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The D1 receptor antagonist, SCH 23390, induces signs of parkinsonism in African green monkeys
Life Sciences, Vol. 49, pp. PL-229 - PL-234 Printed in the U.S.A.
PHARMACOLOGY Accelerated
Pergamon Press
LETTERS
Communication
THE DI RECEPTOR ANTAGONIST, SCH 23390, INDUCES SIGNS OF PARKINSONISM IN AFRICAN GREEN MONKEYS Matthew S. Lawrence, D. Eugene Redmond, Jr.l, J.D. Elsworth, J.R. Taylor and R.H. Roth Neurobehavior Laboratory and Departments of Psychiatry and Pharmacology Yale University School of Medicine 333 Cedar Street New Haven, Ct. 06510, U.S.A. (Submitted September 19, 1991; accepted October ii, 1991; received in final form October 16, 1991)
AbstracL Systemic administration of the selective DI antagonist, SCH 23390, caused significant motor changes in healthy African green monkeys. The effects included the parkinsonian signs of motor freezing, incoordination, bradykinesia, poverty of movement, tremor and depressed blink rate. SCH 23390 administered to MPTP-avated monkeys increased existing parkinsonism. The results are of particular interest in light of recent data that demonstrate the effectiveness of dihydrexidine, a full D l agonist, in alleviating parkinsonism in MPTP-treatezl monkeys. These data implicate DI receptors in the functions impaired by Parkinson's disease and suggest the possibility of parkinsonian side effects in the clinical use of this or similar D l antagonists as treatments for psychiatric disorders.
Introduction Dopamine receptors in the CNS have been subdivided biochemically and pharmacologically into two major groups, Dl and D2, although other receptor subtypes are being described and cloned (1). D1 receptors are positively coupled to adenylate cyclase while D2 receptors are not coupled or are negatively coupled to adenylate cyclase (2). Although this biochemical subdivision exists, a clear distinction between the role of the D1 and D2 receptors has not been established. Abnormalities of the dopamine system in the basal ganglia can elicit dyskinesias, bradykinesia and other locomotor deficits in rodents, but the relative participation of the D1 and D2 receptor subtypes in the mediation of these disorders remains uncertain. Non-selective dopamine agonists such as apomorphine and bromocriptine reverse experimentally-induced parkinsonism and are effective in the treatment of Parkinson's disease. More recently it has been reported that the specific I)2 agonists (+)-PHNO and LY 171555 stimulate motor activity and improve parkinsonism in MPTP-treated monkeys (3,4,5,6). In contrast, the specific dopamine D! agonist, SKF 38393, does not have antiparkinsonian effects in non-human primates and humans (4,6). The antiparkinsonian activity of dopamine I)2 agonists and the lack of such activity by D1 agonists has implicated D2 receptor function in the motor abnormalities of Parkinson's disease, although recent data raise questions about the predictive power of studies of rodents for antiparkinsonian effects in primates or humans (7). Recently, however, a partial D1 agonist, CY208-243, was found to have antiparkinsonian effects in MPTP-treated marmosets (3). This effect was blocked by the D1 antagonist, SCH 23390, and to a lesser extent by the D2 antagonist sulpiride, suggesting that antiparkinsonian effects can be 1 CORRESPONDING AUTHOR: D.E. Redmond, Jr., M.D., Nenrobehavior Laboratory, Yale University School of Medicine, P.O. Box 3333, New Haven, CL 06510, U.S.A. 0024-3205/91 $3.00 + .00 Copyright © 1991 Pergamon Press plc
PL-230
D I Antagonist
Induces
Parkinsonism
Vol.
49, No.
