15. 11. 1975
t369
Speeialia
C h a n g e s of E l e c t r o - S h o c k S e i z u r e T h r e s h o l d in A l l o x a n D i a b e t i c R a t s I n p r e v i o u s e x p e r i m e n t s we f o u n d t h a t t h e effectiveness of d r u g s i n h i b i t i n g t r a n s m i s s i o n process a t t h e p e r i p h e r a l cholinergic s y n a p s e s was altered b y e x p e r i m e n t a l diabetes. The ganglionic b l o c k i n g effect of h e x a m e t h o n i u m , T E A B , a n d D - t u b o c u r a r i n e was f o u n d t o be s i g n i f i c a n t l y less e x p r e s s e d in d e p a n c r e a t i z e d cats t h a n in c o n t r o l s ~,2. I n n o r m a l animals, insulin e x e r t e d an o p p o s i t e effect 3. F u r t h e r m o r e , s u s c e p t i b i l i t y to D - t u b o c u r a r i n e of t h e m o t o r e n d - p l a t e s of alloxan d i a b e t i c r a t s was also s h o w n t o be decreased, w h e r e a s t h e e f f e c t i v i t y of s u x a m e t h o n i u m was p r o l o n g e d 4. T h e s e results were c o n f i r m e d b y QuEVAUVILLER a n d PODEVIN 5. F r o m t h e findings o b t a i n e d t h e conclusion m a y be d r a w n t h a t t h e altered p h a r m a c o l o g i c a l r e a c t i v i t y m i g h t be due to an increased e x c i t a b i l i t y of t h e s y n a p t i c s t r u c t u r e s via a relative corticoid p r e p o n d e r a n c e i n d u c e d b y insulin deficiency. I n t h e p r e s e n t e x p e r i m e n t s , a n a t t e m p t was m a d e t o elucidate w h e t h e r or n o t t h e e x c i t a b i l i t y of t h e c e n t r a l n e r v o u s s y s t e m (CNS) of a l l o x a n d i a b e t i c r a t s was also c h a n g e d . Therefore, t h e e l e c t r o - s h o c k seizure t h r e s h o l d (EST) w a s d e t e r m i n e d . Methods. M e a s u r e m e n t s were carried o u t on female r a t s of R - A m s t e r d a m s t r a i n w e i g h i n g 210-240 g w i t h b i t e m poral electrodes a c c o r d i n g to WOODBURY a n d DAVENPORT 6 on e v e r y 2nd d a y for 4 weeks. A g r o u p of a n i m a l s was i n j e c t e d w i t h 40 m g / k g alloxan (Ftuka) i.v. o n t h e 14th d a y of t h e e x p e r i m e n t . T h e o t h e r g r o u p received t h e s a m e v o l u m e of isotonic saline. T h e a n i m a l s were d i v i d e d i n t o 3 g r o u p s : 1. C o n t r o l (30 r a t s ) ; 2. a l l o x a n - t r e a t e d n o n - d i a b e t i c (22 r a t s : blood s u g a r level u n d e r 200 mg/100 ml, o n l y a t e m p o r a r y glycosuria w i t h o u t w e i g h t loss), a n d 3. a l l o x a n d i a b e t i c g r o u p (26 r a t s : b l o o d sugar level a b o v e 200 mg/100 ml, p e r m a n e n t glycosuria, w e i g h t loss of 20-40 g). Blood sugar was d e t e r m i n e d b y t h e o r t h o t o l u i d i n e r e a g e n t v a t t h e e n d of t h e e x p e r i m e n t .
Changes of EST in alloxan diabetic rats Day of determination
1. 3. 5. 7. 9. 11. 13. Treatment 15. 17. 19. 21. 23. 25. 27.
EST in mA 4- SD Control group (30)
Alloxan~treated non-diabetic group (22)
Alloxan diabetie group (26)
20.4 • 1.2 22.1 4- 1.3 21.8 4- 1.5 22.8 4- 1.4 23.1 i 1.5 23.3 4- 1.4 23.6 4- 1.3 saline 23.3 4- 1.5 23.8 4- 1.4 23.1 4- 1.5 22.9 4- 1.2 22.8 -4- 1.3 22.8 4- 1.4 22.8 4- 1.3
20.5 i 1.4 22.6 • 1.6 22.9 4- 1.4 22,8 4- 1.5 23,3 q- 1.5 23,1 -4- 1.6 23.3 4- 1.4 alloxan 23.6 -~ 1.5 22,4 4- 1.5 22.1 4- 1.6 22.6 + 1.4 22.1 4- 1.4 21.9 4- 1.4 22.1 4- 1.3
21.1 :t_ 1.4 22.3 • 1.5 23.1 4- 1.3 22.9 -1- 1.5 23.5 4- 1.3 23.6 ! 1.4 23.8 -4- 1.4 alloxan 22.3 4- 1.7 20.9 -4- 1.5 20.1 4- 1.5 19.4 • 1.3 18.2 + 1.4 17.8 4- 1.2 17.4 4- 1.2
Difference on Control/alloxan-treated non-diabetic 3.1% p > 0.2 the 27th day (%) Control/alloxan-treated diabetic 23.7% p < 0.001 SD = standard deviation; number of the experimental animals in parentheses.
