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UBC Theses and Dissertations

Intensification of the alcohol withdrawal syndrome by antecedent electroconvulsive shocks Van Oot, Peter H. 1976

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INTENSIFICATION OF THE ALCOHOL WITHDRAWAL SYNDROME BY ANTECEDENT ELECTROCONVULSIVE SHOCKS B.A. U n i v e r s i t y o f D e l a w a r e , 1973 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF THE ARTS THE FACULTY OF GRADUATE STUDIES (Depa r tment o f P s y c h o l o g y ) We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o t h e r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA A u g u s t , 1976 0 Peter H. Van Oot, 1976 by PETER-H.\VAN OOT in In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l l m e n t o f t h e r e q u i r e m e n t s f o r an advanced deg ree a t t h e U n i v e r s i t y o f B r i t i s h C l o u m b i a , I a g ree t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r ag ree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y pu rpo se s may be g r a n t e d by t he Head o f my d e p a r t m e n t o r h i s r e p r e s e n t a t i v e . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i s h i n g t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Depar tment o f P s y c h o l o g y The U n i v e r s i t y o f B r i t i s h C o l u m b i a 2075 Wesbrook P l a c e V a n c o u v e r , B . C . , Canada V6T-1W5 i A b s t r a c t When p e r i o d i c e l e c t r o c o n v u l s i v e shocks (ECSs) were a d m i n i s t e r e d , a p r o g r e s s i v e i n t e n s i f i c a t i o n o f t h e motor s e i z u r e (MS) p a t t e r n o c c u r r e d . T h i s e f f e c t was o b s e r v e d when ECSs a t e i t h e r 15 o r 75 mA were a d m i n i s t e r e d a t 3 - d a y , bu t n o t 1-hr i n t e r v a l s . Theomagn i tude o f t he i n c r e a s e i n s e v e r i t y o f t h e MS p a t t e r n was a f u n c t i o n o f t h e number o f ECSs w h i c h app roached a s y m p t o t e , i n t h e s e e x p e r i m e n t s , a t a p p r o x i m a t e l y t e n ECSs. P e r i o d i c ECSs were a l s o f ound t o p o t e n t i a t e t h e a l c o h o l w i t h d r a w a l s yndrome. In g e n e r a l , t ho se c o n d i t i o n s w h i c h were f ound t o f a c i l i t a t e t h e k i n d l i n g o f MSs were t h e same as t ho se w h i c h p r oduced t he p o t e n t i a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome. F u r t h e r m o r e , t h i s p o t e n t i a t i o n was f ound t o p e r s i s t up t o 3 weeks a f t e r t h e l a s t ECS unde r t h e c o n d i t i o n s used i n t h e s e e x p e r i m e n t s . F i n a l l y , t h e p o t e n t i a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome o c c u r r e d even a f t e r t h e MSs had been p h a r m a c o l o g i c a l l y b l o c k e d . The r e s u l t s o f t h e s e e x p e r i m e n t s were d i s c u s s e d i n l i g h t o f t h e i r i m p l i c a t i o n s t o bo th b a s i c ; varid c l i n i c a l r e s e a r c h . i i T a b l e o f C o n t e n t s A b s t r a c t •.. i T a b l e o f C o n t e n t s i i L i s t o f F i g u r e s v Acknowledgements v i I n t r o d u c t i o n 1 K i n d ! i n g 2 D e f i n i t i o n o f k i n d l i n g 2 C h a r a c t e r i s t i c s o f k i n d ! i n g . 3 F a c t o r s i n f l u e n c i n g k i n d ! i n g . 4 G e n e r a l i t y o f K i n d ! i n g : K i n d l i n g w i t h O t h e r Agen t s 6 M e t r a z o l 6 F l u o r o t h y l 7 C a r b a c h o l 7 L o c a l a n e s t h e t i c s 8 A u d i o g e n i c s t i m u l a t i o n 8 ECS. 9 T r a n s f e r o f K i n d l i n g : I n t e r a c t i o n s Between Agen t s 10 Pu rpose 12 Gene ra l Methods 14 S u b j e c t s j f c j j 14 A p p a r a t u s 14 P r o c e d u r e s 15 S u r g e r y 15 ECS a d m i n i s t r a t i o n s 16 A l c o h o l a d m i n i s t r a t i o n s 17 W i t h d r a w a l o b s e r v a t i o n s 19 S t a t i s t i c a l a n a l y s i s 20 E x p e r i m e n t l_ I n t r o d u c t i o n 21 Methods 21 R e s u l t s 22 E C S - i n d u c e d MSs 22 ( c o n t i n u e d ) i i i A l c o h o l t o l e r a n c e 26 W i t h d r a w a l syndrome 26 D i s c u s s i o n 27 E x p e r i m e n t 2_ 33 I n t r o d u c t i o n 33 Methods . . . 34 R e s u l t s 34 E C S - i n d u c e d MSs 34 A l c o h o l t o l e r a n c e 37 W i t h d r a w a l syndrome. 37 D i s c u s s i o n * y s - 38 E x p e r i m e n t 3_ 43 I n t r o d u c t i o n 43 Methods 4 3 R e s u l t s 4 3 E C S - i n d u c e d MSs 4 4 A l c o h o l t o l e r a n c e 4 4 W i t h d r a w a l syndrome. 4 4 D i s c u s s i o n 49 E x p e r i m e n t 4 51 I n t r o d u c t i o n 51 Methods 51 R e s u l t s 52 E C S - i n d u c e d MSs 52 A l c o h o l t o l e r a n c e 52 Wi t h d r a w a l syndrome 52 D i s c u s s i o n 53 E x p e r i m e n t 5 57 I n t r o d u c t i o n 57 Methods 58 R e s u l t s 59 E G S - i n d u c e d MSs . 5 9 A l c o h o l t o l e r a n c e 59 W i t h d r a w a l syndrome 60 ( c o n t i n u e d ) i v D i s c u s s i o n 60 G e n e r a l D i s c u s s i o n 64 R e f e r e n c e L istTt^-- 73 A p p e n d i c e s 78 V L i s t o f F i g u r e s F i g u r e 1. The p r o g r e s s i v e i n c r e a s e i n MS s e v e r i t y p r o d u c e d by p e r i o d i c ECSs a t two c u r r e n t i n t e n s i t i e s . . . . . . . . 