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Significance of dopamine receptor antagonists in human postural control
Neuroscience Letters, 117 (1990) 81-86 Elsevier Scientific Publishers Ireland Ltd.
81
NSL 07102
Significance of dopamine receptor antagonists in human postural control V. D i e t z , T.J. F e u e r s t e i n a n d W . B e r g e r Department Clinical Neurology and Neurophysiology, University of Freiburg, Freiburg (F.R.G.) (Received 26 March 1990; Revised version received 7 May 1990; Accepted 9 May 1990) Key words: Stance regulation; Dopaminergic system; Parkinson's disease; Dopamine receptor antagonist; Proprioceptive reflex; Leg muscle electromyogram The purpose of this study was to investigate the effect of different dopamine receptor antagonists on the function of proprioceptive reflex mechanisms involved in the regulation of stance and gait. Haloperidol as preferential D2 and the 'pure' dopamine D2 receptor antagonist sulpiride significantly reduced the level of the reflex response in the gastrocnemius muscle following backward perturbation. Flupentixol, however, which in addition blocks DI receptors, had no effect on compensatory gastrocnemius EMG responses. Furthermore, neither the peripherally acting dopamine D2 receptor antagonist domperidon nor the sedative diazepam had any significant influence on this functionally essential reflex mechanism. None of the drugs tested had a significant effect on the tibialis anterior responses elicited following forward perturbation. It is concluded that the reduced stretch sensitivity of the gastrocnemius (but not that of the tibialis anterior) during perturbations of stance described for parkinsonian patients corresponds to these results and arises from an impaired function of central dopamine D2 receptors.
The normal function o f reflex mechanisms involved in h u m a n posture and locomotion has been shown to be dependent on supraspinal control: m o n o s y n a p t i c reflexes are inhibited [8, 12], with polysynaptic spinal reflexes representing the essential mechanism for the compensation o f irregularities o f the support surface [3]. W h e n this supraspinal control is impaired, in patients with spastic paresis, the inhibition o f m o n o s y n a p t i c reflexes is absent and the level o f polysynaptic reflex activity is reduced [4]. Parkinsonian patients represent another g r o u p o f patients with a m o t o r disorder due to impaired supraspinal control. In these patients alterations in central responsiveness [2] and defective utilization o f sensory input [13] have been suggested to be responsible for part o f the impaired m o t o r control. In a recent study [5], it was further shown that in Parkinson's disease the polysynaptic spinal reflex activity is reduced in postural control. It remained to be determined if this impairment o f polysynaptic spinal reflexes is directly m o d u l a t e d by d o p a m i n e receptors. Accordingly, the influence o f different Correspondence: V. Dietz, Department of Clinical Neurology and Neurophysiology, Hansastr. 9, 7800 Freiburg, F.R.G. 0304-3940/90/$ 03.50 © 1990 Elsevier Scientific Publishers Ireland Ltd.
82 drugs (with or without antagonistic effects at peripheral or central Di and D2 dopamine receptors) on the leg muscle E M G activity during various kinds of postural displacement was investigated. The aim of this study was to establish the extent to which spinal interneuronal mechanisms involved in the control of posture and locomotion are dependent on specific dopaminergic pathways. Surface electromyographic activity was recorded from the medial gastrocnemius and tibialis anterior muscles of the right leg during stance in 6 healthy subjects (mean age 24.1 years). The effect of a single dose of the following 5 drugs was tested: haloperidol (6 mg); flupentixol (6 mg); sulpiride (300 mg); domperidon (10 mg); and diazepam (5 mg). A relatively low dosage was chosen in order to avoid unwanted side effects (e.g. dyskinesia); this dosage was suggested to be equivalent for the different drugs (see discussion). In each case, administration of a drug was followed three days later by a test with placebo, then, two days later, by the next drug in the sequence. The order of the sessions was random and unknown to the subjects. The subjects were investigated immediately before, then 1.5, 3, 5 and 6.5 h after the intake of each drug. The pharmacological effects of each of the five drugs was explained to the subjects, who then gave their informed consent. All procedures were approved by the local ethical committee. Forward and backward acceleration impulses were induced while subjects stood on a treadmill (MTR 250-40, Woodway, Weil, F.R.G.). Four different accelerations were initiated in random order and the following displacements were achieved: (a) 5.5 m/s2:4 cm; (b) 11.1 m/s2:7 cm; (c) 16.6 m/s2:10.5 cm; (d) 22 m/s2:15 cm. Impulse duration was held constant at 90 ms. The onset of impulse delivered by a generator was used as a trigger signal for averaging the biomechanical and electromyographic signals. The ankle and knee joint angles were monitored by goniometers fixed at the lateral aspect of