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A spinal sympatho-inhibitory action of chlorpromazine and haloperidol in the cat
Nwrophnrmacology.Vol. IX. pp. 697 10 700 Pergamon Press Ltd 1979 Printed in Great Britain
A SPINAL SYMPATHO-INHIBITORY ACTION OF CHLORPROMAZINE AND HALOPERIDOL IN THE CAT P. J. University
of Oklahoma
BERNTHAL
and
M. C. Koss
Health Sciences Center, College of Medicine, Department P.O. Box 26901, Oklahoma City, OK 73190, U.S.A. (Accepted 27 February
of Pharmacology,
1979)
Summary-Intravenous administration of chlorpromazine (0.03-1.0 mg/kg) or haloperidol (0.03-1.0 mg/kg) resulted in a dose-dependent inhibition of spinally-evoked electrodermal responses (EDRs) in the anesthetized spinal cat. These findings suggest that chlorpromazine and haloperidol act at the level of the spinal cord to depress activity in the sympathetic-cholinergic electrodermal system. Neither drug had a significant effect on pre- or postganglionically-evoked EDRs, further indicating their central action.
Similar central nervous system (CNS) sympathoinhibitory effects have been demonstrated for several drugs which seem to have diverse mechanisms of action. Chlorpromazine (CPZ) has a central sympatho-inhibitory effect on the sympathetic-cholinergic electrodermal response (EDR) and other sympathetic systems (Wang, Kanai, Markee and Wang, 1964; Schallek and Zabransky, 1966; Sigg, Keim and Kepner, 1971; Davison and Koss, 1976). Clonidine also depresses central neural outflow to a variety of sympathetic effecters, including the electrodermal system (Schmitt, Schmitt and FCnard, 1973; Dhawan, Johri, Singh, Srimal and Viswesaram, 1975; Koss, 1976; Koss and Davison, 1976; Haeusler, 1977; Koss, 1977). In spite of the similarities in their sympathoinhibitory effects, data exist which suggest that CPZ and clonidine produce their effects by different mechanisms (Koss, 1977). Recently, the spinal cord has been implicated as a possible site of action for clonidine (Dhawan et al., 1975; Koss, 1976; Haeusler, 1977; Baum and Shropshire, 1977b). The evidence for a spinal site of action for CPZ is less definite (Franz, Hare and Neumayr, 1978). The present study was undertaken to determine quantitatively if two known dopaminergic antagonists, CPZ and haloperidol, produce CNS sympatho-inhibitory effects at the level of the spinal cord. METHODS
Adult cats of either sex (2.M.O kg) were anesthetized with pentobarbital (36 mg/kg, i.p.). A tracheal cannula was inserted for artifical respiration, and catheters were inserted in the right femoral artery and vein to measure blood pressure and administer drugs, respectively. The vago-sympathetic nerve trunks were cut bilaterally at the cervical level. Blood pressure measurements were made with a Statham Key words: chlorpromazine, CNS, electrodermal response,
haloperidol, spinal sympatho-inhibition.
cord,
P23AC pressure transducer, and heart rates were recorded by a Grass tachograph. Electrodermal responses are changes in the dermal membrane potential that are thought to reflect sudorific activity. The sweat glands, although solely innervated by the sympathetic nervous system, have acetylcholine as the neurotransmitter. In this study, evoked electrodermal responses were recorded from the central footpads of the forepaws with Beckman miniature size biopotential electrodes (11 mm diameter). The reference electrode was placed on a shaved region of the same forepaw. All physiological measures were recorded on a Grass model 7B polygraph. Some of the animals were mounted in a Kopf stereotaxic instrument for spinal cord transection, which was performed according to procedures previously described (Koss, 1976). Spinal animals were respired, and some were given gallamine triethiodide. After blood pressure and heart rate recovered from the effects of spinal section, a coaxial electrode (Rhodes model NE-100, center contact diameter 0.5 mm) was positioned at approximately a 60” angle in the left half of the spinal cord at the level of C3-C,, lateral to the dorsolateral sulcus and l-3 mm into the cord. Stimulation parameters necessary to elicit a maximal EDR were 70@9OOpA, 16-32 Hz. 2-3 msec pulse duration, 1-2 set train presented at 30sec intervals. Once a maximal response was obtained, the frequency was lowered until the response amplitude was approximately 80% maximal, usually 12-16 Hz. The stimulation parameters were then held constant for the duration of the experiment. In some non-spinal preparations, the thorax was opened under positive pressure ventilation to expose the right stellate ganglion. A bipolar electrode was positioned under the preganglionic nerve trunk close to the ganglion with the nerve ligated proximal to the site of stimulation. Stimulation parameters necessary to elicit a maximal electrodermal response were l&15 V, 16-32 Hz, 2-3 msec pulse duration, 1-2 set train
697
presented
once
every
30sec.