23 F i g u r e 2 . The i n c i d e n c e o f i n d i v i d u a l a l c o h o l w i t h d r a w a l symptoms i n t h e a n i m a l s o f E x p e r i m e n t 1. . . . 28 F i g u r e 3. The p r o g r e s s i v e change i n MS s e v e r i t y p roduced by p e r i o d i c ECSs a t two i n t e r - E C S i n t e r v a l s 35 F i g u r e 4 . The i n c i d e n c e o f i n d i v i d u a l a l c o h o l w i t h d r a w a l symptoms i n t h e a n i m a l s o f E x p e r i m e n t 2 . 39 F i g u r e 5. The p r o g r e s s i v e i n c r e a s e i n MS s e v e r i t y p r o d u c e d by 2 0 , 15-mA ECSs . 45 F i g u r e 6. The i n c i d e n c e o f i n d i v i d u a l a l c o h o l w i t h d r a w a l symptoms i n t h e a n i m a l s o f E x p e r i m e n t 3 47 F i g u r e 7. The i n c i d e n c e o f i n d i v i d u a l a l c o h o l w i t h d r a w a l symptoms i n t h e a n i m a l s o f E x p e r i m e n t 4 54 F i g u r e 8. The i n c i d e n c e o f i n d i v i d u a l a l c o h o l w i t h d r a w a l symptoms i n t h e a n i m a l s o f E x p e r i m e n t 5. 61 Acknowledgements The a u t h o r w i s h e s t o e x p r e s s h i s d e e p e s t a p p r e c i a t i o n and t hank s f o r t h e c o n t r i b u t i o n s o f t i m e , encou ragemen t , and t e c h n i c a l a d v i s e g i v e n by D r . John P i n e l . S p e c i a l n o t e s o f t h a n k s s h o u l d a l s o be e x t e n d e d t o M r s . C u s h l a C u r t i s f o r h e r i n v a l u a b l e a s s i s t a n c e i n t h e r u n n i n g o f t h e e x p e r i -m e n t s , and t o Ms L i n d a S h e l t o n f o r h e r mora l b a c k i n g and w i l l i n g n e s s t o t y p e t h i s m a n u s c r i p t . 1 I n t r o d u c t i o n When e l e c t r o c o n v u l s i v e s hock s (ECSs) a r e p e r i o d i c a l l y a d m i n i s t e r e d t o e x p e r i m e n t a l a n i m a l s , t h e moto r s e i z u r e s (MSs) e l i c i t e d by each s u c c e s s i v e ECS grow p r o g r e s s i v e l y more s e v e r e . The p r e s e n t i n v e s t i -g a t i o n s d e m o n s t r a t e d t h a t a s e r i e s o f ECSs a l s o i n t e n s i f y an o r g a n i s m ' s c o n v u l s i v e r e s p o n s e t o s u b s e q u e n t a l c o h o l w i t h d r a w a l , and t h e y p r o v i d e d i n f o r m a t i o n on t he e f f e c t s o f v a r i o u s p a r a m e t r i c m a n i p u l a t i o n s on t h i s i n t e r a c t i o n . The i d e a t h a t a s u b j e c t ' s r e s p o n s e t o a c o n v p s r v e t t r e a t m e n t m i gh t be i n t e n s i f i e d by p r i o r , r e p e a t e d ECSs e v o l v e d f r o m r e s e a r c h on t h e s o - c a l l e d k i n d l i n g e f f e c t . K i n d l i n g i s t he deve l opment and i n t e n s i f i c a -t i o n o f s t i m u l a t i o n - i n d u c e d s e i z u r e s p r o d u c e d by p e r i o d i c , e l e c t r i c a l s t i m u l a t i o n o f d i s c r e t e a r e a s o f t h e b r a i n a t i n t e n s i t i e s w h i c h i n i t i a l -l y e l i c i t no o b s e r v a b l e r e s p o n s e s . Thu s , a b r i e f r e v i e w o f some o f t he more r e l e v a n t a s p e c t s o f t he k i n d l i n g e f f e c t c o m p r i s e s t h e f i r s t s e c -t i o n o f t he I n t r o d u c t i o n . The s e cond s e c t i o n in t i iHude ' s s repor t s o f k i n d -l i n g - l i k e e f f e c t s p r o d u c e d by t he p e r i o d i c a d m i n i s t r a t i o n o f a gen t s o t h e r t han l o c a l , e l e c t r i c a l b r a i n s t i m u l a t i o n and t he t h i r d i n c l u d e s r e p o r t s t h a t k i n d l i n g w i t h one a gen t can i n t e n s i f y an o r g a n i s m ' s r e s p o n s e t o o t h e r c o n v u l s i v e a g e n t s . The f o u r t h and f i n a l s e c t i o n o f the I n t r o d u c t i o n c o n t a i n s a summary o f t he r a t i o n a l e and o b j e c t i v e o f t he p r e s e n t s e r i e s o f i n v e s t i g a t i o n s . 2 K i n d ! i n g D e f i n i t i o n o f k i n d l i n g . P e r i o d i c , e l e c t r i c a l s t i m u l a t i o n o f any o f a number o f s i t e s t h r o u g h o u t t h e o l f a c t o r y - l i m b i c s y s t e m o r c o r t e x , even a t i n t e n s i t i e s i n i t i a l l y t oo low t o p r oduce any m a n i f e s t b e h a v i o u r -a l o r e l e c t r o g r a p h i c e f f e c t s , can l e a d t o t he e l i c i t a t i o n and g r a d u a l i n t e n s i f i c a t i o n o f MSs ( G o d d a r d , M c l n t y r e , & L e e c h , 1969; R a c i n e , 1975 ) . Fo r e x a m p l e , i f t h e r a t a m y g d a l o i d c omp lex i s s t i m u l a t e d once p e r day a t a l e v e l w h i c h i n i t i a l l y p r oduce s no o b s e r v a b l e e f f e c t s , e v e n t u a l l y the a f t e r d i s c h a r g e (AD) t h r e s h o l d may be r e d u c e d t o t h e p o i n t t h a t s ub sequen t s t i m u l a t i o n s r e l i a b l y e l i c i t f o c a l ADs ( R a c i n e , 1 972a ) . Each t i m e a f o c a l AD i s e l i c i t e d , i t p r o p a g a t e s t o p r o g r e s s i v e l y more a r e a s o f t h e b r a i n , and becomes more comp lex i n wave fo rm ( R a c i n e , 1972b ) . I t appea r s t o be t h i s g e n e r a l i z a t i o n o f t he AD w h i c h i s c o r r e l a t