25,
1991
mediated through the D1 receptor. It has also been shown that dihydrexidine, another selective D1 agonist, which stimulates adenylate cyclase with full efficacy compared with dopamine, dramatically improves parkinsonism in MPTP-treated African green monkeys (7). While these results have contributed to a reevaluation of the role of the Dl receptor, it should be noted that both CY208-243 and dihydrexidine have limited Dl:D2 selectivity, raising the possibility that some of their antiparkinsonian effects may be mediated through the D2 receptor or by functional interactions between D1 and D2 receptors which are well-described in rodents. CY208-234 also has atypical opioid agonist activities, further confusing the interpretation of its effects. In order to assess further the role of Dl receptor function in motor control, we tested the behavioral effect of blocking the D1 receptor by administering the selective DI antagonist, SCH 23390, both to healthy normal African green monkeys and to MPTP-treated mildly parkinsonian monkeys. SCH 23390 is highly specific for D1 receptors (8,9). At doses 5 to 30 times higher than those employed in the present experiment SCH 23390 also affects 5-HT2 and 5-HTtc receptor subtypes in rats (10). In this experiment, as in other experiments using dihydrexidine (7), the effect of SCH 23390 was assessed by behavioral observations and measurements of spontaneous blink rate. Blink rate appears to be a strong correlate of central dopamine activity. It is depressed in Parkinson's patients and is sensitive to manipulation of both D1 and D2 receptors in healthy monkeys (11,12). Methods The subjects were mature young adult male African green monkeys (Cercopithecus aethiops sabaeus) from the island colony of St. Kitts, West Indies. Eleven monkeys were included in the experiment, five of which had been treated approximately eight months before the study with a cumulative dose of 2.0 mg/kg of MPTP, administered intramuscularly over a period of five days. None of the monkeys had previously received SCH 23390, L-DOPA, or other dopamine agonists or antagonists except one healthy monkey that had received SCH 23390, dihydrexidine, and D2 agonists and antagonists in a previous study six months earlier. The effect of drug treatment was assessed by behavioral observations made at ten minute intervals (-30, -20, -10, +3, + 13, +23, +33, and +43 minutes) before and after the injection of SCH 23390 at time point zero. Behavioral assessments during each interval included a five minute time-sampled observation period (13,14), an observer rating of behaviors and a two minute period during which spontaneous eye blinks were counted (11). The sum of the time-sampled behaviors and the observer rated behaviors allowed a quantification of the behavioral status of the monkeys and the derivation of Parkinsonian, Anxiety, Arousal, Sedation, Quiet O.K. and Tremor Scores. The behavioral scores were derived from previous factor analysis and validated by empirical testing (15). The Parkinsonian Score represents the sum of time-sampled and rated measures of tremor, appearance, freezing, difficulty eating, food response, delay in initiating responses, poverty of movement, response to threat, and time unable to stand (or "facedown"). The Anxiety Score represents the sum of yawn, chew, scratch and selfgroom; Arousal, the sum of shift, tail flag, lookout and vertical climb; and Sedation, the sum of eyes closed and freeze. Qualitative effects were confirmed from complete videotape records of the experiment. (+)-SCH 23390 HC1 (Research Biochemicals Inc., Natick, MA) was administered intramuscularly to four healthy monkeys and five MPTP-treated monkeys at a dose of 0.05 mg/kg. A higher dose (0.3 mg/kg) was administered to another group of four healthy monkeys, two of which had received the lower dose three days beforehand. The drug experiments were conducted over a five day period. Res01t~ Healthy monkeys receiving 0.05 mg/kg SCH 23390 exhibited a dramatic and significant increase in Parkinsonian Score within 13 minutes after injection (figure 1A). This increase was manifested by an onset of motor freezing, incoordination, bradykinesia, tremor and other motor deficits not seen prior to SCH 23390 injection. During the same interval, blink rate correspondingly decreased (figure 1B). Both Parkinsonian Score and blink rate gradually returned to baseline values in the remaining 30 minutes of the observation period. Several other behavioral measures also appeared to change after SCH 23390 adminstration (table I). A dose of 0.3 mg/kg caused a similar elevation in Parkinsonian Score (figure I A) and depression in blink rate (figure 1B) in healthy subjects, but it appeared to have a more lasting effect.