Results and discussion. I n all t h e 3 groups s t u d i e d , a f t e r a t r a n s i t o r y increase, t h e E S T values were stabilized until t h e 14th d a y of t h e e x p e r i m e n t . Z i t h e r in t h e c o n t r o l or in t h e a l l o x a n - t r e a t e d n o n d i a b e t i c groups, n o n considerable c h a n g e o c c u r r e d d u r i n g t h e second 2 weeks, while in d i a b e t i c r a t s E S T s t a r t e d t o decrease 3 or 4 d a y s a f t e r d i a b e t e s h a d been d e v e l o p e d . This d i m i n u t i o n was p r o g r e s s i v e a n d l a s t e d till t h e e n d of t h e e x p e r i m e n t . On t h e 27th d a y t h e a v e r a g e E S T value in d i a b e t i c r a t s was f o u n d t o be lower b y 23.7% t h a n t h a t in c o n t r o l s (a s t a t i s t i c a l l y s i g n i f i c a n t d e c r e m e n t ; p > 0.001; see Table). The decrease in E S T d u r i n g d i a b e t e s suggests t h a t t h e e x c i t a b i l i t y of t h e c o r r e s p o n d i n g areas in t h e CNS is increased. Since alloxan t r e a t m e n t w i t h o u t i n d u c i n g d i a b e t e s fails t o a l t e r E S T , t h e p h e n o m e n o n m a y be e x p l a i n e d b y a h o r m o n a l i m b a l a n c e due t o insulin deficiency. D u r i n g diabetes, a n e n d o g e n e o u s corticoid p r e d o m i n a n c e develops. N a t u r a l glucocorticoids h a v e b e e n s h o w n t o increase e x c i t a b i l i t y of t h e CNS s. Our d a t a s u g g e s t t h a t t h e s e h o r m o n a l c h a n g e s lead t o t h e decrease in E S T d u r i n g e x p e r i m e n t a l diabetes. C o n s e q u e n t l y , an increased e x c i t a b i l i t y is i n d u c e d b y d i a b e t e s n o t only a t t h e perip h e r a l cholinergic synapses, b u t in t h e CNS as well. Summary. D u r i n g a 4-week period, t h e e l e c t r o s h o c k seizure t h r e s h o l d (EST) of tZ A m s t e r d a m r a t s w a s determined. W h e n a l l o x a n i n d u c e d diabetes, t h e E S T values s i g n i f i c a n t l y decreased, while in t h e a l l o x a n - t r e a t e d n o n - d i a b e t i c g r o u p t h e y r e m a i n e d u n c h a n g e d . The results suggest t h a t d i a b e t e s induces increased e x c i t a b i l i t y in t h e central nervous system. M. KOLTAI a n d 2 . MINKER
Department o/ Pharmacology, University Medical School Szeged, P.O. Box 775, H-6707 Szeged (Hungary), and Department o/ Pharmacodynamics, University Medical School Szeged, P.O. Box 121, / / 6 7 0 7 Szeged (Hungary), 12 June 7975.
1 E. MINKERand M. KOLTAI,Acta physiol, hung. 25, 105 (1964). 1V[.I~OLTAI and E, MINKER, Med. Pharmac. exp. 15, 519 (1966). 8 E. 1V[INKERand M. KOLTAI,Naturwissenschaften 52, 263 (1965), 4 E. IV[INKERand IV[. KOLTAI,Acta physiol, hung. 29, 410 (1966). 5 A. QUEVAUVlLLERand R. PODEVI~, Th6rapie 23, 805 (1968). 6 L. A. WOODBURYand V. D. DAV~ENPORT,Archs int. Pharmacodyn. ThOr. 92, 97 (1952). E. HULTMAN,Nature, Lond. 183, 108 (1959). s D. M. WOODBURV,J. Pharmac. exp. Ther. 105, 27 (1952).