e d w i t h t he deve lopment and i n t e n s i f i c a t i o n o f c l o n i c MSs ( R a c i n e , 1972b) . A l t h o u g h k i n d l i n g can be p r o d u c e d f r om any one o f a v a r i e t y o f b r a i n s i t e s , s i n c e Goddard e t a l_. (1969) f ound t h a t t he amygda la r e q u i r e d t he f e w e s t number o f s t i m u l a t i o n s t o p r oduce MSs, t he m a j o r i t y o f i n -v e s t i g a t i o n s o f k i n d l i n g have emp loyed a m y g d a l o i d s t i m u l a t i o n s . The e x a c t f o r m o f k i n d l i n g i s a f u n c t i o n o f t he s i t e o f s t i m u l a t i o n . D u r i n g t h e c o u r s e o f k i n d l i n g f r om most s u b c o r t i c a l s i t e s , even a t h i g h i n t e n s i t i e s , t h e f i r s t few s t i m u l a t i o n s p roduce no o b v i o u s b e h a v i o u r a l e f f e c t s ( R a c i n e , 1972b ) , b u t a f t e r s e v e r a l s t i m u l a t i o n s , m i l d f a c i a l c l o n u s i s r e g u l a r l y e l i c i t e d . T h e n , w i t h each s u c c e s s i v e s t i m u l a t i o n , t he c l o n u s becomes p r o g r e s s i v e l y more g e n e r a l u n t i l e v e n t u a l l y each 3 s t i m u l a t i o n r e l i a b l y e l i c i t e s a c l o n i c MS c h a r a c t e r i z e d by a p r o g r e s s i o n o f symptoms t h r o u g h f a c i a l and f o r e l i m b c l o n u s , r e a r i n g and c u l m i n a t i n g w i t h a l o s s o f e q u i l i b r i u m . In c o n t r a s t , t h e f i r s t s t i m u l a t i o n o f t h e a n t e r i o r n e o c o r t e x , f o r e x a m p l e , t y p i c a l l y e l i c i t s c l o n u s o f t h e f a c e o r f o r e l i m b s s i m i l a r t o t h a t seen d u r i n g t he e a r l y s t a g e s o f k i n d l i n g w i t h s u b c o r t t G a l s ^ t q m u M - t i ' o n s . These n e o c o r t i c a l MSs grow p r o g r e s s i v e l y more i n t e n s e w i t h s ub sequen t s t i m u l a t i o n s u n t i l each s t i m u l a t i o n r e l i a b -l y e l i c i t s a c l o n i c MS c h a r a c t e r i z e d by an immed ia te l o s s o f e q u i l i b r i u m and c u l m i n a t i n g i n a m i l d f o r m o f t o n i c e x t e n s i o n ( R a c i n e , 1975 ) . S i n c e i t s o r i g i n a l d e s c r i p t i o n i n r a t s by Goddard ( 1 9 6 7 ) , k i n d l i n g has been r e p o r t e d i n mice ( L e e c h , 1972 ) , c a t s ( M o r r e l l , 1 973 ) , r a b b i t s ( Tanaka , 1 9 7 2 ) , f r o g s ( M o r r e l l & T s u r u , 1 975 ) , and p r i m a t e s (Wada & S a t o , 1 973 ) . There has even been some i n d i c a t i o n t h a t k i n d l i n g can o c c u r i n humans ( E r v i n , Mark , & S t e v e n s , 1969; S t e v e n s , Ma rk , E r v i n , P a c h e c o , & Suemat su , 1969 ) . A l t h o u g h t he e x a c t m o t o r m m a h i ' f e s t a t i o n s - • k i n d l i n g a r e somewhat d i f f e r e n t i n v a r i o u s s p e c i e s , a p r o g r e s s i v e patT t e r n o f deve l opment and i n t e n s i f i c a t i o n o f MSs i n r e s p o n s e t o t h e s t i m u l a t i o n s has been r e p o r t e d t o be s i m i l a r i n each s p e c i e s . C h a r a c t e r i s t i c s o f k i n d l i n g . One o f t h e more s t r i k i n g f e a t u r e s o f k i n d l i n g i s t h a t t h e changes i n n e u r a l f u n c t i o n w h i c h under ! y i t a r e r e l a t i v e l y e n d u r i n g . Goddard e t a l_. (1969) r e k i n d l e d r a t s a f t e r a 12-week, s t i m u l a t i o n - f r e e p e r i o d and f ound a s a v i n g s o f a b o u t 90% i n t he number o f s t i m u l a t i o n s r e q u i r e d t o e l i c i t g e n e r a l i z e d MSs. R a c i n e (1972a) f ound t h a t r e d u c t i o n s i n t h e AD t h r e s h o l d were a l s o r e l a t i v e l y 4 e n d u r i n g , l a s t i n g a t l e a s t 6 week s . A l t h o u g h t h e permanence o f t h e changes i n MSs 4s more s t r i k i n g and has t hu s been s t u d i e d i n more d e t a i l , t h e changes i n AD t h r e s h o l d a r e p a r t i c u l a r l y i m p o r t a n t s i n c e t h e y can be p r o d u c e d by s u b t h r e s h o l d s t i m u l a t i o n s ( P i n e l , S k e l t o n , & Mucha, 1975 ) . Thu s , p e r i o d i c s t i m u l a t i o n s can p r oduce l a s t i n g changes i n t he o r g a n i s m even when n e i t h e r ADs n o r MSs a r e e l i c i t e d . A n o t h e r s t r i k i n g f e a t u r e o f k i n d l i n g i s t h e e v e n t u a l deve l opment o f spon taneous MSs. Recen t e x p e r i m e n t s have i n d i c a t e d t h a t a m y g d a l o i d k i n d l i n g can e v e n t u a l l y p roduce s p o n t a n e o u s l y r e c u r r i n g MSs i n c a t s (Wada & S a t o , 197<B; Wada, S a t o , & C o r c o r a n , 1 9 7 4 ) , r a t s ( P i n e l , Mucha, & P h i l l i p s , 1975; Rovner & P i n e l , 1976) and baboons (Wada, Osawa, & M i z o g u i c h i , 1975 ) . A l t h o u g h s u g g e s t i o n s have been made t h a t k i n d l i n g c o u l d be a model o f e p i l e p t o g e n e s i s , u n t i l t h e s e s t u d i e s were r e p o r t e d t h i s s u g g e s t i o n had t o be q u e s t i o n e d . The p r i m a r y c h a r a c t e r i s t i c o f e p i l e p s y i s t h a t MSs o c c u r s p o n t a n e o u s l y whereas w i t h t h e e