Vol. 49, No. 25, 1991
D I Antagonist Induces Parkinsonism
A
20
PL-231
B
15
15 10
-t-t
g to
_=
0
--
-40
~
-20
0 Minutes
20
40
-40
I
I
I
I
-20
0
20
40
Minutes
FIG. 1 Four healthy monkeys were injected with 0.05 mg/kg (black diamonds) or 0.3 mg/kg (open squares) SCH 23390 at time point zero. A) ParkinsonianScore showed a significant increase after the adminstration of SCH 23390 in both the low dose and high dose groups (neither the group factor nor the interaction between group and time were significant, but some of the times after drug administration were significantly different: F=I5.0, df=7,70, p
PL-232
D I Antagonist
Induces Parkinsonism
TABLE I 0.3 mg./ke SCH 23390 in Normals (N=4) Time (Minutes) -30 -20 -10 3 13 Parkinsonian Score 0.0 0.0 0.0 8.6 14.6 BlinkRate 11.9 10.4 9.6 5.3 4.1 Anxiety 6.0 7.3 4.5 8.5 0.5 Arousal 13.8 5.5 5.8 15.3 8.0 Sedation 0.0 0.0 0.0 5.3 16.8 Quiet O.K. 3.5 9.3 3.5 2.5 0.0 Tremor 0.0 0.0 0.0 0.5 1.3 0.05 m~k~ SCH 23390 in Normals (N--4) Time (IVlinutes) -30 -20 -10 3 Parkinsonian Score 0.0 0.0 0.0 5.0 Blink Rate 10.4 9.5 10.3 5.1 Anxiety 5.5 9.0 6.0 11.3 Arousal 8.0 7.8 9.8 11.0 Sedation 0.0 0.0 0.0 6.3 Quiet O.K. 3.0 15.0 11.3 3.8 Tremor 0.0 0.0 0.0 0.3
Vol.
49, No.
25,
23
33
43
12.7 4.3 1.0 5.0 22.3 0.0 1.0
9.9 4.9 0.8 3.0 26.0 0.3 0.5
8.5 6.3 1.8 2.8 33.5 0.5 0.3
13
23
33
43
13.0 5.1 0.5 10.0 21.5 0.0 0.5
8.3 5.0 1.0 3.0 35.2 0.5 0.3
5.1 7.2 1.5 4.8 25.5 0.8 0.0
2.0 7.8 1.8 3.8 10.0 1.8 0.0
<0.001 <0.001 <0.001 <0.001 <0.001 <0.01 ns
23
33
43
ANOVA
14.8 5.4 0.8 1.4 7.2 2.8 4.0
12.4 8.1 1.8 1.2 11.0 1.2 3.4
8.8 8.4 4.6 1.4 6.0 4.2 3.6
<0.001 <0.001 <0.001 <0.001 <0.001 <0.01 ns
0,05 mg/kg SCH 23390 in MPTP M0nkgys (N=5) Time (Minutes) -30 -20 -10 3 13 Parkinsonian Score 5.6 5.7 5.9 10.0 18.0 Blink Rate 11.1 9.7 12.5 5.9 5.3 Anxiety 8.6 8.8 10.4 12.2 0.8 Arousal 4.8 3.4 5.8 17.2 5.4 Sedation 1.0 0.6 0.6 0.8 9.2 Quiet O.K. 4.8 2.0 2.0 4.2 1.2 Tremor 3.8 3.8 3.8 2.8 4.0
1991
ANOVA* <0.001 <0.001 <0.001 <0.001 <0.001 <0.01 <0.01 ANOVA
*The mean valueof behavioral measures are given for each groupat each time point beforeand after SCH 23390 administration. Significancevalues are reported from the repeated measures factor(time) froman ANOVA,includingall three groups. There were no groupdifferences in any behavior,except for tremor which was subsequentlyanalyzedseparately. shifts, retropulsion, repeated rotations about the cage, sustained abnormal positioning of the body and limbs, and occasional vigorous grooming (none of which were specifically quantified in the standardized behavioral rating scheme). At the same time, head and eye movements and other behavioral indices of "alermess" decreased, and there was a reduced interest in food. During the interval 13 to 23 minutes post-injection, these movements were increasingly punctuated by periods of body freezing, until this state of inactivity became the dominant behavior. It is important to note that although the interruption of motor movement (motor freezing) contributed significantly to the elevation in Parkinsonian Score, it was accompanied by the onset of incoordination, bradykinesia and tremor and was not a trance-like, purely cataleptic effect. Furthermore, the spontaneous freezing seen is a classic parkinsonian sign defined and recorded in previous MPTP studies. Anxiety and Arousal Scores also dropped significantly below baseline values in the 13 to 23 minutes postinjection. There was a significant difference in tremor between the groups (F= 17.13, df=2,10, p<0.001). SCH 23390 induced a subtle resting head tremor in two of the healthy monkeys that received the low dose and in all four of the monkeys that received the higher dose (F=3.97, df 7,24, p<0.01). The head tremor was periodically accompanied by a slight limb tremor in several subjects. Although the tremor of the MVI'P-treated group was greater than that of the healthy monkeys before treatment (F=19.13, df 1,7, p<.01), SCH 23390 did not make it significantly worse.