As
in the
above
698
P. J. BERNTHALand M. C. Koss Table 1. Stability of spi~aily-evoked EDRs in the cat (N = 4) Min after control period
0 I5
30
60
90
120
10.6 * 2.0
10.5 + 1.9
10.4 + 1.4
10.7 + 2.0
10.3 + 2.6
10.5 * 2.7
100
99.1
98.1
100.9
91.2
99.0
(Controlf
Mean EDR Amplitude -f: SEM (mV) ?d, Control
experiments, the frequency was reduced to one that produced a response amplitude of approximately SO:li, maximal (12-16 Hz). Although the sympatheticcholinergic nature of the EDR should obviate any peripheral effects of CPZ and haloperidol, additional experiments were done to ensure that the drugs had no effect other than a CNS action. In these preparations a bipolar electrode was placed under the ulnar nerve in the right foreleg, with the nerve ligated proximal to the site of stimulation. Peripheral postganglionic EDRs were elicited with a 1 set stimulus train of 2-3 msec pulse duration, 20-3OV, 1-4 Hz, presented once every 30sec. Drugs were given in cumulative doses foilowing a control period of 15-20 mm. Individual doses were spaced about 15 min apart. Mean EDR amplitude values were determined by calculating the average amplitude for 10 consecutive responses in a given experimental condition. RESULTS Sta~~~it~ of sp~~~~~)l-e~oked EL%
The mean amplitude of spinally-evoked electroderma1 responses remained at or above 97% of control
values in 4 cats for the 120 min observation period (Table 1). The control value for each animal was the mean amplitude of 10 consecutive responses obtained before the 120 min observation period was begun. All subsequent values were the average of 10 responses measured at the specified time intervals. Both mean amplitude (mV) and mean percent of control values for the 4 cats are presented in Table 1.
E&t
of
CPZ
and
haloperidol
on
spinally-evoked
EDRS
Chlorpromazine (0.03-1.0 mg/kg, iv.) caused a dose-dependent inhibition of spinalIy-evoked EDRs in 6 cats, depressing the response amplitude from 9.0 f 1.8 mV (control value) to 1.1 + 0.4mV at the largest dose, These data are presented in Figure 1 as a percentage of the control amplitude. The ED,, was approximately 0.1 mg/kg. The degree of depression of the response amplitude was equivalent, regardless of whether the EDR was recorded from the footpad ipsilateral or contralateral to the site of stimulation. Chlorpromazine had no significant inhibitory effect on the amplitude of EDRs evoked by preganglionic nerve stimulation (N = 4).
Fig. 1. Effect of cumulative doses of chlorpromazine (O.O$l.O mg/k& i.v, Panel A, N = 6) and haloperido1 (0.03-1.0 mg/kg, i.v., Panef B, N = 4) on spinally-evoked electrodermal responses in spinal anesthetized cats. All responses were evoked at 30 see intervals with supramaximal intensity and with submaximal frequency of stimulation (12-16 Hz). Vertical bars represent & SEM.
