0
Two rats received haloperidol and flupenthixol, 2 rats flupenthixol and clopenthixol, 4 rats clopenthixol and reserpine. The other 24 rats received only one type. of neuroleptic or both stereoisomers, respectively. The denominator gives the total of animals tested for this neuroleptic. 7” and “1” indicate injection into the right or left a. car&s communlr, respectiveiy.
was additionally fixed by the thread of the proximal ligature. The third thread was then removed. The tube was laid in a subcutaneous circle in order to allow the rat to move its head without risk of injury. The wound was closed by button sutures and the tube fixed by circular plaster behind the front limbs. The tube terminated in a cannula attached to a syringe. Thus, the tube could be drained with Ringer’s solution, avoiding access of air. Draining prevented the blood from clotting. The volume of the tube and cannula was 50~1. Immediately after the operation 200 ~1 of heparin (1600 IU/ml in 14% glucose) were injected via the tube followed by daily instillations of 150 p I of this solution. Four neuroleptics (haloperidol, cis- and transflupenthixol, clopenthixol and reserpine) were injected into the right or left a. carotis via the tube, at intervals of at least 36 hr. Care was taken that the effect of the previous injection had completely ceased. Under the influence of the neuroleptics the rats refused to take in food and water. Therefore they were fed by daily injections of 20ml/kg of 5% glucose; the electrolytes were substituted by 6ml/kg of Ringer’s solution. Solutions of glucose, heparin, halo~ridol, biperiden, reserpine and Ringer’s solution were used sterile as for clinical application. Cisand trans-flupenthixol as well as clopenthixol (kind gift of Lundbeck Pharma, Copenhagen, Denmark) were dissolved in Ringer’s solution (1 mg/ml). RESULTS
The tube could be prevented from blocking up to a maximum of 16 days. The mean time of survival without blocking was 154 hr so that an average of 3 injections of drugs could be performed per animal, although 6 rats died within 3 hr after the injection of ~u~nthixol, clo~nthixol and reserpine, respectively (Table 1). With a latency of 3 min, these rats developed a severe torsion syndrome accompanied by strong abduction of the limbs ipsilaterial to the injection and adduction of the contralateral ones. The reason for this remained unclear; there was no cor-
relation with the type of stereoisomer or the dose used. Sham injections of Ringer’s solution or 5% glucose proved to be behaviourally inert. Postoperatively, intraperitoneal injection of haloperidol (3 mg/kg) induced catalepsy without any lateralized phenomena independent of the side of operation (3 rats). Intracarotid injection of haloperidol(O.3-9 mg/kg) within 2 min elicited a typical posture with abduction of the ipsilateral and adduction of the contralateral limbs. The posture was reproduceable in different individuals (3 trials each) and was more pronounced with increasing dose. It lasted about 24 hr (as far as could be judged by observation) and then vanished spontaneously. It was antagonized by biperiden (3mg/kg). Four of the rats suffered from transient seizures, limited to the contralateral limbs (Table 1). Intra~rotid injection of flu~nthixol and clopenthix01 both stereosp~ifi~lly elicited the same posture after a latency of about 30 min and again the posture was spontaneously reversible after 24 hr. Only the neuroleptically active cis-isomers (Seeman et al., 1976) were effective at a dose of 0.3-0.6 mg/kg while the trans-isomers were ineffective even at 3 mg/kg. The side of abduction varied (Table 1) and did not depend on the side of injection. Again the effect was antagonized by biperiden (3 mg/kg). Intracarotid injection of reserpine (3 mg/kg) also elicited the posture with a latency of about 30 min. The side of abduction varied and did not depend on the side of injection (Table 1). Here, the posture persisted for more than 40 hr. Biperiden (3 mg/kg) did not clearly antagonize the posture, although akinesis and muscular tension were reduced. Intracarotid injection of biperiden (1.5-3 mg/kg) only elicited anisocoria with a latency of 1 min which ended in bilateral mydriasis after another 2 min. In the anisocoria the side of primary mydriasis did not depend on the side of injection. This was seen only in 7 rats which were tested later with flupenthixol and clopenthixol. The side of primary mydriasis correlated with the side of abduction of the limbs after intracarotid injection of the cisisomers of these neuroleptics.