the foot, leg and thigh. The general technique for recording and analysing the electromyographic responses of leg muscles has been fully described in earlier papers [3,4,9]. For statistical assessment (SPSS package) the absolute gastrocnemius responses to all backward impulses and tibialis anterior responses to all forward impulses of all subjects were taken together. A multivariant analysis of variance (repeated measures design) was applied to the results from the subjects after the intake of one of the five specific drugs and to the control (placebo) values. The averaged EMG responses obtained from one subject during an experimental session (i.e. after intake of one drug) were then normalized to the averaged responses obtained before the intake of the drug. Fig. 1 shows the influence of haloperidol, sulpiride and flupentixol on the postural gastrocnemius EMG responses to backward perturbation. For each subject, the EMG response after intake of one of these drugs was normalized with respect to the responses before intake of the drug (time t = 0 ms). The mean EMG responses (with S.D.) to the impulses a~t of all 6 subjects are displayed. The course of the integrated gastrocnemius-EMG responses after intake of sulpiride, a D2 receptor antagonist with purely central action, was very similar to that obtained after intake of haloperidol. Compared to the time course of the postural responses with placebo, a signifi-
83 M.gQslrocnemius
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7h
I
Domperidon
Flupenlixol t
1
2
3
4
5
6
7h
0
1
2
3
4
5
6
7h
Fig. 1. Mean values (with S.D.) of the rectified, averaged (n = 10) and integrated gastrocnemius EMG responses following backward acceleration impulses (impulses a-d were taken together, see text) in 6 subjects before and at different times after intake of each drug. The mean values of the E M G responses after drug intake are normalized to the value obtained before intake of the drug (time t = 0 h) for each subject. Interrupted line indicates the placebo values, solid line the specific drug values. * P < 0.05; * * P < 0.01. (Significance was tested for the absolute values.)
cant reduction of the mean gastrocnemius E M G responses was observed which started 1.5 h after intake of both haloperidol and sulpiride. This depression of the E M G responses lasted over 6.5 h after administration of haloperidol (after this time no further recordings were performed) and 5 h after administration of sulpiride. The displacement velocity at the ankle as well as knee joints did not differ during this time course. The reduction in the E M G response did not lead to any visible failure to compensate for the perturbations. Also other motor disabilities were not observed or reported by the subjects (e.g. during writing). The background E M G activity ( - 40 ms to + 4 0 ms) was not different between the placebo and the haloperidol session. In contrast to haloperidol and sulpiride, flupentixol, a mixed D 1 and D2 antagonist, showed, 5 h after intake, only a weak, single effect on the strength of the gastrocnemius response. Fig. 1. shows also the effect of two additional substances on the gastrocnemius E M G responses: domperidon, which represents a dopamine D 2 receptor antagonist which does not cross the blood-brain barrier, and diazepam, which was selected in
84 order to investigate possible non-specific effects of the dopamine receptor antagonists, e.g. sedation or fatigue, on the postural reactions. Neither domperidon nor diazepam had a significant effect on the gastrocnemius E M G responses. The mean effect of the drugs over the time interval from 1.5 h to 5 h post application was also evaluated, since the markedly shorter half-life of sulpiride (t,.: = 8 h) had to be taken into account for comparability: using this measure, haloperidol and sulpiride did significantly ( P < 0.05) reduce the EMG responses, while the other substances (including flupentixol) had no effect compared to placebo. In addition, the influence of the different drugs on the compensatory tibialis anterior responses to forward perturbations was calculated in the same way as for the gastrocnemius: neither the centrally acting dopamine antagonists (haloperidol, sulpiride, flupentixol) nor the peripherally acting dopamine antagonist domperidon or diazepare had a significant effect on the E M G responses. In a recent study [5] it was demonstrated that parkinsonian patients show reduced polysynaptic reflexes in the leg extensor muscles during perturbation of stance and gait. This effect was also seen after the intake of haloperidol in young healthy subjects. The aim of this study was to discover the extent to which the function ofpolysynaptic reflexes depends on dopamine receptors. To our knowledge this investigation represents the first attempt to correlate D~ and D2 receptor function with functional aspects of motor control. From the results it is clear that: (1) the activity of the polysynaptic spinal reflexes is reduced by neuroleptic drugs with preferential affinity to D2 receptors; (2) the additional blockade of D~ receptors seems to counteract the effects seen with more or less pure D2 antagonists, since