A spinal action of CPZ and haloperidol in the cat Haloperidol (O.OLLl.0 mg/kg, i.v.) produced a dosedependent inhibition of spinally-evoked EDRs similar to that produced by CPZ. The response was depressed from 14.8 -t_ 5.1 mV (control amplitude) to 4.1 ): 2.9 mV at the largest dose. These data are presented in Figure 1 as a percentage of the control amplitude. The EDSo for haloper~dol was approximately 0.1 mg/kg. Haloperidol also had no significant effect on EDRs elicited by either preganglionic or postganglionic stimulation (rV = 8). DISCUSSION
The CNS action of several sympatho-inhibitory agents, including CPZ and clonidine, has been documented in a variety of systems. For example, it was shown in cross-circulation studies that CPZ inhibited centrally-induced cardiovascular responses at a site in the CNS (Wang er a/., 1964). In addition, CPZ decreased spontaneous and centrally evoked preganglionic nerve potentials (Sigg et al.. 1971; Schmitt et ill., 1973), antagonized centrally, but not peripherally, evoked blood pressure increases (Schallek and Zabransky, 1966), and inhibited centrally evoked EDRs (Davison and Koss, 1976; Koss, 1977). A similar effect on sympathetic systems by clonidine has been observed, with the suggestion that clonidine is active at the level of the spinal cord. Administration of clonidine reduced spinally-evoked EDRs (Koss, 1976), spinally-evoked activity in preganglionic sympathetic nerves (Haeusler, 1977; Baum and Shropshire, 1977b). and the amplitude of spinal sym~thetic reflexes (Franz er al., 1978). Additionally, methyldopa has been shown to have a spinal site of action (Baum and Shropshire, 1977a). The present study demonstrates that CPZ and haloperidol, both dopaminergic antagonists, produce central sympatho-inhibition, at least in part, by means of an action at the level of the spinal cord. Although this is the first description of such an action produced by haloperidol, others have suggested that CPZ inhibits spinally-evoked sympathetic responses. For example, intraspinally-evoked sympathetic discharges appeared to be jnhibited by CPZ (Neumayr, Hare and Franz, 19741, and administration of CPZ seemed to increase the depression by clonidine of spinal reflexes and intraspinally-evoked discharges recorded from pregangiionic sympathetic nerves (Franz er at., 1978). Although the presence of dopamine in the spinal cord has been known for some time, evidence of a function other than as a precursor for norepinephrine has been recent. Homovanillic acid, a principle metabolite of dopamine, is produced in the spinal cord (Kessler, Gordon, Reid and Kopin, 1976), and norepinephrine and dopamine can be depleted selectively from the spinal cord (~ommissiong, Galli and Neff, 1978). Additionally, cutting the spinal cord affects levels of norepinephrine and dopamine differently (Magnusson, 1973). These studies suggest that a spinal
699
dopaminergic system may exist independently of spinal norepinephrine neurons, and that dopamine may be acting as a neurotransmitter in the spinal cord. The present findings lend physiological support to the concept of a spinal dopaminergic system. Further support for the existence of a spinal dopaminergic system separate from that involving norepinephrine comes from an earlier study which showed that clonidine, an adrenergic agonist, and CPZ both depressed the amplitude of the electroderma1 response, but they seemed to do it by different mechanisms. Yohimbine. an a-adrenergic blocker, antagonized the effect of clonidine, but not that of CPZ (Koss, 1977). When taken together, the above data suggest that parallel noradrenergic and dopaminergic systems may exist in the spinal cord.
Acknowledgements-This research was supported by USPHS Grants MH 2.5792 and NS 14039 and a grant from the Tulsa Chapter of the American Heart Association. REFERENCES
Baum, T. and Shropshire. A. T. (1977a). Evidence for an inhibitory action of methyldopa on spinal sympathetic reflexes. Eur. J. Pharmac. 46: 259-263. Baum, T. and Shropshire, A. T. (1977b). Susceptibility of spontaneous sympathetic outflow and sympathetic reflexes to depression by clonidine. Eur. J. Pharmac. 44: 121-129. Commissiong, J. W., Galli, C. L. and Neff, N. H. (1978). Di~erentiation of dopaminergic and noradreneraic neurons in rat spinal cord. .I. ~~~r*c~em. 30: 1095IO%. Davison, M. A. and Koss, M. C. (1976). , The action of chlorpromazine on the electrodermai response in the cat. ~euro~harmacoiog~ 15: 197-201. Dhawan, B. N., Johri, M. B., Singh, G. B., Srimal, R. C. and Viswesaram, D. (1975). Effect of clonidine on the excitability of vasomotor loci in the cat. Er. J. Pharmac. 54: 17-21. Franz, D. N., Hare, B. D. and Neumayr, R. J. (1978). Depression of sympathetic preganglionic neurons by clonidine: evidence for stimulation of 5-HT receptors. C/in. exp. Hyperten. 1: 115-140. Haeusler, G. (1977). Neuronal mechanisms influencing transmission in the baroreceptor reflex arc. In: Hyperrension and Brain ~ecba~jsms (DeJong, W., Provoost, A. P., and Shapiro, A. P., Eds), pp. 95-109. Elsevier, Amsterdam. Kessler, J. A., Gordon, E. K., Reid, J. L. and Koplin, I. J. (1976). Homovanillic acid and 3-methoxy-4-hydroxyphenylethyleneglycol production by the monkey spinal cord. J. Neurochem. 26: 1057-1061. Koss, M. C. (1976). Studies on the site of action of clonidine utilizing a sympathetic-cholinergic system. Eur. J. Pharmac. 37: 381-384. Koss, M. C. (1977). Effect of clonidine and chlorpromazine on centrally evoked electrodermal responses and their interaction with yohimbine. Eur. J. Pharmac. 41: 22 l-224. Koss, M. C. and Davison, M. A. (1976). The eiecirodermal response as a model for central sympathetic reactivity: the action of clonidine. Eur. J. Phar~c. 37: 71-78. Magnusson, T. (1973). Effect of chronic transection on dopamine, noradrenaline and 5-hydroxytryptam~ne in the rat spinal cord. Nau~yn-Sehmie~ebergs Archs exp. Path. Pharmac. 278: 13-22.