Vol. 49, No. 25, 1991
D I Antagonist
Induces P a r k l n s o n i s m
PL-233
The results of the original study of 0.3 mg/kg SCH 23390 administered intramuscularly were replicated in five additional monkeys with an almost identical change resulting in parkinsonian motor functions and a reduction in blink rate. None of these changes were observed in the two hours following oral treatment of monkeys with 1 mg/kg (n=2) or 10 mg/kg (n=2) of SCH 23390. Oral delivery of the drug was achieved by placing SCH 23390 in a small piece of banana. Discussion The present study shows that blockade of D1 receptors with SCH 23390 induces classic parkinsonian signs in healthy monkeys and increases the severity of parkinsonism in MPTP-treated monkeys. The freezing, bradykinesia, tremor and other behavioral changes induced by SCH 23390 bear a close resemblance to the permanent motor deficits seen in MPTP-treated African green monkeys. Because MPTP-treated African green monkeys represent the best existing animal model of Parkinson's disease (15), the qualitative and quantitative similarity of the SCH 23390 effect supports the importance of D1 receptors in this condition. Stimulation of the same receptors by a selective Dl agonist has recently been found to alleviate MPTP-induced parkinsonism (7). Although SCH 23390 may have significant effects at 5-HT2 and 5-HT1c receptors, and dihydrexidine and CY208-243 have some activity at D2 receptors, their major and overlapping effects are on D1 receptors. Together these data suggest that Dl receptor function may be more important in the pathophysiology of Parkinson's disease than previously believed. Other investigators have reported that a comparable dose of SCH 23390 (0.05 mg/kg i.m.), administered alone or after chronic haloperidol, produced a dystonic syndrome in Cebus monkeys that had previously received chronic haloperidol treatment (16). The SCH 23390 effect in Cebus monkeys was characterized by oral dyskinesias, torsion and flexion of the trunk and torticollis of the head and neck (16), similar to that produced by the D2 antagonist, raclopride, and haloperidol (16). Significantly, postural freezing, motor inactivity, tremor or other parkinsonian signs were not reported after SCH 23390 in Cebus monkeys (16), after administration alone or after chronic haloperidol treatment. Although we observed dyskinetic locomotor activity and the assumption of awkward postures immediately following drug administration in the African green monkey, these behaviors subsided within 13 to 23 minutes with the onset of postural freezing, tremor and reduced motor activity. Others report that a high dose of SCH 23390 (2.0 mg/kg) increased motor disability scores of MPTP-treated marmosets, but they did not provide data or cite specific behavioral effects (3). Although only motor performance was measured in the present study, it is likely that other functions, such as memory (17), are also affected by SCH 23390 treatment. Chronic administration of 10 mg/kg orally of SCH 23390 has sedative properties in Cebus monkeys, but is without motor effects (19). Such findings have led some to suggest that SCH 23390 would be an antipsychotic drug devoid of undesirable extrapyramidal effects (19). We have confirmed these negative findings after a single oral dose in the African green monkey. However, based on the parkinsonian signs induced by SCH 23390 administered intramuscularly in African green monkeys (at 1/'200th the 10 mg/kg dose studied orally), the clinical utility of chronic administration of SCH 23390 and other DI antagonists may be limited by the emergence of parkinsonian signs and symptoms if effective D1 antagonist doses are used. The prototypical dopamine agonists, bromocriptine and apomorphine, have a greater affinity for D2 than Dl receptors, and their clinical effectiveness has been attributed to their D2 properties. For this reason many investigations and treatments of Parkinson's disease have focused on D2 receptors. Single dose antagonism of D2 receptors in non-human primates, however, does not result in classic parkinsonian signs. Even chronic administration of haloperidol over several months