flupentixol is at least as potent as the other drugs in blocking D2 receptors [10]; (3) the peripheral action of dopamine antagonists does not significantly contribute to this spinal mechanism and, (4) nonspecific effects of these drugs, such as fatigue, drowsiness, or muscle relaxation, have no influence on the postural responses. Apart from flupentixol, all neuroleptics applied have a much higher affinity to D2 dopamine receptors than to Di receptors. Sulpiride and domperidgn are 'pure' D2 receptor blockers with a D2/DI affinity ratio of more than 800 (ratio of haloperidol: 358, ratio of flupentixol: 2; for ref. see ref. 10). The doses of the neuroleptics, with regard to their affinity for D2 dopamine receptors, may be assumed to be equivalent [10]. Thus, it was possible to investigate the influence of the additional D1 receptor blocking property of flupentixol. The duration of action of the different drugs used was also similar, with the exception of sulpiride (half-life of sulpiride only 8 h, as compared to 2 0 ~ 0 h of the other active drugs; for ref. see ref. 14). This was the reason to compare the mean effects of the drugs over the time interval from 1.5 to 5 h post application which compensates for the lower half-life time of sulpiride. The results obtained in this study support earlier suggestions that the interneuronal circuits (probably spinal [3]) which mediate the functional E M G responses are strongly dependent on supraspinal influence; (1) in patients with spastic paresis due to a supraspinal lesion, the polysynaptic responses are reduced or absent [4]; (2) in parkinsonian patients these E M G responses show a reduced stretch sensitivity which correlates with an inability to compensate for the perturbations [5].
85 In the present experiments, the reduction of the compensatory E M G responses after haloperidol and sulpiride was not connected with failure to compensate for the perturbations, as was the case in parkinsonian patients [5]. This is explained by the fact that the reduced responses of the normals were still significantly larger than those seen in the patients (cf. ref. 5). In addition, the dosage of the neuroleptics given to the volunteers was rather small. Because of the differential effects of peripherally and centrally acting dopamine receptor antagonists on the E M G responses, a peripheral effect of haloperidol and sulpiride can largely be excluded. One could argue, however, that the effects observed in the present study are due to a depression of vestibular function which also is involved in the regulation of stance and gait (for ref. see ref. 1). This seems, however, for the following reasons to be unlikely: (1) in patients without labyrinthine function, compensatory gastrocnemius E M G responses are preserved [11]; (2) on the basis of experiments using head and body tilts the vestibular system seems to contribute little to the compensation of fast feet displacement, being mainly involved in the regulation of slow body sway [6, 11]. An effect of haloperidol and sulpiride on the compensatory E M G responses was seen in the gastrocnemius following backward perturbations but not in the tibialis anterior following forward displacement of the feet. Similarly, in parkinsonian patients, only the leg extensor muscles showed a reduced stretch sensitivity [5]. This difference between the antagonistic leg muscles is not so surprising, given the different function fulfilled by these muscles during stance and gait [7]. It is suggested, that the reflex mechanisms involved in gastrocnemius activation are more under supraspinal dopaminergic control. The results obtained may help to understand the influences of dopaminergic central structures on the motor control in natural complex movements and their changes in patients with disorders of motor control. In addition, the results represent, on the one hand, a basis for the control of treatment with dopaminergic drugs in these patients and, on the other, for judgement of the motor impairment caused by therapeutic administration of neuroleptics in patients with psychiatric disorders. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 325). We thank Dr. S. Fellows for correcting the English text. Technical assistance was provided by M. Discher, Mrs. U. R6mmelt and Mrs. U. M611inger. 1 Allum, J.H.J. and Pfaltz, C.R., Visual and vestibular contributions to pitch sway stabilization in the ankle muscles of norrnals and patients with bilateral peripheral vestibular deficits, Exp. Brain Res., 58 (1985)82~4. 2 Berardelli, A., Sabra, A.F. and Hallett, M., Physiological mechanisms of rigidity in Parkinson's disease, J. Neurol. Neurosurg. Psychiatry,46 (1983)45-53. 3 Berger,W., Dietz, V. and Quintern, J., Correctivereactions to stumbling in man: neuronal co-ordination of bilateral leg muscle activityduring gait, J. Physiol.,357 (1984) 109-125. 4 Berger,W., Horstmann, G.A. and Dietz, V., Spastic paresis: impaired spinal reflexesand intact motor programs, J. Neurol. Neurosurg. Psychiat.,51 (1988)568-571. 5 Dietz, V., Berger, W. and Horstmann, G.A., Posture in Parkinson's disease: impairment of reflexes and programming, Ann. Neurol., 24 (1988)660q569.