700
P. J. BERNTHAL and M. C. Koss
Neumayr, R. J., Hare, B. D. and Franz, D. N. (1974). Evidence for bulbospinal control of sympathetic preganghonic neurons by monoaminergi~ pathways. Life Sci. 14: 793-806. Schallek, W. and Zabransky. F. (1966). Effects of psychotropic drugs on pressor responses to central and peripheral stimulation in cat. Archs int. Phnrmacodyn. Tfrer. 161: 126131. Schmitt, H., Schmitt, H. and Fenard, S. (1973). Action of z-adrenergic blocking drugs on the sympathetic centres
and their interactions with the central sympatho-inhibitory effect of cionidine. Arzneimittef-For&. 23: 40-G. Sigg, E. B., Keim, K. L. and Kepner, K. (1971). Selective effect of diazepam on certain central sympathetic components. ~europhur~co~og~ 10: 621-629. Wang, H. H., Kanai, T., Markee, S. and Wang, S. C. (1964). Effects of reserpine and chlorpromazine on the vasomotor center in the medulla oblongata of the dog. J. Pharmac. exp. Ther. 144: 186-195.
A SPINAL SYMPATHO-INHIBITORY ACTION OF CHLORPROMAZINE AND HALOPERIDOL IN THE CAT P. J. University
of Oklahoma
BERNTHAL
and
M. C. Koss
Health Sciences Center, College of Medicine, Department P.O. Box 26901, Oklahoma City, OK 73190, U.S.A. (Accepted 27 February
of Pharmacology,
1979)
Summary-Intravenous administration of chlorpromazine (0.03-1.0 mg/kg) or haloperidol (0.03-1.0 mg/kg) resulted in a dose-dependent inhibition of spinally-evoked electrodermal responses (EDRs) in the anesthetized spinal cat. These findings suggest that chlorpromazine and haloperidol act at the level of the spinal cord to depress activity in the sympathetic-cholinergic electrodermal system. Neither drug had a significant effect on pre- or postganglionically-evoked EDRs, further indicating their central action.
Similar central nervous system (CNS) sympathoinhibitory effects have been demonstrated for several drugs which seem to have diverse mechanisms of action. Chlorpromazine (CPZ) has a central sympatho-inhibitory effect on the sympathetic-cholinergic electrodermal response (EDR) and other sympathetic systems (Wang, Kanai, Markee and Wang, 1964; Schallek and Zabransky, 1966; Sigg, Keim and Kepner, 1971; Davison and Koss, 1976). Clonidine also depresses central neural outflow to a variety of sympathetic effecters, including the electrodermal system (Schmitt, Schmitt and FCnard, 1973; Dhawan, Johri, Singh, Srimal and Viswesaram, 1975; Koss, 1976; Koss and Davison, 1976; Haeusler, 1977; Koss, 1977). In spite of the similarities in their sympathoinhibitory effects, data exist which suggest that CPZ and clonidine produce their effects by different mechanisms (Koss, 1977). Recently, the spinal cord has been implicated as a possible site of action for clonidine (Dhawan et al., 1975; Koss, 1976; Haeusler, 1977; Baum and Shropshire, 1977b). The evidence for a spinal site of action for CPZ is less definite (Franz, Hare and Neumayr, 1978). The present study was undertaken to determine quantitatively if two known dopaminergic antagonists, CPZ and haloperidol, produce CNS sympatho-inhibitory effects at the level of the spinal cord. METHODS
Adult cats of either sex (2.M.O kg) were anesthetized with pentobarbital (36 mg/kg, i.p.). A tracheal cannula was inserted for artifical respiration, and catheters were inserted in the right femoral artery and vein to measure blood pressure and administer drugs, respectively. The vago-sympathetic nerve trunks were cut bilaterally at the cervical level. Blood pressure measurements were made with a Statham Key words: chlorpromazine, CNS, electrodermal response,
haloperidol, spinal sympatho-inhibition.