induced tremor in only 4 out of 21 African green monkeys, and there were no significant motor deficits (18). In Cebus monkeys chronic administration of haloperidol and other D2-selective antipsychotics produce sedation and eventually an extrapyramidal syndrome characterized by limb extensions, facial grimacing, chewing and tongue protrusions (19). The failure of the D1 agonist, SKF 38393, to have antiparkinsonian effects has been an argument against the relevance of DI receptors in the pharmacology of Parkinson's disease (3,4,6). The inactivity of SKF 38393, however, may be accounted for by a number of factors (20), and the antiparkinsonian activity of dihydrexidine and CY208-243 suggests that DI activation can enhance
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PHARMACOLOGY Accelerated
Pergamon Press
LETTERS
Communication
THE DI RECEPTOR ANTAGONIST, SCH 23390, INDUCES SIGNS OF PARKINSONISM IN AFRICAN GREEN MONKEYS Matthew S. Lawrence, D. Eugene Redmond, Jr.l, J.D. Elsworth, J.R. Taylor and R.H. Roth Neurobehavior Laboratory and Departments of Psychiatry and Pharmacology Yale University School of Medicine 333 Cedar Street New Haven, Ct. 06510, U.S.A. (Submitted September 19, 1991; accepted October ii, 1991; received in final form October 16, 1991)
AbstracL Systemic administration of the selective DI antagonist, SCH 23390, caused significant motor changes in healthy African green monkeys. The effects included the parkinsonian signs of motor freezing, incoordination, bradykinesia, poverty of movement, tremor and depressed blink rate. SCH 23390 administered to MPTP-avated monkeys increased existing parkinsonism. The results are of particular interest in light of recent data that demonstrate the effectiveness of dihydrexidine, a full D l agonist, in alleviating parkinsonism in MPTP-treatezl monkeys. These data implicate DI receptors in the functions impaired by Parkinson's disease and suggest the possibility of parkinsonian side effects in the clinical use of this or similar D l antagonists as treatments for psychiatric disorders.
Introduction Dopamine receptors in the CNS have been subdivided biochemically and pharmacologically into two major groups, Dl and D2, although other receptor subtypes are being described and cloned (1). D1 receptors are positively coupled to adenylate cyclase while D2 receptors are not coupled or are negatively coupled to adenylate cyclase (2). Although this biochemical subdivision exists, a clear distinction between the role of the D1 and D2 receptors has not been established. Abnormalities of the dopamine system in the basal ganglia can elicit dyskinesias, bradykinesia and other locomotor deficits in rodents, but the relative participation of the D1 and D2 receptor subtypes in the mediation of these disorders remains uncertain. Non-selective dopamine agonists such as apomorphine and bromocriptine reverse experimentally-induced parkinsonism and are effective in the treatment of Parkinson's disease. More recently it has been reported that the specific I)2 agonists (+)-PHNO and LY 171555 stimulate motor activity and improve parkinsonism in MPTP-treated monkeys (3,4,5,6). In contrast, the specific dopamine D! agonist, SKF 38393, does not have antiparkinsonian effects in non-human primates and humans (4,6). The antiparkinsonian activity of dopamine I)2 agonists and the lack of such activity by D1 agonists has implicated D2 receptor function in the motor abnormalities of Parkinson's disease, although recent data raise questions about the predictive power of studies of rodents for antiparkinsonian effects in primates or humans (7). Recently, however, a partial D1 agonist, CY208-243, was found to have antiparkinsonian effects in MPTP-treated marmosets (3). This effect was blocked by the D1 antagonist, SCH 23390, and to a lesser extent by the D2 antagonist sulpiride, suggesting that antiparkinsonian effects can be 1 CORRESPONDING AUTHOR: D.E. Redmond, Jr., M.D., Nenrobehavior Laboratory, Yale University School of Medicine, P.O. Box 3333, New Haven, CL 06510, U.S.A. 0024-3205/91 $3.00 + .00 Copyright © 1991 Pergamon Press plc
PL-230
D I Antagonist
Induces
Parkinsonism
Vol.
49, No.