Neuroleptics
and brain
As the methods of observation were quite crude and the number of animals small a statistical analysis seemed unsuitable. DISCUSSION
Intracarotid injection of drugs was introduced by Wada (1949). In humans, the asymmetric erect of amytal lasts for only 5 min. This dilrers from the duration of the effects of neuroleptics of more than 24 hr as demonstrated here in the rat. The asymmetric posture phenomenon has already been described in the rat with systemic administration of reserpine following unilateral lesions of the striatum (And& 1967). Thus. the present investigation has established an experimental system functionally-induced behavioural asymmetry, without anatomical brain lesions. This behavioural asymmetry may be interpreted as indicating an asymmetric distribution of the neuroleptics between the hemispheres in this system. However, simple methods of observation were chosen in order to search for phenomena. indicating drugdependent lateralized behaviour after intracarotid administration. Despite their simplicity they clearly revealed asymmetric behaviour following administration of 4 direrent neuroleptics. The functional effectiveness of these neuroleptics could be shown by comparing the efficiency of the stereoisomers. by the spontaneous and drug-induced reversibility. and by the ineffectiveness of sham injections. The relatively large doses correspond to those used in other studies (Campbell and Baldessarini, I98 I ; Hermoni, Lerer, Ebstein and Belmaker, 1980; Seeger. Thal and Garner, 1982). The reason why the latency of onset of the action of the drug after the injection diverged between haloperidol on the one hand and flupenthixol, clopenthixol and reserpine on the other, remains unclear. The same is true concerning whether or not the abduction of the limbs occurred ipsilateral or contralateral to the side of injection. Here again the divergence between haloperidol and the other neuroleptics was striking. Perhaps the long-latency-sidevariable neuroleptics pass the blood-brain barrier less readily and thus act on the brain during their second pass. Here, an unequal distribution could result from occlusion of the one artery. The variability of this supposed second pass effect might be due to differences of the vascular system (Willis’ circle) known in humans to depend even on age. Interactions between consecutive injections of drug in the same animal cannot be excluded because effects of neuroleptic have been found to persist for 7 days (Campbell and Baldessarini, 1982). Such long intervals could not be maintained in these experiments for technical reasons. It must be considered that the investigations of Nagayama, Takagi. Sakurai, Yoshimoto, Nishiwaki and Takahashi (1979) were not disturbed by applying neuroleptics 4 times a day. Tolerance to the neuroleptics (Campbell and Bald-
asymmetry
81
essarini, 1981) due to repeated injections cannot be excluded. It is ascribed to receptor supersensitivity. This is thought to be responsible for tardive dyskinesia (Baldessarini, 1980; Klawans et al., 1980). Waziri’s (1980) specification of this concept towards an asymmetric supersensitivity could be further elucidated by the experimental procedure presented here including in vitro analysis of receptors. Until now. sensitivity of dopamine receptors has not been measured separately in the two hemispheres. either in animals or in humans. Local sensitivity of dopamine receptors might depend on local concentrations of dopamine which might again depend on local blood supply. In the rat, side ditrerences of concentrations of dopamine seem to be behaviourally relevant (Click, Jerussi, Waters and Green. 1974: Denenberg. 1981). It might be speculated that the posturing phenomenon represents an analogy to the often asymmetric acute dystonias observed in humans under treatment with neuroleptics. The pathomechanism of the acute dystonias is still poorly understood (Baldessarini, 1980; Gardos, 1981). In this context it would have been interesting to examine the efTect of unilateral injection of clozapine. which is almost devoid 01 extrapyramidal side effects (Simpson and Varga. 