t369
Speeialia
C h a n g e s of E l e c t r o - S h o c k S e i z u r e T h r e s h o l d in A l l o x a n D i a b e t i c R a t s I n p r e v i o u s e x p e r i m e n t s we f o u n d t h a t t h e effectiveness of d r u g s i n h i b i t i n g t r a n s m i s s i o n process a t t h e p e r i p h e r a l cholinergic s y n a p s e s was altered b y e x p e r i m e n t a l diabetes. The ganglionic b l o c k i n g effect of h e x a m e t h o n i u m , T E A B , a n d D - t u b o c u r a r i n e was f o u n d t o be s i g n i f i c a n t l y less e x p r e s s e d in d e p a n c r e a t i z e d cats t h a n in c o n t r o l s ~,2. I n n o r m a l animals, insulin e x e r t e d an o p p o s i t e effect 3. F u r t h e r m o r e , s u s c e p t i b i l i t y to D - t u b o c u r a r i n e of t h e m o t o r e n d - p l a t e s of alloxan d i a b e t i c r a t s was also s h o w n t o be decreased, w h e r e a s t h e e f f e c t i v i t y of s u x a m e t h o n i u m was p r o l o n g e d 4. T h e s e results were c o n f i r m e d b y QuEVAUVILLER a n d PODEVIN 5. F r o m t h e findings o b t a i n e d t h e conclusion m a y be d r a w n t h a t t h e altered p h a r m a c o l o g i c a l r e a c t i v i t y m i g h t be due to an increased e x c i t a b i l i t y of t h e s y n a p t i c s t r u c t u r e s via a relative corticoid p r e p o n d e r a n c e i n d u c e d b y insulin deficiency. I n t h e p r e s e n t e x p e r i m e n t s , a n a t t e m p t was m a d e t o elucidate w h e t h e r or n o t t h e e x c i t a b i l i t y of t h e c e n t r a l n e r v o u s s y s t e m (CNS) of a l l o x a n d i a b e t i c r a t s was also c h a n g e d . Therefore, t h e e l e c t r o - s h o c k seizure t h r e s h o l d (EST) w a s d e t e r m i n e d . Methods. M e a s u r e m e n t s were carried o u t on female r a t s of R - A m s t e r d a m s t r a i n w e i g h i n g 210-240 g w i t h b i t e m poral electrodes a c c o r d i n g to WOODBURY a n d DAVENPORT 6 on e v e r y 2nd d a y for 4 weeks. A g r o u p of a n i m a l s was i n j e c t e d w i t h 40 m g / k g alloxan (Ftuka) i.v. o n t h e 14th d a y of t h e e x p e r i m e n t . T h e o t h e r g r o u p received t h e s a m e v o l u m e of isotonic saline. T h e a n i m a l s were d i v i d e d i n t o 3 g r o u p s : 1. C o n t r o l (30 r a t s ) ; 2. a l l o x a n - t r e a t e d n o n - d i a b e t i c (22 r a t s : blood s u g a r level u n d e r 200 mg/100 ml, o n l y a t e m p o r a r y glycosuria w i t h o u t w e i g h t loss), a n d 3. a l l o x a n d i a b e t i c g r o u p (26 r a t s : b l o o d sugar level a b o v e 200 mg/100 ml, p e r m a n e n t glycosuria, w e i g h t loss of 20-40 g). Blood sugar was d e t e r m i n e d b y t h e o r t h o t o l u i d i n e r e a g e n t v a t t h e e n d of t h e e x p e r i m e n t .
Changes of EST in alloxan diabetic rats Day of determination
1. 3. 5. 7. 9. 11. 13. Treatment 15. 17. 19. 21. 23. 25. 27.
EST in mA 4- SD Control group (30)
Alloxan~treated non-diabetic group (22)
Alloxan diabetie group (26)
20.4 • 1.2 22.1 4- 1.3 21.8 4- 1.5 22.8 4- 1.4 23.1 i 1.5 23.3 4- 1.4 23.6 4- 1.3 saline 23.3 4- 1.5 23.8 4- 1.4 23.1 4- 1.5 22.9 4- 1.2 22.8 -4- 1.3 22.8 4- 1.4 22.8 4- 1.3
20.5 i 1.4 22.6 • 1.6 22.9 4- 1.4 22,8 4- 1.5 23,3 q- 1.5 23,1 -4- 1.6 23.3 4- 1.4 alloxan 23.6 -~ 1.5 22,4 4- 1.5 22.1 4- 1.6 22.6 + 1.4 22.1 4- 1.4 21.9 4- 1.4 22.1 4- 1.3
21.1 :t_ 1.4 22.3 • 1.5 23.1 4- 1.3 22.9 -1- 1.5 23.5 4- 1.3 23.6 ! 1.4 23.8 -4- 1.4 alloxan 22.3 4- 1.7 20.9 -4- 1.5 20.1 4- 1.5 19.4 • 1.3 18.2 + 1.4 17.8 4- 1.2 17.4 4- 1.2
Difference on Control/alloxan-treated non-diabetic 3.1% p > 0.2 the 27th day (%) Control/alloxan-treated diabetic 23.7% p < 0.001 SD = standard deviation; number of the experimental animals in parentheses.