25,
1991
mediated through the D1 receptor. It has also been shown that dihydrexidine, another selective D1 agonist, which stimulates adenylate cyclase with full efficacy compared with dopamine, dramatically improves parkinsonism in MPTP-treated African green monkeys (7). While these results have contributed to a reevaluation of the role of the Dl receptor, it should be noted that both CY208-243 and dihydrexidine have limited Dl:D2 selectivity, raising the possibility that some of their antiparkinsonian effects may be mediated through the D2 receptor or by functional interactions between D1 and D2 receptors which are well-described in rodents. CY208-234 also has atypical opioid agonist activities, further confusing the interpretation of its effects. In order to assess further the role of Dl receptor function in motor control, we tested the behavioral effect of blocking the D1 receptor by administering the selective DI antagonist, SCH 23390, both to healthy normal African green monkeys and to MPTP-treated mildly parkinsonian monkeys. SCH 23390 is highly specific for D1 receptors (8,9). At doses 5 to 30 times higher than those employed in the present experiment SCH 23390 also affects 5-HT2 and 5-HTtc receptor subtypes in rats (10). In this experiment, as in other experiments using dihydrexidine (7), the effect of SCH 23390 was assessed by behavioral observations and measurements of spontaneous blink rate. Blink rate appears to be a strong correlate of central dopamine activity. It is depressed in Parkinson's patients and is sensitive to manipulation of both D1 and D2 receptors in healthy monkeys (11,12). Methods The subjects were mature young adult male African green monkeys (Cercopithecus aethiops sabaeus) from the island colony of St. Kitts, West Indies. Eleven monkeys were included in the experiment, five of which had been treated approximately eight months before the study with a cumulative dose of 2.0 mg/kg of MPTP, administered intramuscularly over a period of five days. None of the monkeys had previously received SCH 23390, L-DOPA, or other dopamine agonists or antagonists except one healthy monkey that had received SCH 23390, dihydrexidine, and D2 agonists and antagonists in a previous study six months earlier. The effect of drug treatment was assessed by behavioral observations made at ten minute intervals (-30, -20, -10, +3, + 13, +23, +33, and +43 minutes) before and after the injection of SCH 23390 at time point zero. Behavioral assessments during each interval included a five minute time-sampled observation period (13,14), an observer rating of behaviors and a two minute period during which spontaneous eye blinks were counted (11). The sum of the time-sampled behaviors and the observer rated behaviors allowed a quantification of the behavioral status of the monkeys and the derivation of Parkinsonian, Anxiety, Arousal, Sedation, Quiet O.K. and Tremor Scores. The behavioral scores were derived from previous factor analysis and validated by empirical testing (15). The Parkinsonian Score represents the sum of time-sampled and rated measures of tremor, appearance, freezing, difficulty eating, food response, delay in initiating responses, poverty of movement, response to threat, and time unable to stand (or "facedown"). The Anxiety Score represents the sum of yawn, chew, scratch and selfgroom; Arousal, the sum of shift, tail flag, lookout and vertical climb; and Sedation, the sum of eyes closed and freeze. Qualitative effects were confirmed from complete videotape records of the experiment. (+)-SCH 23390 HC1 (Research Biochemicals Inc., Natick, MA) was administered intramuscularly to four healthy monkeys and five MPTP-treated monkeys at a dose of 0.05 mg/kg. A higher dose (0.3 mg/kg) was administered to another group of four healthy monkeys, two of which had received the lower dose three days beforehand. The drug experiments were conducted over a five day period. Res01t~ Healthy monkeys receiving 0.05 mg/kg SCH 23390 exhibited a dramatic and significant increase in Parkinsonian Score within 13 minutes after injection (figure 1A). This increase was manifested by an onset of motor freezing, incoordination, bradykinesia, tremor and other motor deficits not seen prior to SCH 23390 injection. During the same interval, blink rate correspondingly decreased (figure 1B). Both Parkinsonian Score and blink rate gradually returned to baseline values in the remaining 30 minutes of the observation period. Several other behavioral measures also appeared to change after SCH 23390 adminstration (table I). A dose of 0.3 mg/kg caused a similar elevation in Parkinsonian Score (figure I A) and depression in blink rate (figure 1B) in healthy subjects, but it appeared to have a more lasting effect.
Vol. 49, No. 25, 1991
D I Antagonist Induces Parkinsonism
A
20
PL-231
B
15
15 10
-t-t
g to
_=
0
--
-40
~
-20
0 Minutes
20
40
-40
I
I
I
I
-20
0
20
40
Minutes
FIG. 1 Four healthy monkeys were injected with 0.05 mg/kg (black diamonds) or 0.3 mg/kg (open squares) SCH 23390 at time point zero. A) ParkinsonianScore showed a significant increase after the adminstration of SCH 23390 in both the low dose and high dose groups (neither the group factor nor the interaction between group and time were significant, but some of the times after drug administration were significantly different: F=I5.0, df=7,70, p
PL-232
D I Antagonist
Induces Parkinsonism
TABLE I 0.3 mg./ke SCH 23390 in Normals (N=4) Time (Minutes) -30 -20 -10 3 13 Parkinsonian Score 0.0 0.0 0.0 8.6 14.6 BlinkRate 11.9 10.4 9.6 5.3 4.1 Anxiety 6.0 7.3 4.5 8.5 0.5 Arousal 13.8 5.5 5.8 15.3 8.0 Sedation 0.0 0.0 0.0 5.3 16.8 Quiet O.K. 3.5 9.3 3.5 2.5 0.0 Tremor 0.0 0.0 0.0 0.5 1.3 0.05 m~k~ SCH 23390 in Normals (N--4) Time (IVlinutes) -30 -20 -10 3 Parkinsonian Score 0.0 0.0 0.0 5.0 Blink Rate 10.4 9.5 10.3 5.1 Anxiety 5.5 9.0 6.0 11.3 Arousal 8.0 7.8 9.8 11.0 Sedation 0.0 0.0 0.0 6.3 Quiet O.K. 3.0 15.0 11.3 3.8 Tremor 0.0 0.0 0.0 0.3
Vol.