cord,
P23AC pressure transducer, and heart rates were recorded by a Grass tachograph. Electrodermal responses are changes in the dermal membrane potential that are thought to reflect sudorific activity. The sweat glands, although solely innervated by the sympathetic nervous system, have acetylcholine as the neurotransmitter. In this study, evoked electrodermal responses were recorded from the central footpads of the forepaws with Beckman miniature size biopotential electrodes (11 mm diameter). The reference electrode was placed on a shaved region of the same forepaw. All physiological measures were recorded on a Grass model 7B polygraph. Some of the animals were mounted in a Kopf stereotaxic instrument for spinal cord transection, which was performed according to procedures previously described (Koss, 1976). Spinal animals were respired, and some were given gallamine triethiodide. After blood pressure and heart rate recovered from the effects of spinal section, a coaxial electrode (Rhodes model NE-100, center contact diameter 0.5 mm) was positioned at approximately a 60” angle in the left half of the spinal cord at the level of C3-C,, lateral to the dorsolateral sulcus and l-3 mm into the cord. Stimulation parameters necessary to elicit a maximal EDR were 70@9OOpA, 16-32 Hz. 2-3 msec pulse duration, 1-2 set train presented at 30sec intervals. Once a maximal response was obtained, the frequency was lowered until the response amplitude was approximately 80% maximal, usually 12-16 Hz. The stimulation parameters were then held constant for the duration of the experiment. In some non-spinal preparations, the thorax was opened under positive pressure ventilation to expose the right stellate ganglion. A bipolar electrode was positioned under the preganglionic nerve trunk close to the ganglion with the nerve ligated proximal to the site of stimulation. Stimulation parameters necessary to elicit a maximal electrodermal response were l&15 V, 16-32 Hz, 2-3 msec pulse duration, 1-2 set train
697
presented
once
every
30sec.
As
in the
above
698
P. J. BERNTHALand M. C. Koss Table 1. Stability of spi~aily-evoked EDRs in the cat (N = 4) Min after control period
0 I5
30
60
90
120
10.6 * 2.0
10.5 + 1.9
10.4 + 1.4
10.7 + 2.0
10.3 + 2.6
10.5 * 2.7
100
99.1
98.1
100.9
91.2
99.0
(Controlf
Mean EDR Amplitude -f: SEM (mV) ?d, Control
experiments, the frequency was reduced to one that produced a response amplitude of approximately SO:li, maximal (12-16 Hz). Although the sympatheticcholinergic nature of the EDR should obviate any peripheral effects of CPZ and haloperidol, additional experiments were done to ensure that the drugs had no effect other than a CNS action. In these preparations a bipolar electrode was placed under the ulnar nerve in the right foreleg, with the nerve ligated proximal to the site of stimulation. Peripheral postganglionic EDRs were elicited with a 1 set stimulus train of 2-3 msec pulse duration, 20-3OV, 1-4 Hz, presented once every 30sec. Drugs were given in cumulative doses foilowing a control period of 15-20 mm. Individual doses were spaced about 15 min apart. Mean EDR amplitude values were determined by calculating the average amplitude for 10 consecutive responses in a given experimental condition. RESULTS Sta~~~it~ of sp~~~~~)l-e~oked EL%
The mean amplitude of spinally-evoked electroderma1 responses remained at or above 97% of control
values in 4 cats for the 120 min observation period (Table 1). The control value for each animal was the mean amplitude of 10 consecutive responses obtained before the 120 min observation period was begun. All subsequent values were the average of 10 responses measured at the specified time intervals. Both mean amplitude (mV) and mean percent of control values for the 4 cats are presented in Table 1.