1974). and supposedly does not induce supersensitivity of striatal dopamine receptors (Creese and Snyder, 1980). However, the intracarotid injection of its oily solution seemed too risky and uncalculable effects of the carrier had to be expected. Waziri’s (1980) hypothesis of differential effects of drugs due to an unequal blood -&pply to the hemispheres leads to the further question of whether this differential supply, for example with prescursors of neurotransmitters (Growdon, Cohen and Wurtman. 1977), may be psychophysiologically and psychopathologically as relevant as demonstrated for motor function in the rat here. That is, may the dependency of regional blood flow on regional neuronal activity (Deshmukh and Meyer, 1978; Lassen cl/ N/., 1978) occur inversely, too? This question seems important in view of lateralized abnormalities of cerebral blood flow in schizophrenia (Methew. Meyer, Francis. Schoolar, Weinman and Mortel. I98 I ), and in view of the dopamine hypothesis of schizophrenia (Snyder. 1981). A differential supply by neuroactive substances might induce differential receptor sensitivities not only in tardive dyskinesia (Waziri’s hypothesis, 1980). but also in schizophrenia itself. Perhaps the biochemical and pharmacological concepts of brain function should be specified to the concept of two difrerentially specialized. although intensively-interactm; :.*-pans (Bradshaw and Nettleton. 1981). If their , “;‘,:.-ential blood supply is functionally relevant in .his respect, then a differential treatment might be superior to a global one. An analogy may be see I to Cur’s ( 1978. 1979) proposition of a lateralized p:ychotherapy based on the differential cognitive proc,!ssing of the hemi-
82
J. FRITZE
spheres. Perhaps intracarotid application of drugs (Wada, 1949) allows a pharmacologically differential treatment of the brain hemispheres, if the risks of intracarotid injection can be justified in humans. This method could also have therapeutic implications in neurological diseases, like spasmodic torticollis and related disorders, where the putative asymmetry of biochemical parameters still has to be elucidated. Acknowledgement-I wish to thank Professor Dr Max-Paul Engelmeier, Direktor der Rheinischen Landes- und Hochschulklinik fur Psychiatric, D-4300 Essen, FRG, for his kind support. REFERENCES Andtn N.-E. (1967) Physiology and pharmacology of the nigro-neostriatal dopamine neurons. In: Progress in Neurogenetics (Barbeau A. and Brunette J. R., Eds), pp. 265-27 1. Excerpta-Medica Fdn, Amsterdam. Bdldessdrini R. J. (1980) Dopamine and the pathophysiology of dyskinesias induced by antipsychotic drugs. A. Rev. Neurosci. 3: 23-41. Bradshaw J. L. and Nettleton N. C. (1981) The nature of hemispheric specialization in man. Behau. Brain Sci. 4: 51-91. Campbell A. and Baldessarini R. J. (1981) Tolerance to behavioral effects of prolonged administration of haloperidol. Life Sci. 29: i341-1346. Campbell A. and Baldessarini R. J. (1982) Circadian changes in behavioral effects of haloperidol in rats. Psychopharmacology 17: 150-I 55. Creese I. and Snyder S. H. (1980) Chronic neuroleptic treatment and dopamine receptor regulation. In: LongTerm Effects of’ Neuroleptics (Cattabeni F., Racagni G., Spano P. F. and Costa E., Eds), pp. 89-94. Raven Press, New York. Dabbs J. M. Jr and Choo G. (1980) Left-right carotid blood flow predicts specialized mental ability. Neuropsychologia 18: 711-713. Denenberg V. H. (1981) Hemispheric laterality in animals and the effects of early experience. Behav. Brain Sci. 4: 149. Deshmukh V. D. and Meyer J. S. (1978) Noninvasive Measurement of Regional-Cerebral Blood Plow in Man. S.P. Medical and Scientific Books. New York. Gardos G. (1981) Dystonic reactions during maintenance antipsychotic therapy. Am. J. Psychiat. 1%: 114-115. Click S. D.. Jerussi T. P.. Waters D. H. and Green J. P. (1974) Amphetamine-induced changes in striatal dopamine and acetylcholine levels and relationship to rotation (circling behavior) in rats. Biochem. Pharmac. 23: 3223-3225. Growdon J. H., Cohen E. L. and Wurtman R. J. (1977) Treatment of brain disease with dietary precursors of neurotransmitters. A. int. Med. 86: 337-339. Cur R. E. (1978) Left hemisphere dysfunction and left