49, No.
25,
23
33
43
12.7 4.3 1.0 5.0 22.3 0.0 1.0
9.9 4.9 0.8 3.0 26.0 0.3 0.5
8.5 6.3 1.8 2.8 33.5 0.5 0.3
13
23
33
43
13.0 5.1 0.5 10.0 21.5 0.0 0.5
8.3 5.0 1.0 3.0 35.2 0.5 0.3
5.1 7.2 1.5 4.8 25.5 0.8 0.0
2.0 7.8 1.8 3.8 10.0 1.8 0.0
<0.001 <0.001 <0.001 <0.001 <0.001 <0.01 ns
23
33
43
ANOVA
14.8 5.4 0.8 1.4 7.2 2.8 4.0
12.4 8.1 1.8 1.2 11.0 1.2 3.4
8.8 8.4 4.6 1.4 6.0 4.2 3.6
<0.001 <0.001 <0.001 <0.001 <0.001 <0.01 ns
0,05 mg/kg SCH 23390 in MPTP M0nkgys (N=5) Time (Minutes) -30 -20 -10 3 13 Parkinsonian Score 5.6 5.7 5.9 10.0 18.0 Blink Rate 11.1 9.7 12.5 5.9 5.3 Anxiety 8.6 8.8 10.4 12.2 0.8 Arousal 4.8 3.4 5.8 17.2 5.4 Sedation 1.0 0.6 0.6 0.8 9.2 Quiet O.K. 4.8 2.0 2.0 4.2 1.2 Tremor 3.8 3.8 3.8 2.8 4.0
1991
ANOVA* <0.001 <0.001 <0.001 <0.001 <0.001 <0.01 <0.01 ANOVA
*The mean valueof behavioral measures are given for each groupat each time point beforeand after SCH 23390 administration. Significancevalues are reported from the repeated measures factor(time) froman ANOVA,includingall three groups. There were no groupdifferences in any behavior,except for tremor which was subsequentlyanalyzedseparately. shifts, retropulsion, repeated rotations about the cage, sustained abnormal positioning of the body and limbs, and occasional vigorous grooming (none of which were specifically quantified in the standardized behavioral rating scheme). At the same time, head and eye movements and other behavioral indices of "alermess" decreased, and there was a reduced interest in food. During the interval 13 to 23 minutes post-injection, these movements were increasingly punctuated by periods of body freezing, until this state of inactivity became the dominant behavior. It is important to note that although the interruption of motor movement (motor freezing) contributed significantly to the elevation in Parkinsonian Score, it was accompanied by the onset of incoordination, bradykinesia and tremor and was not a trance-like, purely cataleptic effect. Furthermore, the spontaneous freezing seen is a classic parkinsonian sign defined and recorded in previous MPTP studies. Anxiety and Arousal Scores also dropped significantly below baseline values in the 13 to 23 minutes postinjection. There was a significant difference in tremor between the groups (F= 17.13, df=2,10, p<0.001). SCH 23390 induced a subtle resting head tremor in two of the healthy monkeys that received the low dose and in all four of the monkeys that received the higher dose (F=3.97, df 7,24, p<0.01). The head tremor was periodically accompanied by a slight limb tremor in several subjects. Although the tremor of the MVI'P-treated group was greater than that of the healthy monkeys before treatment (F=19.13, df 1,7, p<.01), SCH 23390 did not make it significantly worse.
