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Antagonism of AP-5- and amphetamine-induced behaviour by timelotem as compared with clozapine and haloperidol
L i f e Sciences, Vol. 41, pp. 1909-1914 Printed in the U.S.A.
Pergamon Journals
ANTAGONISM OF AP-5- AND AMPHETAMINE-INDUCED BEHAVIOUR BY TIMELOT~M AS COMPARED WITH CLOZAPINE AND HALOPERIDOL
W.J. Schmidt I), H. Kr~hling 2), M. Ruhland 2) i) Biologisches Institut der Universit~t, Ulmer Str. 227, D - 7000 Stuttgart 60, F.R.G. 2) Kali-Chemie AG, Pharmaceutical Division, Hans-B~ckler-Allee 20, D - 3000 Hannover i, F.R.G. (Received in final form August 18, 1987) SUMMARY Bilateral intrastriatal injection of DL-2-amino-5-phosphonovaleric acid (AP-5), that blocks glutamatergic transmission at the N-mathyl-d-aspartate preferring receptor, induces sniffing and body turns and reduces grooming in rats. Timalotem, a representative of the newly developed chemical class of [ 1,2]-anellated ~,4] benzodiazepines antagonized specifically AP-5-induced sniffing and body turns. Classical (haloperidol) as well as atypical (clozapine) neuroleptics had recently been shown to antagonize AP-5induced sniffing: clozapine, like timelotem, but not haloperidol, additionally antagonized AP-5-induced body turns. Further, timelotem antagonized amphetamine-induced stereotyped behaviour in rats, but was found less active than haloperidol in this test. Comparing the activity of drugs in both paradigms revealed that haloperidol inhibited AP-5-induced sniffing and amphetamine-induced stereotypies within the same dose range, but timalotem and clozapine were found more potent in the AP-5 test than in the amphetamine test. Thus, detailed drug profiles discriminate timelotem and clozapine from haloperidol, linking timelotem again to atypical antipsychotic compounds. Classical neuroleptics share at least one common property: they exhibit pronounced antidopaminergic activity. In consequence, and as widely accepted today, these compounds block dopamine receptors in the corpus striatum and in the limbic areas. Convincing evidence has been established to suggest that the antipsychotic activity of classical neuroleptics is due to their effects on either one or both of these brain areas. Inferentially these findings became a major supporting pillar of the "dopamine hypothesis" of schizophrenia (for ref. see l - 3). Unfortunately, down-regulation of the dopaminergic neurotransmission in the striatum, in particular by postsynaptic D2-receptor blockade, most likely is also responsible for adverse extrapyramidal symptoms, common with all classical neuroleptics. However, the proven antipsychotlc efficacy of the atypical neuroleptic clozapine indicates that an extraordinary D2 blocking activity is not a prerequisite of antipsychotic potency, and an impairment of extrapyramidal functioning is not an indispensable property of antipsychotic compounds (4,5). Specific animal models can help to discriminate the antipsychotic potency
0024-3205/87 $3.00 + .00 Copyright (c) 1987 Pergamon Journals Ltd.