hemisphere overactivation in schizophrenia. J. abnorm. Psychol. 87: 226238. Cur R. E. (1979) Cognitive concomitants of hemispheric dysfunction in schizophrenia. Archs gen. Psychiat. 36: 269-274. Hermoni M., Lerer B., Ebstein R. P. and Belmaker R. H. (1980) Chronic lithium prevents reserpine-induced supersensitivity of adenylate cyclase. J. Pharm. Pharmac. 32: 510-511. Klawans H. L., Goetz C. G. and Perlik S. (1980) Tardive dyskinesia: Review and update. Am. J. Psychiat. 137: 900-908. Lassen N. A., Ingvar D. H. and Skinhoj E. (1978) Brain function and blood flow. Sci. Am. 239: 62-64. Methew R. J., Meyer J. S., Francis D. J., Schoolar J. C., Weinman M. and Mortel K. F. (1981) Regional cerebral blood flow in schizophrenia: a preliminary report. Am. J. Psychiat. 138: 112-l 13. Myslobodski M. S. and Braun H. (1980) Postural asymmetry and directionality of rotation in rats. Pharmac. Biochem. Behav. 13: 743-745. Nagayama H., Takagi A., Sakurai Y., Yoshimoto S., Nishiwaki K. and Takahashi R. (1979) Chronopharmacological study of neuroleptics. III. Circadian rhythm of brain susceptibility to haloperidol. Psychopharmacology 63: 131-135. Seeger T. F., Thai L. and Garner E. L. (1982) Behavioral and biochemical aspects of neuroleptic-induced dopaminergic supersensitivity: studies with chronic clozapine and haloperidol. Psychopharmacology 76: 182-187. Seeman P., Lee T., Chau-Wong M. and Wong K. (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261: 717-718. Simpson G. M. and Varga E. (1974) Clozapine, a new antipsychotic agent. Curr. Ther. Res. 16: 679-686. Snyder S. H., Banerjee S. R., Yamamura H. J. and Greenberg D. (1974) Drugs, neurotransmitters and schizophrenia. Science 184: 1243-1253. Snyder S. H. (1981) Dopamine receptors, neuroleptics and schizophrenia. Am. J.. Psychiat. l%k 460-464. _ Terzian H. (1964) Behavioral and EEG effects of intracarotid sodium’ amytal injections. Acta Neurochir. 12: 23&240. Tomer R., Mintz M. and Myslobodski M. S. (1982) Left hemisphere hyperactivity in schizophrenia: Abnormality inherent to psychosis or neuroleptic side effect? Psychopharmacology 17: 168-170. Wada J. (1949) A new method for the determination of the side of cerebral speech dominance. Med. Biol. 14: 221-222. Waziri R. (1980) Lateralization of neuroleptic-induced dyskinesia indicates pharmacologic asymmetry in the brain. Psychopharmacology 68: 51-53. Wexler B. E. and Heninger G. R. (1979) Alterations in cerebral laterality during acute psychotic illness. Archs gen. Psychiat. 36: 278-284. Wexler B. E. (1980) Cerebral laterality and psychiatry: a review of the literature. Am. J. Psychiat. 137: 279-291.
0028-3908184 $3.00+ 0.00 Copyright 0 1984Pergamon Press Ltd
CAN NEUROLEPTICS INFLUENCE THE FUNCTION OF THE BRAIN HEMISPHERES ASYMMETRICALLY? J. FRITZE Neurologische Klinik, Knappschafts-Krankenhaus Bochum-Langendreer, D-4630 Bochum 7, FRG
Universititsklinik,
(Accepted 7 June 1983) Summary-A long-term intracarotid tube was implanted in 32 rats. Intracarotid injection of 4 different neuroleptics (haloperidol, cis- and tmns-flupenthixol, clopenthixol and reserpine) elicited a typical posture with abduction of the limbs on one side and and adduction on the other. Only the neuroleptically-active &-isomers of flupenthixol and clopenthixol provoked this dystonic reaction. The posture spontaneously vanished after 24 hr and could be antagonized with the anticholinergic biperiden. Sham injections of Ringer’s solution and isotonic glucose proved to be behaviourally inert. These results indicate an asymmetric distribution of the drugs in this experimental procedure. Their implications concerning drug-induced and spontaneous dystonias as well as psythopathology are discussed. Key words: neuroleptics, dystonia, schizophrenia, laterality.