86 6 Dietz, V., Horstmann, G.A. and Berger, W., Involvement of different receptors in the regulation of human posture, Neurosci. Lett., 94 (1988) 82-87. 7 Dietz, V., Horstmann, G.A. and Berger, W., Interlimb co-ordination of leg muscle activation during perturbation of stance in humans, J. Neurophysiol., 62 (1989) 680-4593. 8 Dietz, V., Quintern, J. and Berger, W., Corrective reactions to stumbling in man: functional significance of spinal and transcortical reflexes, Neurosci. Lett., 44 (1984) 131--135. 9 Dietz, V., Quintern, J. and Sillem, M., Stumbling reactions in man: significance of proprioceptive and pre-programmed mechanisms, J. Physiol., 386 (1987) 149 163. 10 Goodwin, G.M. and Metz, A., Neuroleptics. In D.G. Grahame-Smith (Ed.), Psychopharmacology 2, Part 1: Preclinical Psychopharmacology, Elsevier, Amsterdam, 1985, pp. 343 363. 11 Horstmann, G.A. and Dietz, V., The contribution of vestibular input to the stabilization of human posture: a new experimental approach, Neurosci. Lett., 95 (1988) 179 184. 12 Morin, C., Katz, R., Mazidres, L. and Pierrot-Deseilligny, E., Comparison of soleus H reflex facilitation at the onset of soleus contractions produced voluntarily and during the stance phase of human gait, Neurosci. Lett., 33 (1982) 47 53. 13 Tatton, W,G., Bedingham, V., Verrier, M.C. and Blair, R.D.G., Characteristic alterations in response to imposed wrist displacement in parkinsonian rigidity and dystonia musculorum deformans, Can. J. Neurol. Sci., I 1 (1983) 281 287. 14 Trimble, M., Biological Psychiatry, Wiley, Chichester, 1988.
81
NSL 07102
Significance of dopamine receptor antagonists in human postural control V. D i e t z , T.J. F e u e r s t e i n a n d W . B e r g e r Department Clinical Neurology and Neurophysiology, University of Freiburg, Freiburg (F.R.G.) (Received 26 March 1990; Revised version received 7 May 1990; Accepted 9 May 1990) Key words: Stance regulation; Dopaminergic system; Parkinson's disease; Dopamine receptor antagonist; Proprioceptive reflex; Leg muscle electromyogram The purpose of this study was to investigate the effect of different dopamine receptor antagonists on the function of proprioceptive reflex mechanisms involved in the regulation of stance and gait. Haloperidol as preferential D2 and the 'pure' dopamine D2 receptor antagonist sulpiride significantly reduced the level of the reflex response in the gastrocnemius muscle following backward perturbation. Flupentixol, however, which in addition blocks DI receptors, had no effect on compensatory gastrocnemius EMG responses. Furthermore, neither the peripherally acting dopamine D2 receptor antagonist domperidon nor the sedative diazepam had any significant influence on this functionally essential reflex mechanism. None of the drugs tested had a significant effect on the tibialis anterior responses elicited following forward perturbation. It is concluded that the reduced stretch sensitivity of the gastrocnemius (but not that of the tibialis anterior) during perturbations of stance described for parkinsonian patients corresponds to these results and arises from an impaired function of central dopamine D2 receptors.
The normal function o f reflex mechanisms involved in h u m a n posture and locomotion has been shown to be dependent on supraspinal control: m o n o s y n a p t i c reflexes are inhibited [8, 12], with polysynaptic spinal reflexes representing the essential mechanism for the compensation o f irregularities o f the support surface [3]. W h e n this supraspinal control is impaired, in patients with spastic paresis, the inhibition o f m o n o s y n a p t i c reflexes is absent and the level o f polysynaptic reflex activity is reduced [4]. Parkinsonian patients represent another g r o u p o f patients with a m o t o r disorder due to impaired supraspinal control. In these patients alterations in central responsiveness [2] and defective utilization o f sensory input [13] have been suggested to be responsible for part o f the impaired m o t o r control. In a recent study [5], it was further shown that in Parkinson's disease the polysynaptic spinal reflex activity is reduced in postural control. It remained to be determined if this impairment o f polysynaptic spinal reflexes is directly m o d u l a t e d by d o p a m i n e receptors. Accordingly, the influence o f different Correspondence: V. Dietz, Department of Clinical Neurology and Neurophysiology, Hansastr. 9, 7800 Freiburg, F.R.G. 0304-3940/90/$ 03.50 © 1990 Elsevier Scientific Publishers Ireland Ltd.