1910
Antagonism of AP-5 and Neuroleptlcs
Vol. 41, No. 16, 1987
of a compound from its liability to block striatal dopaminergic neurotransmission. Regarding antipsychotic activity a new behavioural model was recently established based on the effects of striatal glutamate at theN-methyl-daspartate- (NMDA)- preferring receptor (6). Blockade of glutamatergic transmission at NMDA preferring receptors by bilateral intrastriatal injection of DL-2-amino-5-phosphonovaleric acid (AP-5) induced sniffing stereotypy in rats similar to that induced by low dose levels of amphetamine. The antagonism of amphetamine-induced stereotypies has been widely used as a screening model for antipsychotic drugs. However, amphetamine-induced stereotypies could be antagonized only by classical neuroleptics (e.g. haloperidol) but not by atypical ones (e.g. clozapine). But AP-5-induced sniffing was antagonized by haloperidol as well as by clozapine. Thus, the AP-5 antagonism parallels the (clinical) antipsychotic efficacy of the drugs. These findings fit to the "glutamate hypothesis" of schizophrenia that suggests a deficient glutamatergic system to be involved in this disease (7, 8). On the other hand, antagonism of amphetamine-induced stereotyped behaviour remains undoubtedly a predictive animal model with regard to striatal dopamine system (9). Timalotem is a representative of a newly developed chemical class of [I, 2 ~anellated [1,4 ]benzodiazepines (I0) which have lost most of the typical properties of benzodiazepine drugs (ii). Previous pharmacological characterization revealed that this compound shows the profile of a potent antipsychotic drug having in addition anxiolytic properties. However, and in contrast to classical neuroleptics, timalotem showed only moderate affinity to central Dg-receptors in vitro, exhibited very low liability to induce catalepsy in rats and was clearly more potent to inhibit the conditioned avoidance response in rats or the apomorphine-induced climbing in mice than to inhibit amphetamine- (rats/mice) or apomorphine- (rats) induced stereotyped behaviour after oral application (ii, 12). These findings gave evidence to assume that timelotem should be classified as an atypical antipsychotic compound and in consequence would possibly have an at least reduced liability to cause extrapyramidal symptoms than classical standard neuroleptics. It was the purpose of this study to evaluate timalotem, a new prospective antipsychotic, in the above mentioned models of stereotypy antagonism, and to compare its respective profile with that of haloperidol and clozapine. MATERIAL AND METHODS
Drugs Timalotem ((+)-lO-fluoro-i, 2, 3,4,4a, 5-hexahydro-3-methyl-7-( 2-thienyl )pyrazino[ i, 2-a ]- [i.4] benzodiazepine dihydrogenmaleate: Kali-Chemie ~, F.R.G.), haloperidol (haloperidol free base; Janssen, Belgium) and clozapine (clozapine free base; Sandoz, Switzerland) were dissolved in saline. Amphetamine (d-amphetamine sulfate; Merck-Schuchart, F.R.G.) was dissolved in distilled water. DL-2-amino-5-phosphonovaleric acid (AP-5; Sigma, F.R.G.) was dissolved as already described (6). Inhibition of AP-5-induced behaviour in rats Animals (male Sprague-Dawley rats: 2~0 - 320 g), housing and feeding, surgery and intrastriatal injection have already been described in detail (6). Briefly, intrastriatal injections (1.7 anterior bregma, L.+2, ¥.5.0) were made in conscious rats through cannulae (0.45 mm diameter), guided by permanently implanted cannulae. The behaviour of animals after bilateral intrastriatal injection of saline served as control and was considered as spontaneous behaviour. Saline or timelotem (1 ~mol/kg in 1 ml/kg or 2 ~mol/kg in 2 ml/kg) were given i.p. 60 rain before bilateral intrastriatal injection of AP-5 (i0 ~g in 0.5 ~I). Immediately after completion of the AP-5 injection the behaviour of the animals was
Vol. 41, No. 16, 1987
Antagonism of AP-5 and Neuroleptics
1911
recorded in an experimental chamber for 5 min considering the following variables: I. Wall contacts: to quantify sniffing intensity 2. Turns: each body turn of 180 @ was counted 3. Grooming: the duration of face washing and body grooming was measured (for details see 6). The results are given as medians and interquartile ranges. Because of individual differences the same animals were used in each experimental schedule, i.e. in saline, saline/timalotem and AP-5/timelotem experiments. The various treatment groups were statistically compared using the Wilcoxon matched pairs signed-ranks test. A p-value <_0.05 was considered to indicate a significant difference. Antagonism of amphetamine-induced stereotyped behaviour in rats The test was performed following Janssen et al. (13) using male SpragueDawley rats (n = 6/dose; 80 - 190 g). Different doses of timelotem, clozapine or haloperidol were given i.p. in i0 ml/kg 60 min before amphetamine administration (I0 mg/kg i.v. in 5 ml/kg). Stereotyped behaviour was rated twice, 55 and 63 min, after amphetamine administration according to the following score: 0 = no stereotyped behaviour 1 = discontinuous stereotyped sniffing 2 = permanent stereotyped sniffing with or without occasional licking or chewing 3 = permanet licking or chewing The total score sum for each dose group (maximal score per dose group) was used to calculate ED50-values. ED50 was dose which reduced the total score sum to 50 % compared to a amine treated control group. ED values were calculated by (14).