as well as the extrapyramidal, effects of neuroleptics are ascribed to their antagonistic competition with the neurotransmitter dopamine at its receptor sites (Seeman, Lee, Chau-Wong and Wong, 1976; Snyder, Banerjee, Yamamura and Greenberg, 1974; Snyder, 1981). Psychophysiological investigations indicate an abnormal brain asymmetry to be involved in the pathogenesis of schizophrenia (for review see Wexler, 1980). This abnormal asymmetry has been found to be reversed with treatment with neuroleptics (Wexler and Heninger, 1979). Otherwise, Tomer, Mintz and Myslobodski (1982) have argued that at least some of the psychophysiological parameters found to indicate abnormal brain asymmetry in schizophrenia might be the consequence of treatment with neuroleptics rather than inherent to psychosis. Long-term treatment with neuroleptics may cause tardive dyskinesia (TD) which is ascribed to supersensitivity of dopamine receptors (Baldessarini, 1980; Klawans, Goetz and Perlik, 1980). Waziri (1980) postulated the asymmetric phenomena in tardive dyskinesia to be due to asymmetric supersensitivity of dopamine receptors which might be the consequence of a difference of blood supply and thus drug supply between the hemispheres. A (even interhemispherically) differential blood supply, depending on regional neuronal activity, is well documented (Dabbs and Choo, 1980; Deshmukh and Meyer, 1978; Lassen, Ingvar and Skinhoj, 1978). The scope of the present investigation was to find an animal system in which Waziri’s (1980) hypothesis of a functionally-relevant interhemispheric gradient of neuroleptics could be tested. Wada (1949), introduced the method of intracarotid administration of sodium amytal to determine the side of speech dom-
inance. Terzian (1964), demonstrated specific effects on mood in humans depending on the side of injection of sodium amytal. Thus, this procedure appeared to be promising for application to neuroleptics.
The antipsychotic,
METHODS Thirty-two male Wistar rats, weighing 250-400 g were used. They were maintained 2 per cage with a 12 hr light-dark cycle and free access to food and
water. Room temperaturp was kept constant at 25°C. After being operated on, the rats had to be maintained singly in order to prevent them from destroying the plaster fixation of the outer part of their intracarotid tube. Rats were tested for laterality of motor behaviour before and after the operation as well as under the influence of drugs, using observation of spontaneous behaviour in the open field (2 x 2m), the tail suspension test (Myslobodski and Braun, 1980), and an additional simple method where the animal was suspended at its centre of gravity by one finger of each hand and then let suddenly fall from a height of about 10 cm. The o’ ;ation was performed under pentobarbit 2 anaesthesia (30 mg/kg). After a median ventrai ncision of the neck, the a. carotis communis was prepared and carefully separated from n. vagus. As the polyethylene tube would obliterate the artery completely (outer diameter 0.6 mm) the latter was tied up on the heart side of the planned incision. Thus, severe bleeding was avoided. Surgical silk (size zero) was used. Another 2 threads were laid, the cranial one for avoiding bleeding by cautiously pulling and the other for tieing up the tube after its implantation. The artery was incised by ophthalmological scissors. After the tube had been implanted it 79
80
J. FRITZE Table I. Synopsis of the effects of intracarotid
injection of various neuroleptics
Posture Duration -.__ Drug------_._-~.Haloperidoi Cis-flupcnthixol Trans-flupenthixol Cis-clopenthixol ~r~~s-cIo~nthixol Reserpine Ringer’s solution
Abduction ipsilateral IO/IO (5/5r t- S/51) 5/14 (4/5r + l/91) 0 5/s (31% + 2131) 0 518 (2/3r + 3jSl) 0
Exit under ipsilateral abduction and torsion
posture
Antagonism of posture by ~____ biperiden
24 hr
+
0
5114 (1/5r+4/91) 0
24hr
+
218 (1/5r + l/31)
24hr
i-
0 40 hr
O?
