188宝金博页面版

Copyright 1983. Production and Hosting by Elseiver B.V. On behalf of Japanese Pharmacological Society.This is an open access article under the CC BY-NC-ND License (http://creativecommons.org/licenses/by-nc-nd/).222 Ρ Ρ-159) E f f e c t o f t i m i p e r o n e on 3 H - s p i r o p e r i d o l b i n d i n g i n t h e r a t b r a i n . T e r u k i y o Yamasaki, Takeo S a k u r a i , S h i n i c h i K a w a j i r i , H i r o s h i Koj ima and A k i r a A k a s h i • L a b o r a t o r y o f Pharmacology, D a i i c h i S e i y a k u Co., L t d . , Tokyo 13^, Japan. We have r e p o r t e d p r e v i o u s l y t h a t t i m i p e r o n e ( T ) , a new p o t e n t a n t i p s y c h o t i c d r u g o f b u t y r o p h e n o n e t y p e , m a r k e d l y a c c e l e r a t e s dopamine t u r n o v e r i n t h e r a t b r a i n . I n t h e p r e s e n t s t u d y , i n h i b i t o r y e f f e c t s o f Τ and r e f e r e n c e drugs on 3 H - s p i r o p e r i d o l (3 H-SPP) b i n d i n g t o r a t b r a i n membranes were examined i n v i t r o and ex v i v o . On t h e b a s i s o f t h e i n h i b i t o r y s p e c t r u m o f t h e s e d r u g s i n v i t r o , b i n d i n g s i t e s o f 3 H-SPP were c o n f i r m e d as dopamine 2 ( D 2 ) r e c e p t o r s i n t h e s t r i a t u m ( S T ) , n u c l e u s accumbens (AC) and t u b e r c u l u m o l f a c t r i u m (TO) and as s e r o t o n i n 2 ( S 2 ) r e c e p t o r s i n t h e f r o n t a l c o r t e x (PC). I C5 0 v a l u e s o f Τ f o r t h e ST, AC, TO and FC were c a l c u l a t e d t o be 0.504, Ο.395, Ο.548 and 2.29 nM, r e s p e c t i v e l y . The i n h i b i t o r y e f f e c t s o f Τ were 5-1 ( S T ) , 6.0 (AC) , 7-8 (TO) and l 6 (FC) t i m e s more p o t e n t t h a n t h o s e o f h a l o p e r i d o l . I n ex v i v o e x p e r i m e n t s , I D5 0 v a l u e s o b t a i n e d a t 2 h r a f t e r o r a l a d m i n i s t r a t i o n were 0.25, 0.21, O.6O and 1.4 mg/kg i n t h e ST, AC, TO and FC, r e s p e c t i v e l y . Τ was 6.4 ( S T ) , 5-2 (AC), 6.8(TO) and 2.4 (FC) t i m e s as p o t e n t as h a l o p e r i d o l i n s u p p r e s s i n g t h e b i n d i n g o f 3 H-SPP. I n i n v i t r o and ex v i v o systems, t h e r e was no r e m a r k a b l e d i f f e r e n c e among t h e a f f i n i t i e s o f Τ f o r D 2 r e c e p t o r s i n t h e ST, AC and TO. These r e s u l t s suggest t h a t Τ b l o c k s D 2 and S 2 r e c e p t o r s more p o t e n t l y t h a n h a l o p e r i d o l , and b i n d s t o D 2 r e c e p t o r s more s e l e c t i v e l y t h a n t o S 2 ones. P-160) D o p a m i n e r g i c s u p e r s e n s i t i v i t y i n r a t s w i t h a r e p e a t e d a d m i n i s t r a t i o n o f h a l o p e r i d o l : S t u d i e s on s t e r e o t y p y and l o c o m o t o r a c t i v i t y . K i m i o Hara, Y u k i h i r o Ikoma, Y u k a r i T o k i y o r i , Y u k i e Nakada and Nozomu Oshino. Department o f Research, N i h o n S c h e r i n g K.K., Yodogawa-ku, Osaka 532, Japan. Rats were p r e t r e a t e d d a i l y w i t h h a l o p e r i d o l (0.5 mg/kg i . p . , t w i c e a day) f o r 2 weeks and t h e r e a f t e r t e s t e d f o r a l t e r a t i o n s i n dopamine(DA)-mediated b e h a v i o r . 1) The above p r e t r e a t m e n t a b o l i s h e d t h e h y p o m o t i l i t y i n d u c e d by l o w doses o f l i s u r i d e and apomorphine and p o t e n t i a t e d t h e h y p e r a c t i v i t y i n d u c e d by medium doses o f t h e two a g e n t s . 2) The p r e t r e a t m e n t r a i s e d t h e i n t e n s i t y o f l i s u r i d e - and a p o m o r p h i n e - i n d u c e d s n i f f i n g , w h i c h was a n t a g o n i z e d by s u l p i r i d e . On t h e o t h e r hand, a p o m o r p h i n e - i n d u c e d l i c k i n g showed no i n t e r f e r e n c e by t h e h a l o p e r i d o l p r e t r e a t m e n t and w i t h a f u r t h e r i n j e c t i o n o f s u l p i r i d e . However, b o t h t h e two p a t t e r n s o f s t e r e o t y p e d be­h a v i o r i n response t o apomorphine d i s a p p e a r e d i n t h e p r e s e n c e o f h a l o p e r i d o l . 3) L i s u r i d e caused t h e s t e r e o t y p e d l i c k i n g o n l y under t h e c o m p l e t e i n h i b i t i o n by s u l p i r i d e o f s n i f f i n g . These r e s u l t s s u g g e s t e x i s t e n c e o f two t y p e s o f p o s t s y n a p t i c DA r e c e p t o r s i n mesolymbic and n i g r o s t r i a t a l systems; one, w h i c h i s s u s c e p t i b l e t o s u l p i r i d e , i s i n v o l v e d i n l o c o m o t i o n and s n i f f i n g , and t h e o t h e r i s i n v o l v e d i n l i c k i n g . F u r t h e r ­more, i t i s c o n c l u d e d t h a t t h e p r e t r e a t m e n t w i t h h a l o p e r i d o l l e a d s t o a p r e f e r e n t i a l i n d u c t i o n o f s u p e r s e n s i t i v i t y i n t h e f o r m e r r e c e p t o r .