sum = 36 points defined as the %~hicle/amphetprobit analysis
RESULTS Antagonism of amphetamine-induced stereotyped behaviour Haloperidol and timelotem dose-dependently antagonized the amphetamineinduced stereotyped behaviour in rats. The potency of haloperidol proved to be more than twenty times higher than the potency of timalotem in this test. Clozapine was found to be ineffective in this animal model up to the highest dose tested (table i). TABLE i Effects of timelotem (TIM), clozapine (CLOZ) and haloperidol (HALO) on the amphetamine-induced stereotyped behaviour in rats 2 h after i.p. application. Given are ED50-values (EDS0) and 95 % confidence limits (conf. lira.) in ~mol/kg as well as the number of animals per dose (N).
TIM
ED50 conf. lim. N
CLOZ
14 > 147 10-20 i0 I0
HALO
0.51 O. 35-0.69 I0
1912
Antagonism of AP-5 and Neuroleptics
Vol. 41, No. 16, 1987
WCIII contoct
~p:
s
0015
p=O.01~
r-1>015~
~p=Q06~
100
50
+ i
i
i
sotme
soline
AP-5
i
AP-5
TIM
TIM
TIM 2 9
9
,
AP-5
9
introstriotolly peripherolly
1
2
i/n',ol/kg
9
9
N
FIG. I Wall contacts (stereotyped sniffing: median _+ interquartile ranges) during 5-min sessions. Saline or AP-5 were given into the striatum. Timelotem (TIM) was given intraperitoneally. Statistical evaluations ~ r e performed using Wilcoxon's retched pair signed ranks test. P-values corresponding to indicated comparisons are given.
turns
~p=0.058 ~p-01S.
p=0015~ .p:007.
30
20
+
i
i
i
sctllne
saline
AP-5
TIM 2 9
9
9
i
i
AP-5
AP-5
mtrost riatally
TIM
TIM
peripheroUy
1
2
I~rnol/kg
9
9
N
FIG. 2 Number of body turns of 180 ° (median + interguartile ranges) during 5rain sessions. Details correspond to fig. ~.
Vol. 41, No. 16, 1987
Antagonism of AP-5 and Neuroleptics
1913
Antagonism of AP-5-induced behaviour by timelotem Wall contacts (stereotyped sniffing): Timelotem (2 Nmol/kg) did not change the number of spontaneous wall contacts. AP-5 significantly increased the number of wall contacts. Prior intraperitoneally administered timelotem antagonized dose-dependently the AP-5-induced increase in wall contacts (at 2 ~mol/kg of timelotem: p
gfoe~j (sl
150 -
~ p =0,01 ~p-015~
, p - 0.15-~ , p~O15-~
100
50.
I
i
i
i
i
saline
saline
AP-5
AP-5
AP-5
TIM
TIM
1
2
9
9
TIM 2 9
9
9
intrastriatady peripheraUy
N
FIG. 3 Cumulative duration of grooming (face washing and body grooming; median + interquartile ranges) during 5-rain sessions. Details correspond to fig. I. DISCUSSION Timelotem antagonized dose-dependently sniffing and body turns induced by AP-5, but per se did not change spontaneously occurring sniffing or body turns. Neither spontaneous grooming nor AP-5-induced reduction of grooming was altered by timelotem. Conioaring these results with those of clozapine and haloperidol (6) reveals: all three compounds significantly antagonized AP-5-induced sniffing. However, timelotem and clozapine differ from haloperidol as both compounds did not antagonize spontaneous sniffing but did antagonize AP-5-induced turns. On the other hand, the reduction of grooming caused by AP-5 was significantly antagonized by haloperidol (6) but not by timelotem or clozapine (6).