2/14 (2/90 2114 Q/91) l/8 (ll5r) 0 I/S (1/3r) 0
Of
Contralateral _____~_ 0
2;8 (2151) 0
0
0
Contralateral seizures --_-. -. 4;10 0 0 0 0 0 0
Two rats received haloperidol and flupenthixol, 2 rats flupenthixol and clopenthixol, 4 rats clopenthixol and reserpine. The other 24 rats received only one type. of neuroleptic or both stereoisomers, respectively. The denominator gives the total of animals tested for this neuroleptic. 7” and “1” indicate injection into the right or left a. car&s communlr, respectiveiy.
was additionally fixed by the thread of the proximal ligature. The third thread was then removed. The tube was laid in a subcutaneous circle in order to allow the rat to move its head without risk of injury. The wound was closed by button sutures and the tube fixed by circular plaster behind the front limbs. The tube terminated in a cannula attached to a syringe. Thus, the tube could be drained with Ringer’s solution, avoiding access of air. Draining prevented the blood from clotting. The volume of the tube and cannula was 50~1. Immediately after the operation 200 ~1 of heparin (1600 IU/ml in 14% glucose) were injected via the tube followed by daily instillations of 150 p I of this solution. Four neuroleptics (haloperidol, cis- and transflupenthixol, clopenthixol and reserpine) were injected into the right or left a. carotis via the tube, at intervals of at least 36 hr. Care was taken that the effect of the previous injection had completely ceased. Under the influence of the neuroleptics the rats refused to take in food and water. Therefore they were fed by daily injections of 20ml/kg of 5% glucose; the electrolytes were substituted by 6ml/kg of Ringer’s solution. Solutions of glucose, heparin, halo~ridol, biperiden, reserpine and Ringer’s solution were used sterile as for clinical application. Cisand trans-flupenthixol as well as clopenthixol (kind gift of Lundbeck Pharma, Copenhagen, Denmark) were dissolved in Ringer’s solution (1 mg/ml). RESULTS
The tube could be prevented from blocking up to a maximum of 16 days. The mean time of survival without blocking was 154 hr so that an average of 3 injections of drugs could be performed per animal, although 6 rats died within 3 hr after the injection of ~u~nthixol, clo~nthixol and reserpine, respectively (Table 1). With a latency of 3 min, these rats developed a severe torsion syndrome accompanied by strong abduction of the limbs ipsilaterial to the injection and adduction of the contralateral ones. The reason for this remained unclear; there was no cor-
relation with the type of stereoisomer or the dose used. Sham injections of Ringer’s solution or 5% glucose proved to be behaviourally inert. Postoperatively, intraperitoneal injection of haloperidol (3 mg/kg) induced catalepsy without any lateralized phenomena independent of the side of operation (3 rats). Intracarotid injection of haloperidol(O.3-9 mg/kg) within 2 min elicited a typical posture with abduction of the ipsilateral and adduction of the contralateral limbs. The posture was reproduceable in different individuals (3 trials each) and was more pronounced with increasing dose. It lasted about 24 hr (as far as could be judged by observation) and then vanished spontaneously. It was antagonized by biperiden (3mg/kg). Four of the rats suffered from transient seizures, limited to the contralateral limbs (Table 1). Intra~rotid injection of flu~nthixol and clopenthix01 both stereosp~ifi~lly elicited the same posture after a latency of about 30 min and again the posture was spontaneously reversible after 24 hr. Only the neuroleptically active cis-isomers (Seeman et al., 1976) were effective at a dose of 0.3-0.6 mg/kg while the trans-isomers were ineffective even at 3 mg/kg. The side of abduction varied (Table 1) and did not depend on the side of injection. Again the effect was antagonized by biperiden (3 mg/kg). Intracarotid injection of reserpine (3 mg/kg) also elicited the posture with a latency of about 30 min. The side of abduction varied and did not depend on the side of injection (Table 1). Here, the posture persisted for more than 40 hr. Biperiden (3 mg/kg) did not clearly antagonize the posture, although akinesis and muscular tension were reduced. Intracarotid injection of biperiden (1.5-3 mg/kg) only elicited anisocoria with a latency of 1 min which ended in bilateral mydriasis after another 2 min. In the anisocoria the side of primary mydriasis did not depend on the side of injection. This was seen only in 7 rats which were tested later with flupenthixol and clopenthixol. The side of primary mydriasis correlated with the side of abduction of the limbs after intracarotid injection of the cisisomers of these neuroleptics.