a r l y s t u d i e s o f k i n d l i n g , MSs had t o be e l i c i t e d . These more r e c e n t s t u d i e s have thus e s t a b l i s h e d t h a t k i n d l i n g can l e a d t o t he p r o g r e s s i v e d e v e l o p -ment o f a bona f i d e e p i l e p t i c syndrome. T h u s , t h e k i n d l i n g model c o u l d p r ove t o be a v a l u a b l e t o o l i n t h e c o n t r o l l e d s t u d y o f t h e f a c t o r s a s s o c i a t e d w i t h e p i l e p t o g e n e s i s . F a c t o r s i n f l u e n c i n g k i n d l i n g . The d u r a t i o n o f t h e i n t e r v a l b e -tween s t i m u l a t i o n s i s an i m p o r t a n t d e t e r m i n a n t o f t h e number o f s t i m u -l a t i o n s t o t h e f i r s t g e n e r a l i z e d MS. Goddard e t aj_. (1969) were t h e f i r s t t o r e p o r t an i n v e r s e r e l a t i o n between t he number o f s t i m u l a t i o n s 5 t o t h e f i r s t g e n e r a l i z e d MS and t he d u r a t i o n o f t h e i n t e r s t i m u l a t i o n i n t e r v a l s . They were u n a b l e t o k i n d l e a n i m a l s w i t h i n t e r v a l s o f l e s s than 20 m i n ; w h e r e a s , t h e f e w e s t number o f s t i m u l a t i o n s were f ound t o be r e q u i r e d a t i n t e r v a l s o f 24 h r o r more. As a r e s u l t , s t i m u l a t i o n s have been t y p i c a l l y a d m i n i s t e r e d a t d a i l y i n t e r v a l s i n most k i n d l i n g s t u d i e s . R a c i n e , G a r t n e r , Burnham, and L e v i t a n (1973) c o n f i r m e d t h e g e n e r a l i n v e r s e r e l a t i o n between t he i n t e r s t i m u l a t i o n i n t e r v a l and k i n d l i n g r a t e and showed t h a t massed s t i m u l a t i o n s n e i t h e r p r o d u c e d k i n d l i n g n o r s i g n i f i c a n t l y r e d u c e d t h e number o f s t i m u l a t i o n s r e q u i r e d f o r s u b s e q u e n t k i n d l i n g a t l o n g e r i n t e r v a l s . However, R a c i n e e t a l . (1973) a r g u e d t h a t a n i m a l s c o u l d be e f f i c i e n t l y k i n d l e d a t i n t e r v a l s as s h o r t a a s l l h h r . C u r r e n t i n t e n s i t y a l s o appea r s t o be an i m p o r t a n t f a c t o r i n d e t e r -m i n i n g t h e number o f s t i m u l a t i o n s r e q u i r e d f o r k i n d l i n g ; h i g h e r i n t e n -s i t i e s g e n e r a l l y p r oduce k i n d l i n g i n f ewe r s t i m u l a t i o n s . T h i s r e l a t i o n , however , seems t o be p r i m a r i l y a t t r i b u t a b l e t o t h e f a c t t h a t c u r r e n t i n t e n s i t i e s t o o low t o e l i c i t ADs do n o t k i n d l e MSs. R a c i n e (1972b) f ound t h a t no k i n d l i n g o c c u r r e d i n r e s p o n s e t o s t i m u l a t i o n s k e p t be low t he AD t h r e s h o l d . T h i s i s n o t s s u p p r i M n g i n i n t i t h a t R R a c i n e ' e s t a b l i s h e d , i n t he same e x p e r i m e n t , t h a t i t was t h e s p r e a d o f ADs w h i c h was c o r r e l a t e d w i t h MS d e v e l o p m e n t . In t h i s s t u d y , R a c i n e f ound no d i f f e r e n c e s i n t h e number o f s t i m u l a t i o n s t o t h e f i r s t g e n e r a l i z e d MS e l i c i t e d by two , s u p r a t h r e s h o l d - i n t e n s i t y s t i m u l a t i o n s . He, t h e r e f o r e , c o n c l u d e d t h a t t h e e n t i r e e f f e c t o f c u r r e n t i n t e n s i t y depended on w h e t h e r o r n o t ADs were e l i c i t e d by t he s t i m u l a t i o n s ( R a c i n e , ;. 1972b ) . P i n e l , P h i l l i p s , 6 and Deol ( 1 9 7 4 ) , however , d i d f i n d some d i f f e r e n c e s i n k i n d l i n g w i t h d i f f e r e n t s u p r a t h r e s h o l d i n t e n s i t i e s . When two g roups o f r a t s were k i n d l e d a t two i n t e n s i t i e s , one j u s t above t h r e s h o l d (X = 75 r ».A) and., t h e o t h e r a t a much h i g h e r l e v e l (X = 500j*.A).,, the. d u r a t i o n o f t h e ADs and MSs e l i c i t e d by t he h i g h e r i n t e n s i t y s t i m u l a t i o n s ^ v a r i e d l e s s between s t i m u l a t i o n s . The re was a l s o a s l i g h t , b u t s i g n i f i c a n t l y more r a p i d p r o g r e s s i o n o f k i n d l i n g a t t he h i g h e r i n t e n s i t i e s . G e n e r a l i t y o f K i n d l i n g : K i n d ! i n g w i t h O t h e r Agent s A l t h o u g h t he t e rm " k i n d l i n g " i s t y p i c a l l y used i n r e f e r e n c e t o t he deve l opment and i n t e n s i f i c a t i o n o f MSs p r o d u c e d by l o c a l , e l e c t r i c a l b r a i n s t i m u l a t i o n s , s i m i l a r e f f e c t s have b e e n . r e p o r t e d f o l l o w i n g p e r i o d i c a d m i n i s t r a t i o n s o f a v a r i e t y o f o t h e r p o t e n t i a l l y c o n v u l s i v e a g e n t s . M e t r a z o l . Mason and Cooper (1972) a d m i n i s t e r e d m e t r a z o l ( p e n -t y l e n e t e t r a z o l ) t o r a t s a t 3-day i n t e r v a l s , i n doses w h i c h were i n i t i a l l y s u b c o n v u l s i v e . A f t e r s e v e r a l i n j e c t i o n s , m i l d c o n v u l s i v e r e s pon se s were e l i c i t e d w h i c h became p r o g r e s s i v e l y more i n t e n s e w i t h each i n j e c t i o n u n t i l g e n e r