1914
Antagonism of AP-5 and Neuroleptics
Vol. 41, No. 16, 1987
Thus, it can be summarized that the effects of timalotem on AP-5-induced behavioural changes correspond closely to the respective effects of clozapine. Regarding amphetamine-induced stereotyped behaviour the present results show in accordance with previous investigations that haloperidol, but not clozapine, potently and dose-dependently antagonized amphetamine-induced stereotypies. Timalotem also antagonized amphetamine-induced stereotypies but only at considerably higher dose levels than haloperidol. Thus, whereas haloperidol was found to inhibit AP-5-induced sniffing (minimum significant dose: 0.27 Hmol/kg (6)) and amphetamine-induced stereotypies (EDL0:0.51 ~mol/kg) within the same dose range, timelotem was clearly more active in the AP-5 test (minimum significant dose: 2 ~mol/kg) than in the amphetamine test (ED50: 14 ~mol/kg). Clozapine was found only active in the AP-5 test (6). In conclusion, timelotem, clozapine and haloperidol have been proven active to antagonize stereotyped sniffing elicited by k~4DA-receptor blockade within the striatum. However, the full profiles as evaluated in the present studies as well as in former investigations discriminate timelotem and clozapine from haloperidol. This again supports the similarity of timelotem with atypical antipsychotics. Since timelotem and clozapine exhibit only moderate affinity to central D2-receptors as compared with haloperidol (12) their effects in animal models linked to antipsychotic activity seems to be at least in addition mediated via other transmitter systems - the glutamatergic one may be considered. REFERENCES i. D. PICKAR, Psychiatr. Clin. North Am. 9, 35 - 48 (1986) 2. E.N. GREENBLATT, J. COUPET, E. RAUH, V.A. SZUCS-MYERS, Arch. Int. Pharmacodyn. 248, 1 0 5 - 119 (1980) 3. R. MILLER, Psychol. Med. 14, 779 - 789 (1984) 4. H.R. BORKI, E. EICHENBERGER, A.C. SAYERS, T.G. m I T E , Pharmacopsychiat. 8, 115 - 121 (1975) 5. S. BISCHOFF, H.R. B--0RKI, H.M. ~MRICH, J. JAECKEL, J. KORNHUBER, M. RUHLAND, W.J. SCHMIDT, B. WOGGON, Pharmacopsychiat. 19, 1 4 0 - 144 (1986) 6. W.J. SCHMIDT, Psychopharmacol. 90, 1 2 3 - 130 (1986) 7. J.S. KIM, H.H. KORNHUBER, W. SCHMID-BURGK, B. HOLZMOLLER, Neurosci. Lett. 20, 379 - 382 (1980) 8. H.D. KO~K]BER, Archly Psychiatr. Nervenkr. 233, 415 - 422 (1983) 9. P.H. KELLY, P.W. SEVIOUR, S.D. IVERSEN, Brain Res. 94, 507 - 522 (1975) I0. H. LIEPMANN, M. RUHLAND, H. MUSCH, W. BENSON, H. HEIN~ANN, H. ZEUGNER, Chem. Abstr. i00, 34570j (1984) Ii. M. RUHLAND, and A.M. ~JCHS, Pharmacopsychiat. 19, 216 - 217 (1986) 12. M. RUHLAND, M. qI]LP, H.R. MDSCH, A.M. ~CHS, Pharmacopsychiat. 19, 218 - 219 (1986) 13. P.A.J. JANSSEN, C.J.E. NI~EGEERS, K.H.L. SCHELLEKENS, Arzneim. Forsch. 15, 1 0 4 - 117; 1 1 9 6 - 1206 (1965) 14. J.---D.FINNEY, Cambridge University Press, third edition, Cambridge, pp. i 0 0 - 126 (1971) m