E&t
of
CPZ
and
haloperidol
on
spinally-evoked
EDRS
Chlorpromazine (0.03-1.0 mg/kg, iv.) caused a dose-dependent inhibition of spinalIy-evoked EDRs in 6 cats, depressing the response amplitude from 9.0 f 1.8 mV (control value) to 1.1 + 0.4mV at the largest dose, These data are presented in Figure 1 as a percentage of the control amplitude. The ED,, was approximately 0.1 mg/kg. The degree of depression of the response amplitude was equivalent, regardless of whether the EDR was recorded from the footpad ipsilateral or contralateral to the site of stimulation. Chlorpromazine had no significant inhibitory effect on the amplitude of EDRs evoked by preganglionic nerve stimulation (N = 4).
Fig. 1. Effect of cumulative doses of chlorpromazine (O.O$l.O mg/k& i.v, Panel A, N = 6) and haloperido1 (0.03-1.0 mg/kg, i.v., Panef B, N = 4) on spinally-evoked electrodermal responses in spinal anesthetized cats. All responses were evoked at 30 see intervals with supramaximal intensity and with submaximal frequency of stimulation (12-16 Hz). Vertical bars represent & SEM.
A spinal action of CPZ and haloperidol in the cat Haloperidol (O.OLLl.0 mg/kg, i.v.) produced a dosedependent inhibition of spinally-evoked EDRs similar to that produced by CPZ. The response was depressed from 14.8 -t_ 5.1 mV (control amplitude) to 4.1 ): 2.9 mV at the largest dose. These data are presented in Figure 1 as a percentage of the control amplitude. The EDSo for haloper~dol was approximately 0.1 mg/kg. Haloperidol also had no significant effect on EDRs elicited by either preganglionic or postganglionic stimulation (rV = 8). DISCUSSION
The CNS action of several sympatho-inhibitory agents, including CPZ and clonidine, has been documented in a variety of systems. For example, it was shown in cross-circulation studies that CPZ inhibited centrally-induced cardiovascular responses at a site in the CNS (Wang er a/., 1964). In addition, CPZ decreased spontaneous and centrally evoked preganglionic nerve potentials (Sigg et al.. 1971; Schmitt et ill., 1973), antagonized centrally, but not peripherally, evoked blood pressure increases (Schallek and Zabransky, 1966), and inhibited centrally evoked EDRs (Davison and Koss, 1976; Koss, 1977). A similar effect on sympathetic systems by clonidine has been observed, with the suggestion that clonidine is active at the level of the spinal cord. Administration of clonidine reduced spinally-evoked EDRs (Koss, 1976), spinally-evoked activity in preganglionic sympathetic nerves (Haeusler, 1977; Baum and Shropshire, 1977b). and the amplitude of spinal sym~thetic reflexes (Franz er al., 1978). Additionally, methyldopa has been shown to have a spinal site of action (Baum and Shropshire, 1977a). The present study demonstrates that CPZ and haloperidol, both dopaminergic antagonists, produce central sympatho-inhibition, at least in part, by means of an action at the level of the spinal cord. Although this is the first description of such an action produced by haloperidol, others have suggested that CPZ inhibits spinally-evoked sympathetic responses. For example, intraspinally-evoked sympathetic discharges appeared to be jnhibited by CPZ (Neumayr, Hare and Franz, 19741, and administration of CPZ seemed to increase the depression by clonidine of spinal reflexes and intraspinally-evoked discharges recorded from pregangiionic sympathetic nerves (Franz er at., 1978). Although the presence of dopamine in the spinal cord has been known for some time, evidence of a function other than as a precursor for norepinephrine has been recent. Homovanillic acid, a principle metabolite of dopamine, is produced in the spinal cord (Kessler, Gordon, Reid and Kopin, 1976), and norepinephrine and dopamine can be depleted selectively from the spinal cord (~ommissiong, Galli and Neff, 1978). Additionally, cutting the spinal cord affects levels of norepinephrine and dopamine differently (Magnusson, 1973). These studies suggest that a spinal
699
dopaminergic system may exist independently of spinal norepinephrine neurons, and that dopamine may be acting as a neurotransmitter in the spinal cord. The present findings lend physiological support to the concept of a spinal dopaminergic system. Further support for the existence of a spinal dopaminergic system separate from that involving norepinephrine comes from an earlier study which showed that clonidine, an adrenergic agonist, and CPZ both depressed the amplitude of the electroderma1 response, but they seemed to do it by different mechanisms. Yohimbine. an a-adrenergic blocker, antagonized the effect of clonidine, but not that of CPZ (Koss, 1977). When taken together, the above data suggest that parallel noradrenergic and dopaminergic systems may exist in the spinal cord.