a l i z e d c l o n i c MSs, somet imes c u l m i n a t i n g i n myotonus , were r e l i a b l y p r o d u c e d . When a n i m a l s p r e v i o u s l y k i n d l e d w i t h m e t r a z o l were r e t e s t e d a f t e r a 21 -day i n j e c t i o n - f r e e p e r i o d , no d i m -i n u t i o n i n t he s e v e r i t y o f t he c o n v u l s i v e r e s p o n s e .to m e t r a z o l was n o t e d . Thu s , a t l e a s t s u p e r f i c i a l l y , k i n d l i n g w i t h m e t r a z o l seems t o be l i k e 7 k i n d l i n g w i t h l o c a l e l e c t r i c a l b r a i n s t i m u l a t i o n . F 1 u o r o t h y l . W i t h each s u c c e s s i v e p e r i o d i c e x p o s u r e t o f l u o r o t h y l v apou r ( h ' e x a f l u o r o d i e t h y l e t h e r ) d e c r e a s e s i n t he l a t e n c y t o s u s t a i n e d MS and i n c r e a s e s i n t h e s e v e r i t y o f t h e o v e r a l l i V i M S f p a t t e r n may' r e s u l t ( P r i c h a r d , G a l l a g h e r , & G l a s e r , 1 968 ) . F l u o r o t h y l i s a v o l a t i l e c o n -v u l s i v e e t h e r t y p i c a l l y a d m i n i s t e r e d by i n h a l a t i o n , and p r oduce s MSs w h i c h c l o s e l y r e s e m b l e t h o s e p r o d u c e d by m e t r a z o l . P r i c h a r d e t a l . (1968) f ound t h a t p r o g r e s s i v e i n c r e a s e s i n t he s e v e r i t y o f t h e f l u o r o -t h y l - i n d u c e d MSs were p r o d u c e d o n l y when t he e t h e r was p r e s e n t e d a t i n t e r v a l s o f a t l e a s t 24 h r . When f l u o r o t h y l was p r e s e n t e d a t 1 -hr i n t e r v a l s , t h e l a t e n c y t o s u s t a i n e d MS was t e m p o r a r i l y i n c r e a s e d . MSs e l i c i t e d a t i n t e r v a l s o f 20 min o r l e s s by l o c a l b r a i n s t i m u l a t i o n have been f ound t o p r oduce s i m i l a r i n h i b i t o r y e f f e c t s (Goddard e t a l . , 1969 ) . Thu s , a l t h o u g h f l u o r o t h y l and l o c a l b r a i n s t i m u l a t i o n a r e s i m i -l a r i n t h e i r r e s p o n s e t o t he e f f e c t s o f i n t e r v a l , t he c r i t i c a l i n t e r v a l s a p p e a r t o be q u i t e d i f f e r e n t . Whereas k i n d l i n g w i l l p r o c e e d w i t h l o c a l b r a i n s t i m u l a t i o n s a d m i n i s t e r e d once e v e r y h r , f l u o r o t h y l p r e -s e n t e d a t t h i s i n t e r v a l p r oduce s marked i n h i b i t o r y e f f e c t s . C a r b a c h o l . Vosu and Wise (1975) compared t h e r e s u l t s o f d i r e c t i n j e c t i o n s o f c a r b a c h o l , a c h o l i n o m i m e t i c , i n t o t h e a m y g d a l a , c a u d a t e , and h ippocampus once e v e r y o t h e r day . They f ound a p r o g r e s s i v e d e v e l o p -ment o f MSs a t a l l s i t e s c ompa rab l e t o t h a t o b s e r v e d by Goddard e t a l . (1969) w i t h l o c a l , e l e c t r i c a l s t i m u l a t i o n o f t h e s e same a r e a s . Mo re -8 o v e r , t h e r e l a t i v e k i n d l i n g r a t e s a t t he t h r e e s i t e s were s i m i l a r t o t he r e l a t i v e r a t e s o f k i n d l i n g w i t h e l e c t r i c a l s t i m u l a t i o n o f t h e same s i t e s (Goddard ejt a l _ . , 1 969 ) ; t h e amygdala r e q u i r e d f e w e r i n j e c t i o n s t han d i d t he c a u d a t e , and t h e c a u d a t e f ewe r t han t h e h ippocampus i n bo th e x p e r i m e n t s . L o c a l a n e s t h e t i c s . R e c e n t l y t he deve l opment and i n t e n s i f i c a t i o n o f MSs was r e p o r t e d w i t h p e r i o d i c a d m i n i s t r a t i o n s o f two forms o f l o c a l a n e s t h e t i c , c o c a i n e ( P o s t & Kppanda, 1975; P o s t , Kopanda, & B l a c k , 1975) and l i d o c a i n e ( P o s t , Kopanda, & L e e , 1975) . Fo r e x a m p l e , when i n i t i a l l y s u b c o n v u l s i v e i . p . doses o f l i d o c a i n e were a d m i n i s t e r e d t o r a t s once e v e r y d a y , MSs w h i c h c l o s e l y r e s e m b l e d t h e g e n e r a l i z e d c l o n i c MSs e l i c i t e d by a m y g d a l o i d s t i m u l a t i o n s were e v e n t u a l l y e l i c i t e d . A s i m i l a r deve l opment o f e p i l e p t o g e n i c i t y was p r o d u c e d by p e r i o d i c i . v . i n j e c t i o n s o f c o c a i n e i n r h e s u s monkeys ( P o s t , Kopanda, & B l a c k , 1975 ) . A u d i o g e n i c s t i m u l a t i o n . Leech (1972) o b s e r v e d t h a t m ice w h i c h were i n i t i a l l y r e s i s t a n t t o a u d i o g e n i c a l l y - i n d u c e d s e i z u r e s e v e n t u a l l y became r e s p o n s i v e i f t h e y were expo sed t o s h o r t b u r s t s o f h i g h - i n t e n s i t y a u d i o g e n i c s t i m u l a t i o n ( n o i s e ) once each day . A t f i r s t t h e sound e l i c i t e d no-more t han a s t a r t l e r e s p o n s e i n most o f t h e m ice o f t h e " r e s i s t a n t " s t r a i n s , b u t a f t e r a few e x p o s u r e s , paroxysms o f r u n n i n g and j u m p i n g were e l i c i t e d . MSs c o u l d be e v e n t u a l l y e l i c i t e d i n t h i s manner i n even t h e most " r e s i s t a n t " s t r a i n s . 