m
Pergamon Journals
ANTAGONISM OF AP-5- AND AMPHETAMINE-INDUCED BEHAVIOUR BY TIMELOT~M AS COMPARED WITH CLOZAPINE AND HALOPERIDOL
W.J. Schmidt I), H. Kr~hling 2), M. Ruhland 2) i) Biologisches Institut der Universit~t, Ulmer Str. 227, D - 7000 Stuttgart 60, F.R.G. 2) Kali-Chemie AG, Pharmaceutical Division, Hans-B~ckler-Allee 20, D - 3000 Hannover i, F.R.G. (Received in final form August 18, 1987) SUMMARY Bilateral intrastriatal injection of DL-2-amino-5-phosphonovaleric acid (AP-5), that blocks glutamatergic transmission at the N-mathyl-d-aspartate preferring receptor, induces sniffing and body turns and reduces grooming in rats. Timalotem, a representative of the newly developed chemical class of [ 1,2]-anellated ~,4] benzodiazepines antagonized specifically AP-5-induced sniffing and body turns. Classical (haloperidol) as well as atypical (clozapine) neuroleptics had recently been shown to antagonize AP-5induced sniffing: clozapine, like timelotem, but not haloperidol, additionally antagonized AP-5-induced body turns. Further, timelotem antagonized amphetamine-induced stereotyped behaviour in rats, but was found less active than haloperidol in this test. Comparing the activity of drugs in both paradigms revealed that haloperidol inhibited AP-5-induced sniffing and amphetamine-induced stereotypies within the same dose range, but timalotem and clozapine were found more potent in the AP-5 test than in the amphetamine test. Thus, detailed drug profiles discriminate timelotem and clozapine from haloperidol, linking timelotem again to atypical antipsychotic compounds. Classical neuroleptics share at least one common property: they exhibit pronounced antidopaminergic activity. In consequence, and as widely accepted today, these compounds block dopamine receptors in the corpus striatum and in the limbic areas. Convincing evidence has been established to suggest that the antipsychotic activity of classical neuroleptics is due to their effects on either one or both of these brain areas. Inferentially these findings became a major supporting pillar of the "dopamine hypothesis" of schizophrenia (for ref. see l - 3). Unfortunately, down-regulation of the dopaminergic neurotransmission in the striatum, in particular by postsynaptic D2-receptor blockade, most likely is also responsible for adverse extrapyramidal symptoms, common with all classical neuroleptics. However, the proven antipsychotlc efficacy of the atypical neuroleptic clozapine indicates that an extraordinary D2 blocking activity is not a prerequisite of antipsychotic potency, and an impairment of extrapyramidal functioning is not an indispensable property of antipsychotic compounds (4,5). Specific animal models can help to discriminate the antipsychotic potency
0024-3205/87 $3.00 + .00 Copyright (c) 1987 Pergamon Journals Ltd.
