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Sertindole, a new neuroleptic with extreme selectivity on A10 versus A9 dopamine neurones in the rat
European Journal of Pharmacology, 182 (1990) 613-614
613
Elsevier EJP 0261R
Rapid communication
Sertindole, a new neuroleptic with extreme selectivity on A10 versus A9 dopamine neurones in the rat T o r b e n Skarsfeldt a n d Jens P c r r c g a a r d Research Departments, H. Lundbeck A / S , Ottiliavej 7-9, DK-2500 Valby, Copenhagen, Denmark
Received 21 June 1990, accepted 22 June 1990
Neuroleptic-induced e x t r a p y r a m i d a l sideeffects (i.e. dystonia, parkinsonism and akathisia) are troublesome and difficult to treat. Unsuccessful treatment of neurological side-effects often leads to poor medication compliance. Since the introduction of chlorpromazine in the mid 1950s, extensive efforts have been directed towards the development of new neuroleptics without extrapyramidal side-effects. However, almost all of the neuroleptics introduced since then have been classical (i.e. they induce extrapyramidal sideeffects) while only clozapine has been characterized as an atypical neuroleptic (i.e. it does not induce extrapyramidal side-effects). Previous reports (Bunney and Grace, 1978; White and Wang, 1983; Skarsfeldt 1988) have suggested that the inhibition of a number of spontaneously active dopaminergic (DA) neurones in the substantia nigra pars compacta (A9) observed after chronic drug treatment accounts for the development of extrapyramidal side-effects. In addition, inhibition of DA activity in the ventral tegmental area (A10) indicates that a compound has antipsychotic potential. In the present study we used populations of DA neurones in the A9 and A10 areas of rat brains to characterize the effects of a new neuroleptic sertindole (code no. Lu 23-174) (1-[2-[4-[5-
Correspondence to: T. Skarsfeldt, Research Departments, H. Lundbeck A/S, Ottiliavej 7-9, DK-2500 Valby, Copenhagen, Denmark.
chloro-l-(4-fluorophenyl)-lH-indol-3-yl]-l-piperidinyl]ethyl]-2-imidazolidinone) (Perregaard, 1987). Skarsfeldt (1988) has recently described the method used. Briefly, male Wistar rats (250-300 g) received daily doses of sertindole (0.0057, 0.023, 0.091, 0.36 and 2.8 /~mol/kg) by intragastric intubation for 21 days. Five rats were used at each dose level. The animals were anaesthetized with chloral hydrate (2.4 m m o l / k g i.p.) and catheterized in the femoral vein to maintain anaesthesia (490 /~mol/kg i.v. once per h). The rats were mounted in a stereotaxic instrument and DA populations were studied as described elsewhere. Registration was started 2 h after the last injection. The DA neurones were identified acording to the method of Bunney and Grace (1978). Fourteen untreated rats provided reference levels of spontaneous activity in neurones of the A10 and A9 areas. In the A10 area, the number of cells per track was 0 . 9 0 _ 0.027 ( m e a n _ S.E.M.) while in the A9 area the activity of the DA neurones was 0.84 _ 0.029 (mean _+ S.E.M.) cells per track. Sertindole induced a dose-dependent decrease in the number of spontaneously active DA neurones in A10 after a 21-day treatment. The EDs0 value for inhibition of the A10 neurones was 0.015 /~mol/kg per day. Much higher doses were needed to inhibit the activity of A9 neurones (fig. 1). The EDs0 value for inhibition of A9 neurones was 1.6 /zmol/kg per day. The EDs0 values were calculated by log-probit analysis using data obtained with the three highest doses applied to the A9 area and the three lowest doses applied to the A10
0014-2999/90/$03.50 © 1990 ElsevierSciencePublishers B.V. (Biomedical Division)
614 INACTIVATION OF'DA NEURONES AFTER 3 WEEKS TREATMENT Sertindole active DA neurones
100 80 60 40 20 0 0.001
0.01
h
0.1 1.0 10 doily dose 0.a'nol/kg, p.o.) Fig. 1. The effect of repeated treatment (21 days p.o.) with sertindole on the number of spontaneously active DA neurones in the A9 and A10 area in rats. The abcissa indicates the daily doses in /~mol/kg and the ordinate indicates the percent inhibition of the number of spontaneously active DA neurones compared to the control level. There were five rats for each dose level of sertindole. The control level (mean + S.E.M.) (A9: 0.84+0.029 cells per track, A10:0.90+0.027 cells per track) represents data from 14 rats.