9 E l e c t r o c o n v u l s i v e s h o c k . From t h e examples p r e v i o u s l y d i s c u s s e d , i t i s c l e a r t h a t p e r i o d i c a d m i n i s t r a t i o n s o f a v a r i e t y o f a gen t s can p roduce k i n d l i n g - l i k e e f f e c t s . The e f f e c t s o f r e p e a t e d ECSs , however , s t a n d i n a p p a r e n t c o n t r a d i c t i o n t o t he o t h e r k i n d l i n g - l i k e e f f e c t s d i s c u s s e d i n t h i s I n t r o d u c t i o n . In bo th humans ( H o l m b e r g , 1954) and e x p e r i m e n t a l a n i m a l s ( E s s i g & F lanawyv 1966; E s s i g , G r o c e , & W i l l i a m s o n , 1961) an i n c r e a s e , r a t h e r t h a n a d e c r e a s e , i n t he c o n v u l s i v e t h r e s h o l d had been r e p o r t e d as t he u sua l r e s u l t o f p e r i o d i c ECSs. For e x a m p l e , E s s i g e_t al_. (1961) f ound t h a t i f ECSs were a d m i n i s t e r e d t o c a t s t w i c e a day , a p r o g r e s s i v e i n c r e a s e i n t h e c o n v u l s i v e t h r e s h o l d was p r o d u c e d w h i c h r e t u r n e d t o normal l e v e l s a few days a f t e r t h e s t i m u l a t i o n s were d i s c o n t i n u e d . Even g r e a t e r i n c r e a s e s i n t h r e s h o l d were p r o d u c e d when ECSs were a d m i n i s t e r e d f o u r t i m e s a day . S i m i l a r l y , Ho lmberg (1954) f ound t h a t i n o r d e r t o p roduce s u c c e s s i v e c o n v u l s i o n s o f c o m p a r a b l e s e v e r i t y i n human p a t i e n t s , t h e c u r r e n t i n t e n s i t y had t o be p r o g r e s s i v e -l y i n c r e a s e d . Ramer and P i n e l (1975) examined t he a p p a r e n t d i s c r e p a n c y between t he e f f e c t s o f r e p e a t e d ECSs and t h o s e o f o t h e r c o n v u l s i v e a g e n t s . In one o f t h e i r s t u d i e s , ECSs were a d m i n i s t e r e d once e v e r y t h r e e days t o two groups o f r a t s , ; t h e s u b j e c t s i n one group were s t i m u l a t e d a t 15 mA and t he o t h e r a t 2 5 . A t bo th i n t e n s i t i e s t h e r e s u l t s were t h e same; w i t h each s u c c e s s i v e s t i m u l a t i o n t h e r e was a p r o g r e s s i v e i n c r e a s e i n t he s e v e r i t y o f t h e MS p a t t e r n as r e f l e c t e d by s h o r t e r l a t e n c i e s t o f o r e - and h i n d l i m b t o n i c e x t e n s i o n and a g r e a t e r e x t e n t o f t o n i c e x t e n -s i o n : . T h u s , i n c o n t r a s t t o t h e e a r l i e r r e p o r t s , p e r i o d i c ECSs p r o -10 duced k i n d l i n g - l i k e e f f e c t s . Ramer and P i n e l (1975) p o s t u l a t e d t h a t t h i s a p p a r e n t c o n t r a d i c t i o n between t he r e s u l t s o f p r e v i o u s e x p e r i m e n t s and t h e i r own c o u l d b e . a c c o u n t e d f o r by d i f f e r e n c e s i n t he i n t e r v a l between ECS a d m i n i s t r a t i o n s . To t e s t t h i s h y p o t h e s i s , t e n ECSs were a d m i n i s t e r e d t o d i f f e r e n t g roups o f r a t s a t 1 - h r , 1 -day, o r 3-day i n t e r v a l s . In t h e 3-day c o n d i t i o n a p r o g r e s s i v e i n c r e a s e i n MS s e v e r i t y was p r o d u c e d , b u t i n t he 1-hr c o n -d i t i o n t he r e s u l t s were c o n s o n a n t w i t h t h e e a r l i e r r e p o r t s ; t h e r e was a g r a d u a l d e c r e a s e i n the s e v e r i t y o f t he MSs w i t h each s u c c e s s i v e ECS. No s y s t e m a t i c changes i n MS s e v e r i t y were o b s e r v e d a t t h e i n t e r m e d i a t e , 1 -day, i n t e r v a l . A c l o s e e x a m i n a t i o n o f t h e e a r l i e r l i t e r a t u r e r e v e a l e d t h a t i n t h o s e s t u d i e s i n w h i c h i n h i b i t i o n had been r e p o r t e d , i n t e r v a l s o f l e s s t han 1 day had been u s e d . However, k i n d l i n g - l i k e e f f e c t s had been r e p o r t e d i n t h o s e few e a r l i e r s t u d i e s w h i c h had emp loyed l o n g e r i n t e r - E C S i n t e r v a l s ( Z a r r o w , P a w l o w s k i , & Denenberg , 1962; P o l l a c k , R o s e n t h a l , & Macey, 1963 ) . Thu s , t h e p r o g r e s s i v e e f f e c t s o f p e r i o d i c ECSs a r e s i m i l a r , a t l e a s t s u p e r f i c i a l l y , t o t h o s e p r o d u c e d by o t h e r k i n d l i n g a g e n t s . A l t h o u g h t h e e f f e c t s o f t h e i n t e r v a l seem t o be a f u n c t i o n o f t h e s p e c i f i c a g e n t u s e d , i n g e n e r a l k i n d l i n g o c c u r s a t l o n g i n t e r v a l s ; w h e r e a s , i n h i b i t o r y e f f e c t s a r e more p r o m i n e n t when t he i n t e r v a l s a r e s h o r t . T r a n s f e r o f K i n d l i n g : I n t e r a c t i o n s b'etfoegn'hAgefttsnt-? P e r i o d i c a d m i n i s t r a t i o n s o f one k i n d l i n g a g e n t can g r e a t l y p o t e n t i a t e t h e a n i m a l ' s c o n v u l s i v e r e spon se t o a d m i n i s t r a t i o n s o f a n -11 o t h e r a g e n t . Fo r e x a m p l e , P i n e l , Van O o t , and Mucha (1975) f ound t h a t t h e a l c o h o l w i t h d r a w a l syndrome i n r a t s was m a r k e d l y i n t e n s i f i e d by 45 p e r i o d i c , e l e c t r i c a l s t i m u l a t i o n s o f t he amygda l a . Those a n i m a l s r e -c e i v i n g s u p r a t h r e s h o l d s