1910
Antagonism of AP-5 and Neuroleptlcs
Vol. 41, No. 16, 1987
of a compound from its liability to block striatal dopaminergic neurotransmission. Regarding antipsychotic activity a new behavioural model was recently established based on the effects of striatal glutamate at theN-methyl-daspartate- (NMDA)- preferring receptor (6). Blockade of glutamatergic transmission at NMDA preferring receptors by bilateral intrastriatal injection of DL-2-amino-5-phosphonovaleric acid (AP-5) induced sniffing stereotypy in rats similar to that induced by low dose levels of amphetamine. The antagonism of amphetamine-induced stereotypies has been widely used as a screening model for antipsychotic drugs. However, amphetamine-induced stereotypies could be antagonized only by classical neuroleptics (e.g. haloperidol) but not by atypical ones (e.g. clozapine). But AP-5-induced sniffing was antagonized by haloperidol as well as by clozapine. Thus, the AP-5 antagonism parallels the (clinical) antipsychotic efficacy of the drugs. These findings fit to the "glutamate hypothesis" of schizophrenia that suggests a deficient glutamatergic system to be involved in this disease (7, 8). On the other hand, antagonism of amphetamine-induced stereotyped behaviour remains undoubtedly a predictive animal model with regard to striatal dopamine system (9). Timalotem is a representative of a newly developed chemical class of [I, 2 ~anellated [1,4 ]benzodiazepines (I0) which have lost most of the typical properties of benzodiazepine drugs (ii). Previous pharmacological characterization revealed that this compound shows the profile of a potent antipsychotic drug having in addition anxiolytic properties. However, and in contrast to classical neuroleptics, timalotem showed only moderate affinity to central Dg-receptors in vitro, exhibited very low liability to induce catalepsy in rats and was clearly more potent to inhibit the conditioned avoidance response in rats or the apomorphine-induced climbing in mice than to inhibit amphetamine- (rats/mice) or apomorphine- (rats) induced stereotyped behaviour after oral application (ii, 12). These findings gave evidence to assume that timelotem should be classified as an atypical antipsychotic compound and in consequence would possibly have an at least reduced liability to cause extrapyramidal symptoms than classical standard neuroleptics. It was the purpose of this study to evaluate timalotem, a new prospective antipsychotic, in the above mentioned models of stereotypy antagonism, and to compare its respective profile with that of haloperidol and clozapine. MATERIAL AND METHODS
Drugs Timalotem ((+)-lO-fluoro-i, 2, 3,4,4a, 5-hexahydro-3-methyl-7-( 2-thienyl )pyrazino[ i, 2-a ]- [i.4] benzodiazepine dihydrogenmaleate: Kali-Chemie ~, F.R.G.), haloperidol (haloperidol free base; Janssen, Belgium) and clozapine (clozapine free base; Sandoz, Switzerland) were dissolved in saline. Amphetamine (d-amphetamine sulfate; Merck-Schuchart, F.R.G.) was dissolved in distilled water. DL-2-amino-5-phosphonovaleric acid (AP-5; Sigma, F.R.G.) was dissolved as already described (6). Inhibition of AP-5-induced behaviour in rats Animals (male Sprague-Dawley rats: 2~0 - 320 g), housing and feeding, surgery and intrastriatal injection have already been described in detail (6). Briefly, intrastriatal injections (1.7 anterior bregma, L.+2, ¥.5.0) were made in conscious rats through cannulae (0.45 mm diameter), guided by permanently implanted cannulae. The behaviour of animals after bilateral intrastriatal injection of saline served as control and was considered as spontaneous behaviour. Saline or timelotem (1 ~mol/kg in 1 ml/kg or 2 ~mol/kg in 2 ml/kg) were given i.p. 60 rain before bilateral intrastriatal injection of AP-5 (i0 ~g in 0.5 ~I). Immediately after completion of the AP-5 injection the behaviour of the animals was
Vol. 41, No. 16, 1987
Antagonism of AP-5 and Neuroleptics
1911
recorded in an experimental chamber for 5 min considering the following variables: I. Wall contacts: to quantify sniffing intensity 2. Turns: each body turn of 180 @ was counted 3. Grooming: the duration of face washing and body grooming was measured (for details see 6). The results are given as medians and interquartile ranges. Because of individual differences the same animals were used in each experimental schedule, i.e. in saline, saline/timalotem and AP-5/timelotem experiments. The various treatment groups were statistically compared using the Wilcoxon matched pairs signed-ranks test. A p-value <_0.05 was considered to indicate a significant difference. Antagonism of amphetamine-induced stereotyped behaviour in rats The test was performed following Janssen et al. (13) using male SpragueDawley rats (n = 6/dose; 80 - 190 g). Different doses of timelotem, clozapine or haloperidol were given i.p. in i0 ml/kg 60 min before amphetamine administration (I0 mg/kg i.v. in 5 ml/kg). Stereotyped behaviour was rated twice, 55 and 63 min, after amphetamine administration according to the following score: 0 = no stereotyped behaviour 1 = discontinuous stereotyped sniffing 2 = permanent stereotyped sniffing with or without occasional licking or chewing 3 = permanet licking or chewing The total score sum for each dose group (maximal score per dose group) was used to calculate ED50-values. ED50 was dose which reduced the total score sum to 50 % compared to a amine treated control group. ED values were calculated by (14).