82 drugs (with or without antagonistic effects at peripheral or central Di and D2 dopamine receptors) on the leg muscle E M G activity during various kinds of postural displacement was investigated. The aim of this study was to establish the extent to which spinal interneuronal mechanisms involved in the control of posture and locomotion are dependent on specific dopaminergic pathways. Surface electromyographic activity was recorded from the medial gastrocnemius and tibialis anterior muscles of the right leg during stance in 6 healthy subjects (mean age 24.1 years). The effect of a single dose of the following 5 drugs was tested: haloperidol (6 mg); flupentixol (6 mg); sulpiride (300 mg); domperidon (10 mg); and diazepam (5 mg). A relatively low dosage was chosen in order to avoid unwanted side effects (e.g. dyskinesia); this dosage was suggested to be equivalent for the different drugs (see discussion). In each case, administration of a drug was followed three days later by a test with placebo, then, two days later, by the next drug in the sequence. The order of the sessions was random and unknown to the subjects. The subjects were investigated immediately before, then 1.5, 3, 5 and 6.5 h after the intake of each drug. The pharmacological effects of each of the five drugs was explained to the subjects, who then gave their informed consent. All procedures were approved by the local ethical committee. Forward and backward acceleration impulses were induced while subjects stood on a treadmill (MTR 250-40, Woodway, Weil, F.R.G.). Four different accelerations were initiated in random order and the following displacements were achieved: (a) 5.5 m/s2:4 cm; (b) 11.1 m/s2:7 cm; (c) 16.6 m/s2:10.5 cm; (d) 22 m/s2:15 cm. Impulse duration was held constant at 90 ms. The onset of impulse delivered by a generator was used as a trigger signal for averaging the biomechanical and electromyographic signals. The ankle and knee joint angles were monitored by goniometers fixed at the lateral aspect of the foot, leg and thigh. The general technique for recording and analysing the electromyographic responses of leg muscles has been fully described in earlier papers [3,4,9]. For statistical assessment (SPSS package) the absolute gastrocnemius responses to all backward impulses and tibialis anterior responses to all forward impulses of all subjects were taken together. A multivariant analysis of variance (repeated measures design) was applied to the results from the subjects after the intake of one of the five specific drugs and to the control (placebo) values. The averaged EMG responses obtained from one subject during an experimental session (i.e. after intake of one drug) were then normalized to the averaged responses obtained before the intake of the drug. Fig. 1 shows the influence of haloperidol, sulpiride and flupentixol on the postural gastrocnemius EMG responses to backward perturbation. For each subject, the EMG response after intake of one of these drugs was normalized with respect to the responses before intake of the drug (time t = 0 ms). The mean EMG responses (with S.D.) to the impulses a~t of all 6 subjects are displayed. The course of the integrated gastrocnemius-EMG responses after intake of sulpiride, a D2 receptor antagonist with purely central action, was very similar to that obtained after intake of haloperidol. Compared to the time course of the postural responses with placebo, a signifi-
83 M.gQslrocnemius
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Domperidon
Flupenlixol t
1
2
3
4
5
6
7h
0
1
2
3
4
5
6
7h
Fig. 1. Mean values (with S.D.) of the rectified, averaged (n = 10) and integrated gastrocnemius EMG responses following backward acceleration impulses (impulses a-d were taken together, see text) in 6 subjects before and at different times after intake of each drug. The mean values of the E M G responses after drug intake are normalized to the value obtained before intake of the drug (time t = 0 h) for each subject. Interrupted line indicates the placebo values, solid line the specific drug values. * P < 0.05; * * P < 0.01. (Significance was tested for the absolute values.)