Neuroleptics
and brain
As the methods of observation were quite crude and the number of animals small a statistical analysis seemed unsuitable. DISCUSSION
Intracarotid injection of drugs was introduced by Wada (1949). In humans, the asymmetric erect of amytal lasts for only 5 min. This dilrers from the duration of the effects of neuroleptics of more than 24 hr as demonstrated here in the rat. The asymmetric posture phenomenon has already been described in the rat with systemic administration of reserpine following unilateral lesions of the striatum (And& 1967). Thus. the present investigation has established an experimental system functionally-induced behavioural asymmetry, without anatomical brain lesions. This behavioural asymmetry may be interpreted as indicating an asymmetric distribution of the neuroleptics between the hemispheres in this system. However, simple methods of observation were chosen in order to search for phenomena. indicating drugdependent lateralized behaviour after intracarotid administration. Despite their simplicity they clearly revealed asymmetric behaviour following administration of 4 direrent neuroleptics. The functional effectiveness of these neuroleptics could be shown by comparing the efficiency of the stereoisomers. by the spontaneous and drug-induced reversibility. and by the ineffectiveness of sham injections. The relatively large doses correspond to those used in other studies (Campbell and Baldessarini, I98 I ; Hermoni, Lerer, Ebstein and Belmaker, 1980; Seeger. Thal and Garner, 1982). The reason why the latency of onset of the action of the drug after the injection diverged between haloperidol on the one hand and flupenthixol, clopenthixol and reserpine on the other, remains unclear. The same is true concerning whether or not the abduction of the limbs occurred ipsilateral or contralateral to the side of injection. Here again the divergence between haloperidol and the other neuroleptics was striking. Perhaps the long-latency-sidevariable neuroleptics pass the blood-brain barrier less readily and thus act on the brain during their second pass. Here, an unequal distribution could result from occlusion of the one artery. The variability of this supposed second pass effect might be due to differences of the vascular system (Willis’ circle) known in humans to depend even on age. Interactions between consecutive injections of drug in the same animal cannot be excluded because effects of neuroleptic have been found to persist for 7 days (Campbell and Baldessarini, 1982). Such long intervals could not be maintained in these experiments for technical reasons. It must be considered that the investigations of Nagayama, Takagi. Sakurai, Yoshimoto, Nishiwaki and Takahashi (1979) were not disturbed by applying neuroleptics 4 times a day. Tolerance to the neuroleptics (Campbell and Bald-
asymmetry
81
essarini, 1981) due to repeated injections cannot be excluded. It is ascribed to receptor supersensitivity. This is thought to be responsible for tardive dyskinesia (Baldessarini, 1980; Klawans et al., 1980). Waziri’s (1980) specification of this concept towards an asymmetric supersensitivity could be further elucidated by the experimental procedure presented here including in vitro analysis of receptors. Until now. sensitivity of dopamine receptors has not been measured separately in the two hemispheres. either in animals or in humans. Local sensitivity of dopamine receptors might depend on local concentrations of dopamine which might again depend on local blood supply. In the rat, side ditrerences of concentrations of dopamine seem to be behaviourally relevant (Click, Jerussi, Waters and Green. 1974: Denenberg. 1981). It might be speculated that the posturing phenomenon represents an analogy to the often asymmetric acute dystonias observed in humans under treatment with neuroleptics. The pathomechanism of the acute dystonias is still poorly understood (Baldessarini, 1980; Gardos, 1981). In this context it would have been interesting to examine the efTect of unilateral injection of clozapine. which is almost devoid 01 extrapyramidal side effects (Simpson and Varga. 