sum = 36 points defined as the %~hicle/amphetprobit analysis
RESULTS Antagonism of amphetamine-induced stereotyped behaviour Haloperidol and timelotem dose-dependently antagonized the amphetamineinduced stereotyped behaviour in rats. The potency of haloperidol proved to be more than twenty times higher than the potency of timalotem in this test. Clozapine was found to be ineffective in this animal model up to the highest dose tested (table i). TABLE i Effects of timelotem (TIM), clozapine (CLOZ) and haloperidol (HALO) on the amphetamine-induced stereotyped behaviour in rats 2 h after i.p. application. Given are ED50-values (EDS0) and 95 % confidence limits (conf. lira.) in ~mol/kg as well as the number of animals per dose (N).
TIM
ED50 conf. lim. N
CLOZ
14 > 147 10-20 i0 I0
HALO
0.51 O. 35-0.69 I0
1912
Antagonism of AP-5 and Neuroleptics
Vol. 41, No. 16, 1987
WCIII contoct
~p:
s
0015
p=O.01~
r-1>015~
~p=Q06~
100
50
+ i
i
i
sotme
soline
AP-5
i
AP-5
TIM
TIM
TIM 2 9
9
,
AP-5
9
introstriotolly peripherolly
1
2
i/n',ol/kg
9
9
N
FIG. I Wall contacts (stereotyped sniffing: median _+ interquartile ranges) during 5-min sessions. Saline or AP-5 were given into the striatum. Timelotem (TIM) was given intraperitoneally. Statistical evaluations ~ r e performed using Wilcoxon's retched pair signed ranks test. P-values corresponding to indicated comparisons are given.
turns
~p=0.058 ~p-01S.
p=0015~ .p:007.
30
20
+
i
i
i
sctllne
saline
AP-5
TIM 2 9
9
9
i
i
AP-5
AP-5
mtrost riatally
TIM
TIM
peripheroUy
1
2
I~rnol/kg
9
9
N
FIG. 2 Number of body turns of 180 ° (median + interguartile ranges) during 5rain sessions. Details correspond to fig. ~.
Vol. 41, No. 16, 1987
Antagonism of AP-5 and Neuroleptics
1913
Antagonism of AP-5-induced behaviour by timelotem Wall contacts (stereotyped sniffing): Timelotem (2 Nmol/kg) did not change the number of spontaneous wall contacts. AP-5 significantly increased the number of wall contacts. Prior intraperitoneally administered timelotem antagonized dose-dependently the AP-5-induced increase in wall contacts (at 2 ~mol/kg of timelotem: p
gfoe~j (sl
150 -
~ p =0,01 ~p-015~
, p - 0.15-~ , p~O15-~
100
50.
I
i
i
i
i
saline
saline
AP-5
AP-5
AP-5
TIM
TIM
1
2
9
9
TIM 2 9
9
9
intrastriatady peripheraUy
N
FIG. 3 Cumulative duration of grooming (face washing and body grooming; median + interquartile ranges) during 5-rain sessions. Details correspond to fig. I. DISCUSSION Timelotem antagonized dose-dependently sniffing and body turns induced by AP-5, but per se did not change spontaneously occurring sniffing or body turns. Neither spontaneous grooming nor AP-5-induced reduction of grooming was altered by timelotem. Conioaring these results with those of clozapine and haloperidol (6) reveals: all three compounds significantly antagonized AP-5-induced sniffing. However, timelotem and clozapine differ from haloperidol as both compounds did not antagonize spontaneous sniffing but did antagonize AP-5-induced turns. On the other hand, the reduction of grooming caused by AP-5 was significantly antagonized by haloperidol (6) but not by timelotem or clozapine (6).