cant reduction of the mean gastrocnemius E M G responses was observed which started 1.5 h after intake of both haloperidol and sulpiride. This depression of the E M G responses lasted over 6.5 h after administration of haloperidol (after this time no further recordings were performed) and 5 h after administration of sulpiride. The displacement velocity at the ankle as well as knee joints did not differ during this time course. The reduction in the E M G response did not lead to any visible failure to compensate for the perturbations. Also other motor disabilities were not observed or reported by the subjects (e.g. during writing). The background E M G activity ( - 40 ms to + 4 0 ms) was not different between the placebo and the haloperidol session. In contrast to haloperidol and sulpiride, flupentixol, a mixed D 1 and D2 antagonist, showed, 5 h after intake, only a weak, single effect on the strength of the gastrocnemius response. Fig. 1. shows also the effect of two additional substances on the gastrocnemius E M G responses: domperidon, which represents a dopamine D 2 receptor antagonist which does not cross the blood-brain barrier, and diazepam, which was selected in
84 order to investigate possible non-specific effects of the dopamine receptor antagonists, e.g. sedation or fatigue, on the postural reactions. Neither domperidon nor diazepam had a significant effect on the gastrocnemius E M G responses. The mean effect of the drugs over the time interval from 1.5 h to 5 h post application was also evaluated, since the markedly shorter half-life of sulpiride (t,.: = 8 h) had to be taken into account for comparability: using this measure, haloperidol and sulpiride did significantly ( P < 0.05) reduce the EMG responses, while the other substances (including flupentixol) had no effect compared to placebo. In addition, the influence of the different drugs on the compensatory tibialis anterior responses to forward perturbations was calculated in the same way as for the gastrocnemius: neither the centrally acting dopamine antagonists (haloperidol, sulpiride, flupentixol) nor the peripherally acting dopamine antagonist domperidon or diazepare had a significant effect on the E M G responses. In a recent study [5] it was demonstrated that parkinsonian patients show reduced polysynaptic reflexes in the leg extensor muscles during perturbation of stance and gait. This effect was also seen after the intake of haloperidol in young healthy subjects. The aim of this study was to discover the extent to which the function ofpolysynaptic reflexes depends on dopamine receptors. To our knowledge this investigation represents the first attempt to correlate D~ and D2 receptor function with functional aspects of motor control. From the results it is clear that: (1) the activity of the polysynaptic spinal reflexes is reduced by neuroleptic drugs with preferential affinity to D2 receptors; (2) the additional blockade of D~ receptors seems to counteract the effects seen with more or less pure D2 antagonists, since flupentixol is at least as potent as the other drugs in blocking D2 receptors [10]; (3) the peripheral action of dopamine antagonists does not significantly contribute to this spinal mechanism and, (4) nonspecific effects of these drugs, such as fatigue, drowsiness, or muscle relaxation, have no influence on the postural responses. Apart from flupentixol, all neuroleptics applied have a much higher affinity to D2 dopamine receptors than to Di receptors. Sulpiride and domperidgn are 'pure' D2 receptor blockers with a D2/DI affinity ratio of more than 800 (ratio of haloperidol: 358, ratio of flupentixol: 2; for ref. see ref. 10). The doses of the neuroleptics, with regard to their affinity for D2 dopamine receptors, may be assumed to be equivalent [10]. Thus, it was possible to investigate the influence of the additional D1 receptor blocking property of flupentixol. The duration of action of the different drugs used was also similar, with the exception of sulpiride (half-life of sulpiride only 8 h, as compared to 2 0 ~ 0 h of the other active drugs; for ref. see ref. 14). This was the reason to compare the mean effects of the drugs over the time interval from 1.5 to 5 h post application which compensates for the lower half-life time of sulpiride. The results obtained in this study support earlier suggestions that the interneuronal circuits (probably spinal [3]) which mediate the functional E M G responses are strongly dependent on supraspinal influence; (1) in patients with spastic paresis due to a supraspinal lesion, the polysynaptic responses are reduced or absent [4]; (2) in parkinsonian patients these E M G responses show a reduced stretch sensitivity which correlates with an inability to compensate for the perturbations [5].