Results and discussion. I n all t h e 3 groups s t u d i e d , a f t e r a t r a n s i t o r y increase, t h e E S T values were stabilized until t h e 14th d a y of t h e e x p e r i m e n t . Z i t h e r in t h e c o n t r o l or in t h e a l l o x a n - t r e a t e d n o n d i a b e t i c groups, n o n considerable c h a n g e o c c u r r e d d u r i n g t h e second 2 weeks, while in d i a b e t i c r a t s E S T s t a r t e d t o decrease 3 or 4 d a y s a f t e r d i a b e t e s h a d been d e v e l o p e d . This d i m i n u t i o n was p r o g r e s s i v e a n d l a s t e d till t h e e n d of t h e e x p e r i m e n t . On t h e 27th d a y t h e a v e r a g e E S T value in d i a b e t i c r a t s was f o u n d t o be lower b y 23.7% t h a n t h a t in c o n t r o l s (a s t a t i s t i c a l l y s i g n i f i c a n t d e c r e m e n t ; p > 0.001; see Table). The decrease in E S T d u r i n g d i a b e t e s suggests t h a t t h e e x c i t a b i l i t y of t h e c o r r e s p o n d i n g areas in t h e CNS is increased. Since alloxan t r e a t m e n t w i t h o u t i n d u c i n g d i a b e t e s fails t o a l t e r E S T , t h e p h e n o m e n o n m a y be e x p l a i n e d b y a h o r m o n a l i m b a l a n c e due t o insulin deficiency. D u r i n g diabetes, a n e n d o g e n e o u s corticoid p r e d o m i n a n c e develops. N a t u r a l glucocorticoids h a v e b e e n s h o w n t o increase e x c i t a b i l i t y of t h e CNS s. Our d a t a s u g g e s t t h a t t h e s e h o r m o n a l c h a n g e s lead t o t h e decrease in E S T d u r i n g e x p e r i m e n t a l diabetes. C o n s e q u e n t l y , an increased e x c i t a b i l i t y is i n d u c e d b y d i a b e t e s n o t only a t t h e perip h e r a l cholinergic synapses, b u t in t h e CNS as well. Summary. D u r i n g a 4-week period, t h e e l e c t r o s h o c k seizure t h r e s h o l d (EST) of tZ A m s t e r d a m r a t s w a s determined. W h e n a l l o x a n i n d u c e d diabetes, t h e E S T values s i g n i f i c a n t l y decreased, while in t h e a l l o x a n - t r e a t e d n o n - d i a b e t i c g r o u p t h e y r e m a i n e d u n c h a n g e d . The results suggest t h a t d i a b e t e s induces increased e x c i t a b i l i t y in t h e central nervous system. M. KOLTAI a n d 2 . MINKER
Department o/ Pharmacology, University Medical School Szeged, P.O. Box 775, H-6707 Szeged (Hungary), and Department o/ Pharmacodynamics, University Medical School Szeged, P.O. Box 121, / / 6 7 0 7 Szeged (Hungary), 12 June 7975.
1 E. MINKERand M. KOLTAI,Acta physiol, hung. 25, 105 (1964). 1V[.I~OLTAI and E, MINKER, Med. Pharmac. exp. 15, 519 (1966). 8 E. 1V[INKERand M. KOLTAI,Naturwissenschaften 52, 263 (1965), 4 E. IV[INKERand IV[. KOLTAI,Acta physiol, hung. 29, 410 (1966). 5 A. QUEVAUVlLLERand R. PODEVI~, Th6rapie 23, 805 (1968). 6 L. A. WOODBURYand V. D. DAV~ENPORT,Archs int. Pharmacodyn. ThOr. 92, 97 (1952). E. HULTMAN,Nature, Lond. 183, 108 (1959). s D. M. WOODBURV,J. Pharmac. exp. Ther. 105, 27 (1952).