t i m u l a t i o n s (1 s e c , 400-^.A, 60 -Hz ) were k i n d l e d d u r i n g t h e c o u r s e o f t h e e x p e r i m e n t ; w h e r e a s , t h o s e a n i m a l s whose l e v e l s o f s t i m u l a t i o n were i n d i v i d u a l l y a d j u s t e d t o keep them be l ow t h e r a p i d l y d e c l i n i n g AD t h r e s h o l d s d i s p l a y e d no MSs. In bo th c a s e s , howeve r , s ub sequen t a l c o h o l w i t h d r a w a l r e a c t i o n s were i n t e n s i f i e d . Thu s , even s t i m u l a t i o n s a t i n t e n s i t i e s t o o low t o p r oduce any o b v i o u s b e h a v i o u r a l e f f e c t s a r e c a p a b l e o f i n t e n s i f y i n g t h e a l c o h o l w i t h d r a w a l s yndrome. The a l c o h o l w i t h d r a w a l syndrome has a l s o been i n t e n s i f i e d by p r i o r m e t r a z o l k i n d l i n g ( P i n e l & Van O o t , 1 975 ) . F u r t h e r m o r e , P i n e l , S k e l t o n , and Mucha (1974) f ound t h a t p r i o r a m y g d a l o i d s t i m u l a t i o n s c o u l d i n -t e n s i f y m e t r a z o l - i n d u c e d MSs, w h e t h e r o r n o t MSs were p r oduced by t he a m y g d a l o i d s t i m u l a t i o n s t h e m s e l v e s . However , i n none o f t h e s e s t u d i e s was t h e r e a s y s t e m a t i c r e l a t i o n between t h e deg ree o f i n i t i a l MS deve lopment i n r e spon se t o t h e r e p e a t e d s t i m u l a t i o n s and t h e s ub sequen t i n t e n s i f i c a t i o n o f t h e r e a c t i o n t o t h e c o n v u l s i v e a g e n t s . F o r e x a m p l e , P i n e l , S k e l t o n , and Mucha (1975) a t t e m p t e d t o r e l a t e a s p e c t s o f an a n i m a l ' s r e s p o n s i v e n e s s t o a m y g d a l o i d s t i m u l a t i o n s t o i t s s ub sequen t r e s p o n s i v e n e s s t o m e t r a z o l - i n d u c e d MSs. No c l e a r r e l a t i o n s between t h e number o f ADs o r MSs e l i c i t e d by t h e s t i m u l a t i o n s ; t h e i n i t i a l o r f i n a l AD t h r e s h o l d v a l u e s , o r t he d i f f e r e n c e between them; o r t h e number o f ADs t o t h e f i r s t g e n e r a l i z e d MS were f o u n d . T h u s , a l t h o u g h t h i s t r a n s -f e r o f s u s c e p t i b i l i t y seems t o be a r e l i a b l e and r e a s o n a b l y g e n e r a l e f f e c t , t h e mechanisms u n d e r l y i n g t r a n s f e r a r e u n c l e a r . A l t h o u g h t h e 12 r a t i o n a l e f o r t he p r e s e n t i n v e s t i g a t i o n s was d e v e l o p e d f r om t h e k i n d l i n g l i t e r a t u r e , i t appea r s t h a t t h e k i n d l i n g o f MSs p e r se may n o t be e s s e n t i a l f o r t h e p o t e n t i a t i o n o f an a n i m a l ' s r e s p o n s e t o o t h e r a g e n t s . Pu rpo se The i n i t i a l pu rpo se o f t h e p r e s e n t i n v e s t i g a t i o n s was t o r e p l i c a t e the " E C S - k i n d l i n g " e f f e c t , and t hen t o i n v e s t i g a t e a s p e c t s o f t h e i n t e r a c t i o n o f p e r i o d i c ECSs w i t h t h e a l c o h o l w i t h d r a w a l syndrome. E C S - k i n d l i n g , i n s t e a d o f k i n d l i n g w i t h some o t h e r a g e n t , was s t u d i e d f o r two m a j o r r e a s o n s . The f i r s t was t h a t a l m o s t a l l p r e v i o u s k i n d l i n g e x p e r i m e n t s have used a m y g d a l o i d s t i m u l a t i o n s , and a t ho r ough i n v e s t i -g a t i o n o f k i n d l i n g w i t h some o t h e r a g e n t m i g h t p r o v i d e much-needed p e r s p e c t i v e t o t he k i n d l i n g l i t e r a t u r e . A t t e m p t s t o e x p l a i n t h e b a s i s o f t h e k i n d l i n g phenomenon h a v e , t hu s f a r , been a t t e m p t s t o e x p l a i n t he b a s i s o f k i n d l i n g w i t h l o c a l b r a i n s t i m u l a t i o n s . K i n d l i n g , how-e v e r , seems t o be a much more g e n e r a l phenomenon, and by s t u d y i n g i t s v a r i o u s f o r m s , v a l u a b l e i n s i g h t s i n t o t he mechanisms u n d e r l y i n g i t m i g h t be g a i n e d . The second r e a s o n was t h a t becau se ECS i s one o f t he most w i d e l y - u s e d forms o f c l i n i c a l t r e a t m e n t , an i n v e s t i g a t i o n o f k i n d l i n g w i t h ECS i s l i k e l y t o have p r a c t i c a l i m p l i c a t i o n s . The i n t e r -a c t i o n between p e r i o d i c ECSs and t h e a l c o h o l w i t h d r a w a l syndrome was ( i n v e s t i g a t e d a l s o f o r l a r g e l y p r a c t i c a l r e a s o n s . Because o f t h e e x t e n s i v e c on sumpt i on o f a l c o h o l i n o u r s o c i e t y , i n f o r m a t i o n c o n c e r n i n g 13 a l c o h o l w i t h d r a w a l m i g h t be o f g r e a t e r p r a c t i c a l r e l e v a n c e t han compar -a b l e i n f o r m a t i o n on one o f t h e l e s s commonly o c c u r r i n g c o n v u l s i v e a g e n t s . E x p e r i m e n t 1 c o n f i r m e d t he f a c t t h a t p e r i o d i c ECSs p r oduce k i n d l i n g - l i k e e f f e c t s , and a l s o showed t h a t ECSs can p o t e n t i a t e a s u b -s e q u e n t a l c o h o l w i t h d r a w a l s yndrome. In t he r e m a i n i n g f o u r e x p e r i m e n t s , v a r i o u s p a r a m e t r i c i n f l u e n c e s on E C S - k i n d l i n g and t h e i n t e r a c t i o n b e -tween p e r i o d i c ECSs and t h e a l c o h o l w i t h d r a w a l syndrome were i n v e s t -i g a t e d . The i n t e n t o f theseeexper i i imentsvjwasr.notssorr imueh•.toff ind o u t what happens i n a c l i n i c a l s i t u a t i o n , b u t r a t h e r t o p r o v i d e g u i d e l i n e s f o r f u t u r e r e s e a r c h and e x p e r i m e n t a t i o n w i t h a c t u a l c l i n i c a l p o p u l a t i o n s . 