1914
Antagonism of AP-5 and Neuroleptics
Vol. 41, No. 16, 1987
Thus, it can be summarized that the effects of timalotem on AP-5-induced behavioural changes correspond closely to the respective effects of clozapine. Regarding amphetamine-induced stereotyped behaviour the present results show in accordance with previous investigations that haloperidol, but not clozapine, potently and dose-dependently antagonized amphetamine-induced stereotypies. Timalotem also antagonized amphetamine-induced stereotypies but only at considerably higher dose levels than haloperidol. Thus, whereas haloperidol was found to inhibit AP-5-induced sniffing (minimum significant dose: 0.27 Hmol/kg (6)) and amphetamine-induced stereotypies (EDL0:0.51 ~mol/kg) within the same dose range, timelotem was clearly more active in the AP-5 test (minimum significant dose: 2 ~mol/kg) than in the amphetamine test (ED50: 14 ~mol/kg). Clozapine was found only active in the AP-5 test (6). In conclusion, timelotem, clozapine and haloperidol have been proven active to antagonize stereotyped sniffing elicited by k~4DA-receptor blockade within the striatum. However, the full profiles as evaluated in the present studies as well as in former investigations discriminate timelotem and clozapine from haloperidol. This again supports the similarity of timelotem with atypical antipsychotics. Since timelotem and clozapine exhibit only moderate affinity to central D2-receptors as compared with haloperidol (12) their effects in animal models linked to antipsychotic activity seems to be at least in addition mediated via other transmitter systems - the glutamatergic one may be considered. REFERENCES i. D. PICKAR, Psychiatr. Clin. North Am. 9, 35 - 48 (1986) 2. E.N. GREENBLATT, J. COUPET, E. RAUH, V.A. SZUCS-MYERS, Arch. Int. Pharmacodyn. 248, 1 0 5 - 119 (1980) 3. R. MILLER, Psychol. Med. 14, 779 - 789 (1984) 4. H.R. BORKI, E. EICHENBERGER, A.C. SAYERS, T.G. m I T E , Pharmacopsychiat. 8, 115 - 121 (1975) 5. S. BISCHOFF, H.R. B--0RKI, H.M. ~MRICH, J. JAECKEL, J. KORNHUBER, M. RUHLAND, W.J. SCHMIDT, B. WOGGON, Pharmacopsychiat. 19, 1 4 0 - 144 (1986) 6. W.J. SCHMIDT, Psychopharmacol. 90, 1 2 3 - 130 (1986) 7. J.S. KIM, H.H. KORNHUBER, W. SCHMID-BURGK, B. HOLZMOLLER, Neurosci. Lett. 20, 379 - 382 (1980) 8. H.D. KO~K]BER, Archly Psychiatr. Nervenkr. 233, 415 - 422 (1983) 9. P.H. KELLY, P.W. SEVIOUR, S.D. IVERSEN, Brain Res. 94, 507 - 522 (1975) I0. H. LIEPMANN, M. RUHLAND, H. MUSCH, W. BENSON, H. HEIN~ANN, H. ZEUGNER, Chem. Abstr. i00, 34570j (1984) Ii. M. RUHLAND, and A.M. ~JCHS, Pharmacopsychiat. 19, 216 - 217 (1986) 12. M. RUHLAND, M. qI]LP, H.R. MDSCH, A.M. ~CHS, Pharmacopsychiat. 19, 218 - 219 (1986) 13. P.A.J. JANSSEN, C.J.E. NI~EGEERS, K.H.L. SCHELLEKENS, Arzneim. Forsch. 15, 1 0 4 - 117; 1 1 9 6 - 1206 (1965) 14. J.---D.FINNEY, Cambridge University Press, third edition, Cambridge, pp. i 0 0 - 126 (1971) m
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