Acknowledgements-This research was supported by USPHS Grants MH 2.5792 and NS 14039 and a grant from the Tulsa Chapter of the American Heart Association. REFERENCES
Baum, T. and Shropshire. A. T. (1977a). Evidence for an inhibitory action of methyldopa on spinal sympathetic reflexes. Eur. J. Pharmac. 46: 259-263. Baum, T. and Shropshire, A. T. (1977b). Susceptibility of spontaneous sympathetic outflow and sympathetic reflexes to depression by clonidine. Eur. J. Pharmac. 44: 121-129. Commissiong, J. W., Galli, C. L. and Neff, N. H. (1978). Di~erentiation of dopaminergic and noradreneraic neurons in rat spinal cord. .I. ~~~r*c~em. 30: 1095IO%. Davison, M. A. and Koss, M. C. (1976). , The action of chlorpromazine on the electrodermai response in the cat. ~euro~harmacoiog~ 15: 197-201. Dhawan, B. N., Johri, M. B., Singh, G. B., Srimal, R. C. and Viswesaram, D. (1975). Effect of clonidine on the excitability of vasomotor loci in the cat. Er. J. Pharmac. 54: 17-21. Franz, D. N., Hare, B. D. and Neumayr, R. J. (1978). Depression of sympathetic preganglionic neurons by clonidine: evidence for stimulation of 5-HT receptors. C/in. exp. Hyperten. 1: 115-140. Haeusler, G. (1977). Neuronal mechanisms influencing transmission in the baroreceptor reflex arc. In: Hyperrension and Brain ~ecba~jsms (DeJong, W., Provoost, A. P., and Shapiro, A. P., Eds), pp. 95-109. Elsevier, Amsterdam. Kessler, J. A., Gordon, E. K., Reid, J. L. and Koplin, I. J. (1976). Homovanillic acid and 3-methoxy-4-hydroxyphenylethyleneglycol production by the monkey spinal cord. J. Neurochem. 26: 1057-1061. Koss, M. C. (1976). Studies on the site of action of clonidine utilizing a sympathetic-cholinergic system. Eur. J. Pharmac. 37: 381-384. Koss, M. C. (1977). Effect of clonidine and chlorpromazine on centrally evoked electrodermal responses and their interaction with yohimbine. Eur. J. Pharmac. 41: 22 l-224. Koss, M. C. and Davison, M. A. (1976). The eiecirodermal response as a model for central sympathetic reactivity: the action of clonidine. Eur. J. Phar~c. 37: 71-78. Magnusson, T. (1973). Effect of chronic transection on dopamine, noradrenaline and 5-hydroxytryptam~ne in the rat spinal cord. Nau~yn-Sehmie~ebergs Archs exp. Path. Pharmac. 278: 13-22.
700
P. J. BERNTHAL and M. C. Koss
Neumayr, R. J., Hare, B. D. and Franz, D. N. (1974). Evidence for bulbospinal control of sympathetic preganghonic neurons by monoaminergi~ pathways. Life Sci. 14: 793-806. Schallek, W. and Zabransky. F. (1966). Effects of psychotropic drugs on pressor responses to central and peripheral stimulation in cat. Archs int. Phnrmacodyn. Tfrer. 161: 126131. Schmitt, H., Schmitt, H. and Fenard, S. (1973). Action of z-adrenergic blocking drugs on the sympathetic centres
and their interactions with the central sympatho-inhibitory effect of cionidine. Arzneimittef-For&. 23: 40-G. Sigg, E. B., Keim, K. L. and Kepner, K. (1971). Selective effect of diazepam on certain central sympathetic components. ~europhur~co~og~ 10: 621-629. Wang, H. H., Kanai, T., Markee, S. and Wang, S. C. (1964). Effects of reserpine and chlorpromazine on the vasomotor center in the medulla oblongata of the dog. J. Pharmac. exp. Ther. 144: 186-195.