1974). and supposedly does not induce supersensitivity of striatal dopamine receptors (Creese and Snyder, 1980). However, the intracarotid injection of its oily solution seemed too risky and uncalculable effects of the carrier had to be expected. Waziri’s (1980) hypothesis of differential effects of drugs due to an unequal blood -&pply to the hemispheres leads to the further question of whether this differential supply, for example with prescursors of neurotransmitters (Growdon, Cohen and Wurtman. 1977), may be psychophysiologically and psychopathologically as relevant as demonstrated for motor function in the rat here. That is, may the dependency of regional blood flow on regional neuronal activity (Deshmukh and Meyer, 1978; Lassen cl/ N/., 1978) occur inversely, too? This question seems important in view of lateralized abnormalities of cerebral blood flow in schizophrenia (Methew. Meyer, Francis. Schoolar, Weinman and Mortel. I98 I ), and in view of the dopamine hypothesis of schizophrenia (Snyder. 1981). A differential supply by neuroactive substances might induce differential receptor sensitivities not only in tardive dyskinesia (Waziri’s hypothesis, 1980). but also in schizophrenia itself. Perhaps the biochemical and pharmacological concepts of brain function should be specified to the concept of two difrerentially specialized. although intensively-interactm; :.*-pans (Bradshaw and Nettleton. 1981). If their , “;‘,:.-ential blood supply is functionally relevant in .his respect, then a differential treatment might be superior to a global one. An analogy may be see I to Cur’s ( 1978. 1979) proposition of a lateralized p:ychotherapy based on the differential cognitive proc,!ssing of the hemi-
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spheres. Perhaps intracarotid application of drugs (Wada, 1949) allows a pharmacologically differential treatment of the brain hemispheres, if the risks of intracarotid injection can be justified in humans. This method could also have therapeutic implications in neurological diseases, like spasmodic torticollis and related disorders, where the putative asymmetry of biochemical parameters still has to be elucidated. Acknowledgement-I wish to thank Professor Dr Max-Paul Engelmeier, Direktor der Rheinischen Landes- und Hochschulklinik fur Psychiatric, D-4300 Essen, FRG, for his kind support. REFERENCES Andtn N.-E. (1967) Physiology and pharmacology of the nigro-neostriatal dopamine neurons. In: Progress in Neurogenetics (Barbeau A. and Brunette J. R., Eds), pp. 265-27 1. Excerpta-Medica Fdn, Amsterdam. Bdldessdrini R. J. (1980) Dopamine and the pathophysiology of dyskinesias induced by antipsychotic drugs. A. Rev. Neurosci. 3: 23-41. Bradshaw J. L. and Nettleton N. C. (1981) The nature of hemispheric specialization in man. Behau. Brain Sci. 4: 51-91. Campbell A. and Baldessarini R. J. (1981) Tolerance to behavioral effects of prolonged administration of haloperidol. Life Sci. 29: i341-1346. Campbell A. and Baldessarini R. J. (1982) Circadian changes in behavioral effects of haloperidol in rats. Psychopharmacology 17: 150-I 55. Creese I. and Snyder S. H. (1980) Chronic neuroleptic treatment and dopamine receptor regulation. In: LongTerm Effects of’ Neuroleptics (Cattabeni F., Racagni G., Spano P. F. and Costa E., Eds), pp. 89-94. Raven Press, New York. Dabbs J. M. Jr and Choo G. (1980) Left-right carotid blood flow predicts specialized mental ability. Neuropsychologia 18: 711-713. Denenberg V. H. (1981) Hemispheric laterality in animals and the effects of early experience. Behav. Brain Sci. 4: 149. Deshmukh V. D. and Meyer J. S. (1978) Noninvasive Measurement of Regional-Cerebral Blood Plow in Man. S.P. Medical and Scientific Books. New York. Gardos G. (1981) Dystonic reactions during maintenance antipsychotic therapy. Am. J. Psychiat. 1%: 114-115. Click S. D.. Jerussi T. P.. Waters D. H. and Green J. P. (1974) Amphetamine-induced changes in striatal dopamine and acetylcholine levels and relationship to rotation (circling behavior) in rats. Biochem. Pharmac. 23: 3223-3225. Growdon J. H., Cohen E. L. and Wurtman R. J. (1977) Treatment of brain disease with dietary precursors of neurotransmitters. A. int. Med. 86: 337-339. Cur R. E. (1978) Left hemisphere dysfunction and left
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