85 In the present experiments, the reduction of the compensatory E M G responses after haloperidol and sulpiride was not connected with failure to compensate for the perturbations, as was the case in parkinsonian patients [5]. This is explained by the fact that the reduced responses of the normals were still significantly larger than those seen in the patients (cf. ref. 5). In addition, the dosage of the neuroleptics given to the volunteers was rather small. Because of the differential effects of peripherally and centrally acting dopamine receptor antagonists on the E M G responses, a peripheral effect of haloperidol and sulpiride can largely be excluded. One could argue, however, that the effects observed in the present study are due to a depression of vestibular function which also is involved in the regulation of stance and gait (for ref. see ref. 1). This seems, however, for the following reasons to be unlikely: (1) in patients without labyrinthine function, compensatory gastrocnemius E M G responses are preserved [11]; (2) on the basis of experiments using head and body tilts the vestibular system seems to contribute little to the compensation of fast feet displacement, being mainly involved in the regulation of slow body sway [6, 11]. An effect of haloperidol and sulpiride on the compensatory E M G responses was seen in the gastrocnemius following backward perturbations but not in the tibialis anterior following forward displacement of the feet. Similarly, in parkinsonian patients, only the leg extensor muscles showed a reduced stretch sensitivity [5]. This difference between the antagonistic leg muscles is not so surprising, given the different function fulfilled by these muscles during stance and gait [7]. It is suggested, that the reflex mechanisms involved in gastrocnemius activation are more under supraspinal dopaminergic control. The results obtained may help to understand the influences of dopaminergic central structures on the motor control in natural complex movements and their changes in patients with disorders of motor control. In addition, the results represent, on the one hand, a basis for the control of treatment with dopaminergic drugs in these patients and, on the other, for judgement of the motor impairment caused by therapeutic administration of neuroleptics in patients with psychiatric disorders. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 325). We thank Dr. S. Fellows for correcting the English text. Technical assistance was provided by M. Discher, Mrs. U. R6mmelt and Mrs. U. M611inger. 1 Allum, J.H.J. and Pfaltz, C.R., Visual and vestibular contributions to pitch sway stabilization in the ankle muscles of norrnals and patients with bilateral peripheral vestibular deficits, Exp. Brain Res., 58 (1985)82~4. 2 Berardelli, A., Sabra, A.F. and Hallett, M., Physiological mechanisms of rigidity in Parkinson's disease, J. Neurol. Neurosurg. Psychiatry,46 (1983)45-53. 3 Berger,W., Dietz, V. and Quintern, J., Correctivereactions to stumbling in man: neuronal co-ordination of bilateral leg muscle activityduring gait, J. Physiol.,357 (1984) 109-125. 4 Berger,W., Horstmann, G.A. and Dietz, V., Spastic paresis: impaired spinal reflexesand intact motor programs, J. Neurol. Neurosurg. Psychiat.,51 (1988)568-571. 5 Dietz, V., Berger, W. and Horstmann, G.A., Posture in Parkinson's disease: impairment of reflexes and programming, Ann. Neurol., 24 (1988)660q569.
86 6 Dietz, V., Horstmann, G.A. and Berger, W., Involvement of different receptors in the regulation of human posture, Neurosci. Lett., 94 (1988) 82-87. 7 Dietz, V., Horstmann, G.A. and Berger, W., Interlimb co-ordination of leg muscle activation during perturbation of stance in humans, J. Neurophysiol., 62 (1989) 680-4593. 8 Dietz, V., Quintern, J. and Berger, W., Corrective reactions to stumbling in man: functional significance of spinal and transcortical reflexes, Neurosci. Lett., 44 (1984) 131--135. 9 Dietz, V., Quintern, J. and Sillem, M., Stumbling reactions in man: significance of proprioceptive and pre-programmed mechanisms, J. Physiol., 386 (1987) 149 163. 10 Goodwin, G.M. and Metz, A., Neuroleptics. In D.G. Grahame-Smith (Ed.), Psychopharmacology 2, Part 1: Preclinical Psychopharmacology, Elsevier, Amsterdam, 1985, pp. 343 363. 11 Horstmann, G.A. and Dietz, V., The contribution of vestibular input to the stabilization of human posture: a new experimental approach, Neurosci. Lett., 95 (1988) 179 184. 12 Morin, C., Katz, R., Mazidres, L. and Pierrot-Deseilligny, E., Comparison of soleus H reflex facilitation at the onset of soleus contractions produced voluntarily and during the stance phase of human gait, Neurosci. Lett., 33 (1982) 47 53. 13 Tatton, W,G., Bedingham, V., Verrier, M.C. and Blair, R.D.G., Characteristic alterations in response to imposed wrist displacement in parkinsonian rigidity and dystonia musculorum deformans, Can. J. Neurol. Sci., I 1 (1983) 281 287. 14 Trimble, M., Biological Psychiatry, Wiley, Chichester, 1988.