T h e m e c h a n i s m b e h i n d the selective effect of s e r t i n d o l e is n o t k n o w n a l t h o u g h we have prel i m i n a r y e v i d e n c e to suggest t h a t c h r o n i c treatm e n t with s e r t i n d o l e p r o d u c e s a d e p o l a r i z a t i o n block. A c u t e i.v. i n j e c t i o n of a p o m o r p h i n e (0.21 / ~ m o l / k g ) o r b a c l o f e n (5.8 / x m o l / k g ) c o m p l e t e l y reversed the activity of s e r t i n d o l e (3 weeks treatm e n t with 3.6 / ~ m o l / k g p e r d a y p.o.). This is in a g r e e m e n t w i t h o b s e r v a t i o n s m a d e with, e.g. h a l o p e r i d o l ( B u n n e y a n d G r a c e , 1978). T h e results i n d i c a t e t h a t s e r t i n d o l e is a p o t e n tial a n t i p s y c h o t i c c o m p o u n d w i t h o u t e x t r a p y r a m i d a l side-effects.
Acknowledgements The authors thank Dorte Frigast and Tina Vase for their excellent technical assistance.
References area. Selective i n a c t i v a t i o n of A 1 0 D A n e u r o n e s h a s b e e n o b s e r v e d after r e p e a t e d t r e a t m e n t with higher doses of the a t y p i c a l n e u r o l e p t i c c l o z a p i n e ( B u n n e y a n d G r a c e , 1978; W h i t e a n d W a n g , 1983). Skarsfeldt (1988) f o u n d EDs0 values of > 120 a n d 56 / x m o l / k g p e r d a y p.o. in A 9 a n d A 1 0 D A neurones, respectively. H o w e v e r , s e r t i n d o l e is m u c h m o r e p o t e n t . F u r t h e r , the r a t i o b e t w e e n the EDs0 values in the A10 a n d A 9 was > 100, indic a t i n g t h a t s e r t i n d o l e has a m u c h g r e a t e r l i m b i c specificity t h a n o t h e r p o t e n t i a l antipsychotics.
Bunney, B.S. and A.A. Grace, 1978, Acute and chronic haloperidol treatment: Comparison of effects on nigral dopaminergic cell activity, Life Sci. 23, 1715. Perregaard, J., U.S. Patent no. 4.710.500, 1987, Chem. Abstr. 106, 67110 m. Skarsfeldt, T., 1988, Differential effects after repeated treatment with haloperidol, dozapine, thioridazine and tefludazine on SNC and VTA dopamine neurones in rats, Life Sci. 42, 1037. White, F.J. and R.Y. Wang, 1983, Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons, Science 221, 1054.
613
Elsevier EJP 0261R
Rapid communication
Sertindole, a new neuroleptic with extreme selectivity on A10 versus A9 dopamine neurones in the rat T o r b e n Skarsfeldt a n d Jens P c r r c g a a r d Research Departments, H. Lundbeck A / S , Ottiliavej 7-9, DK-2500 Valby, Copenhagen, Denmark
Received 21 June 1990, accepted 22 June 1990
Neuroleptic-induced e x t r a p y r a m i d a l sideeffects (i.e. dystonia, parkinsonism and akathisia) are troublesome and difficult to treat. Unsuccessful treatment of neurological side-effects often leads to poor medication compliance. Since the introduction of chlorpromazine in the mid 1950s, extensive efforts have been directed towards the development of new neuroleptics without extrapyramidal side-effects. However, almost all of the neuroleptics introduced since then have been classical (i.e. they induce extrapyramidal sideeffects) while only clozapine has been characterized as an atypical neuroleptic (i.e. it does not induce extrapyramidal side-effects). Previous reports (Bunney and Grace, 1978; White and Wang, 1983; Skarsfeldt 1988) have suggested that the inhibition of a number of spontaneously active dopaminergic (DA) neurones in the substantia nigra pars compacta (A9) observed after chronic drug treatment accounts for the development of extrapyramidal side-effects. In addition, inhibition of DA activity in the ventral tegmental area (A10) indicates that a compound has antipsychotic potential. In the present study we used populations of DA neurones in the A9 and A10 areas of rat brains to characterize the effects of a new neuroleptic sertindole (code no. Lu 23-174) (1-[2-[4-[5-
Correspondence to: T. Skarsfeldt, Research Departments, H. Lundbeck A/S, Ottiliavej 7-9, DK-2500 Valby, Copenhagen, Denmark.