Vol. 49, No. 25, 1991
D I Antagonist
Induces P a r k l n s o n i s m
PL-233
The results of the original study of 0.3 mg/kg SCH 23390 administered intramuscularly were replicated in five additional monkeys with an almost identical change resulting in parkinsonian motor functions and a reduction in blink rate. None of these changes were observed in the two hours following oral treatment of monkeys with 1 mg/kg (n=2) or 10 mg/kg (n=2) of SCH 23390. Oral delivery of the drug was achieved by placing SCH 23390 in a small piece of banana. Discussion The present study shows that blockade of D1 receptors with SCH 23390 induces classic parkinsonian signs in healthy monkeys and increases the severity of parkinsonism in MPTP-treated monkeys. The freezing, bradykinesia, tremor and other behavioral changes induced by SCH 23390 bear a close resemblance to the permanent motor deficits seen in MPTP-treated African green monkeys. Because MPTP-treated African green monkeys represent the best existing animal model of Parkinson's disease (15), the qualitative and quantitative similarity of the SCH 23390 effect supports the importance of D1 receptors in this condition. Stimulation of the same receptors by a selective Dl agonist has recently been found to alleviate MPTP-induced parkinsonism (7). Although SCH 23390 may have significant effects at 5-HT2 and 5-HT1c receptors, and dihydrexidine and CY208-243 have some activity at D2 receptors, their major and overlapping effects are on D1 receptors. Together these data suggest that Dl receptor function may be more important in the pathophysiology of Parkinson's disease than previously believed. Other investigators have reported that a comparable dose of SCH 23390 (0.05 mg/kg i.m.), administered alone or after chronic haloperidol, produced a dystonic syndrome in Cebus monkeys that had previously received chronic haloperidol treatment (16). The SCH 23390 effect in Cebus monkeys was characterized by oral dyskinesias, torsion and flexion of the trunk and torticollis of the head and neck (16), similar to that produced by the D2 antagonist, raclopride, and haloperidol (16). Significantly, postural freezing, motor inactivity, tremor or other parkinsonian signs were not reported after SCH 23390 in Cebus monkeys (16), after administration alone or after chronic haloperidol treatment. Although we observed dyskinetic locomotor activity and the assumption of awkward postures immediately following drug administration in the African green monkey, these behaviors subsided within 13 to 23 minutes with the onset of postural freezing, tremor and reduced motor activity. Others report that a high dose of SCH 23390 (2.0 mg/kg) increased motor disability scores of MPTP-treated marmosets, but they did not provide data or cite specific behavioral effects (3). Although only motor performance was measured in the present study, it is likely that other functions, such as memory (17), are also affected by SCH 23390 treatment. Chronic administration of 10 mg/kg orally of SCH 23390 has sedative properties in Cebus monkeys, but is without motor effects (19). Such findings have led some to suggest that SCH 23390 would be an antipsychotic drug devoid of undesirable extrapyramidal effects (19). We have confirmed these negative findings after a single oral dose in the African green monkey. However, based on the parkinsonian signs induced by SCH 23390 administered intramuscularly in African green monkeys (at 1/'200th the 10 mg/kg dose studied orally), the clinical utility of chronic administration of SCH 23390 and other DI antagonists may be limited by the emergence of parkinsonian signs and symptoms if effective D1 antagonist doses are used. The prototypical dopamine agonists, bromocriptine and apomorphine, have a greater affinity for D2 than Dl receptors, and their clinical effectiveness has been attributed to their D2 properties. For this reason many investigations and treatments of Parkinson's disease have focused on D2 receptors. Single dose antagonism of D2 receptors in non-human primates, however, does not result in classic parkinsonian signs. Even chronic administration of haloperidol over several months induced tremor in only 4 out of 21 African green monkeys, and there were no significant motor deficits (18). In Cebus monkeys chronic administration of haloperidol and other D2-selective antipsychotics produce sedation and eventually an extrapyramidal syndrome characterized by limb extensions, facial grimacing, chewing and tongue protrusions (19). The failure of the D1 agonist, SKF 38393, to have antiparkinsonian effects has been an argument against the relevance of DI receptors in the pharmacology of Parkinson's disease (3,4,6). The inactivity of SKF 38393, however, may be accounted for by a number of factors (20), and the antiparkinsonian activity of dihydrexidine and CY208-243 suggests that DI activation can enhance
PHARMACOLOGY& THERAPEUTICS The Journal of The International Encyclopediaof Pharmacology and Therapeutics I
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