chloro-l-(4-fluorophenyl)-lH-indol-3-yl]-l-piperidinyl]ethyl]-2-imidazolidinone) (Perregaard, 1987). Skarsfeldt (1988) has recently described the method used. Briefly, male Wistar rats (250-300 g) received daily doses of sertindole (0.0057, 0.023, 0.091, 0.36 and 2.8 /~mol/kg) by intragastric intubation for 21 days. Five rats were used at each dose level. The animals were anaesthetized with chloral hydrate (2.4 m m o l / k g i.p.) and catheterized in the femoral vein to maintain anaesthesia (490 /~mol/kg i.v. once per h). The rats were mounted in a stereotaxic instrument and DA populations were studied as described elsewhere. Registration was started 2 h after the last injection. The DA neurones were identified acording to the method of Bunney and Grace (1978). Fourteen untreated rats provided reference levels of spontaneous activity in neurones of the A10 and A9 areas. In the A10 area, the number of cells per track was 0 . 9 0 _ 0.027 ( m e a n _ S.E.M.) while in the A9 area the activity of the DA neurones was 0.84 _ 0.029 (mean _+ S.E.M.) cells per track. Sertindole induced a dose-dependent decrease in the number of spontaneously active DA neurones in A10 after a 21-day treatment. The EDs0 value for inhibition of the A10 neurones was 0.015 /~mol/kg per day. Much higher doses were needed to inhibit the activity of A9 neurones (fig. 1). The EDs0 value for inhibition of A9 neurones was 1.6 /zmol/kg per day. The EDs0 values were calculated by log-probit analysis using data obtained with the three highest doses applied to the A9 area and the three lowest doses applied to the A10
0014-2999/90/$03.50 © 1990 ElsevierSciencePublishers B.V. (Biomedical Division)
614 INACTIVATION OF'DA NEURONES AFTER 3 WEEKS TREATMENT Sertindole active DA neurones
100 80 60 40 20 0 0.001
0.01
h
0.1 1.0 10 doily dose 0.a'nol/kg, p.o.) Fig. 1. The effect of repeated treatment (21 days p.o.) with sertindole on the number of spontaneously active DA neurones in the A9 and A10 area in rats. The abcissa indicates the daily doses in /~mol/kg and the ordinate indicates the percent inhibition of the number of spontaneously active DA neurones compared to the control level. There were five rats for each dose level of sertindole. The control level (mean + S.E.M.) (A9: 0.84+0.029 cells per track, A10:0.90+0.027 cells per track) represents data from 14 rats.
T h e m e c h a n i s m b e h i n d the selective effect of s e r t i n d o l e is n o t k n o w n a l t h o u g h we have prel i m i n a r y e v i d e n c e to suggest t h a t c h r o n i c treatm e n t with s e r t i n d o l e p r o d u c e s a d e p o l a r i z a t i o n block. A c u t e i.v. i n j e c t i o n of a p o m o r p h i n e (0.21 / ~ m o l / k g ) o r b a c l o f e n (5.8 / x m o l / k g ) c o m p l e t e l y reversed the activity of s e r t i n d o l e (3 weeks treatm e n t with 3.6 / ~ m o l / k g p e r d a y p.o.). This is in a g r e e m e n t w i t h o b s e r v a t i o n s m a d e with, e.g. h a l o p e r i d o l ( B u n n e y a n d G r a c e , 1978). T h e results i n d i c a t e t h a t s e r t i n d o l e is a p o t e n tial a n t i p s y c h o t i c c o m p o u n d w i t h o u t e x t r a p y r a m i d a l side-effects.
Acknowledgements The authors thank Dorte Frigast and Tina Vase for their excellent technical assistance.
References area. Selective i n a c t i v a t i o n of A 1 0 D A n e u r o n e s h a s b e e n o b s e r v e d after r e p e a t e d t r e a t m e n t with higher doses of the a t y p i c a l n e u r o l e p t i c c l o z a p i n e ( B u n n e y a n d G r a c e , 1978; W h i t e a n d W a n g , 1983). Skarsfeldt (1988) f o u n d EDs0 values of > 120 a n d 56 / x m o l / k g p e r d a y p.o. in A 9 a n d A 1 0 D A neurones, respectively. H o w e v e r , s e r t i n d o l e is m u c h m o r e p o t e n t . F u r t h e r , the r a t i o b e t w e e n the EDs0 values in the A10 a n d A 9 was > 100, indic a t i n g t h a t s e r t i n d o l e has a m u c h g r e a t e r l i m b i c specificity t h a n o t h e r p o t e n t i a l antipsychotics.
Bunney, B.S. and A.A. Grace, 1978, Acute and chronic haloperidol treatment: Comparison of effects on nigral dopaminergic cell activity, Life Sci. 23, 1715. Perregaard, J., U.S. Patent no. 4.710.500, 1987, Chem. Abstr. 106, 67110 m. Skarsfeldt, T., 1988, Differential effects after repeated treatment with haloperidol, dozapine, thioridazine and tefludazine on SNC and VTA dopamine neurones in rats, Life Sci. 42, 1037. White, F.J. and R.Y. Wang, 1983, Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons, Science 221, 1054.