14 G e n e r a l Methods The same b a s i c methods were employed i n each o f t h e f i v e e x p e r i -ments p r e s e n t e d i n t h i s t h e s i s . Thu s , i n t h i s s e c t i o n , a d e s c r i p t i o n o f t h e m e t h o d o l o g i c a l f e a t u r e s common t o each e x p e r i m e n t i s p r e s e n t e d . In each e x p e r i m e n t , t h e p r o g r e s s i v e changes i n t h e MSs p r o d u c e d by a s e r i e s o f ECSs and t he e f f e c t s o f a s e r i e s o f ECSs on t h e i n c i d e n c e o f w i t h d r a w a l symptoms f o l l o w i n g a p e r i o d o f f o r c e d a l c o h o l a d m i n i s t r a t i o n s was a s s e s s e d . S u b j e c t s The s u b j e c t s i n each o f t h e f i v e e x p e r i m e n t s were 240 - t o 340-gm, m a l e , b l a c k - h o o d e d r a t s p u r c h a s e d f rom t h e Canad i an B r e e d i n g Farms and L a b o r a t o r i e s (La P r a i r i e , Q u e . ) . Each a n i m a l was i n d i v i d u a l l y housed i n a w i r e - m e s h cage (24x18x18 cm) w i t h ad l i b i t u m a c c e s s t o w a t e r and P u r i n a Lab Chow p e l l e t s . The w e i g h t and g e n e r a l a ppea r ance o f each a n i m a l were c l o s e l y m o n i t o r e d , and i f an a n i m a l l o s t w e i g h t , o r a p p e a r e d i l l , t h a t an ima l r e c e i v e d s upp l emen t s o f w e t , mashed f o o d and/o r p e n i -c i l l i n u n t i l normal h e a l t h was r e g a i n e d . S u b j e c t s were s a c r i f i c e d by e x p o s u r e t o c a r b o n d i o x i d e f o l l o w i n g t h e U n i v e r s i t y F e d e r a t i o n o f An ima l W e l f a r e s t a n d a r d s o f e u t h a n a s i a ( T - W - F i e n n e s , H a r r i s o n , Ray, & S c o t t , 1972 ) . 15 A p p a r a t u s ECSs were d e l i v e r e d f r o m an 8 00 -V , c o n s t a n t - c u r r e n t power s o u r c e . I n i t i a t i o n o f t h e ECS a c t i v a t e d a t i m e r w h i c h was v i d e o t a p e d w i t h each MS so t h a t t h e l a t e n c y and d u r a t i o n o f each phase o f t h e MS c o u l d be a c c u r a t e l y d e t e r m i n e d (± 0.05 s e c ) . The a l c o h o l was a d m i n i s t e r e d i n t r a g a s t r i c a l l y f r o m a s y r i n g e t h r o u g h a #8, s i n g l e - h o l e d , r u b b e r c a t h e t e r . F o l l o w i n g t h e w i t h d r a w a l o f a l c o h o l , i n d i v i d u a l a n i m a l s were o b s e r v e d i n a t r a n s p a r e n t , P l e x i -g l a s box (20x16x40 cm) and t h e i n c i d e n c e o f b e h a v i o u r a l w i t h d r a w a l symptoms was r e c o r d e d . P r o c e d u r e s S u r g e r y . Each a n i m a l was a n e s t h e t i z e d w i t h a c o m b i n a t i o n o f Nembutal (50 mg/cc; 50/mg/kg) and c h l o r a l h y d r a t e (100 mg/cc; 100 mg/kg). The c r a n i u m was t h e n expo sed and f o u r s t a i n l e s s s t e e l s k u l l s c rews were i n s e r t e d , one i n t he c e n t r e o f each o f t h e two rcaso-frontal i s b one s , a p p r o x i m a t e l y 2 mm a n t e r i o r t o b regma, and t h e r e m a i n i n g t w o , 4 mm b i l a t e r a l t o t h e m i d l i n e , midway between bregma and l ambda. A 1.3-cm l e n g t h o f w i r e r o d was t h e n a t t a c h e d t o each o f t h e two p o s t -e r i o r s k u l l s c r e w s . The e n t i r e a s s emb l y was h e l d i n p l a c e and i n -s u l a t e d f r o m t h e s u r r o u n d i n g t i s s u e by a l a y e r o f d e n t a l a c r y l i c f r o m w h i c h p r o t r u d e d t h e two w i r e r o d s . P e n i c i l l i n (30 ,000 I.U.) was r o u t i n e l y a d m i n i s t e r e d f o l l o w i n g s u r g e r y and each a n i m a l was h a n d l e d 16 once e v e r y 2 days d u r i n g t h e 1-week, p o s t - o p e r a t i v e r e c o v e r y p e r i o d . ECS a d m i n i s t r a t i o n s . The 0 . 2 - s e c ECSs were d e l i v e r e d t h r o u g h a p a i r o f a l l i g a t o r c l i p s a t t a c h e d t o t he p r o t r u d i n g w i r e r o d s . ECS t y p i c a l l y e l i c i t s a MS c h a r a c t e r i z e d by an i n i t i a l t o n i c f l e x i o n o f t he body f o l l o w e d by t o n i c e x t e n s i o n and t e r m i n a t i n g i n a b r i e f p e r i o d o f c l o n u s . D u r i n g t h e deve l opment o f t o n i c e x t e n s i o n a " w a v e " o f r i g i d i t y s p r e a d s c a u d a l l y a l o n g t h e body u n t i l t h e back i s a r c h e d and t he f o r e l i m b s and t he h ind- l imbs a r e f u l l y e x t e n d e d . A MS e l i c i t e d by l o w - i n t e n s i t y ECS, however , may l a c k t h i s t o n i c phase c o m p l e t e l y o r be c h a r a c t e r i z e d by a p a r t i a l t onu s l i m i t e d t o t h e r o s t r a l p o r t i o n s o f t h e body (Woodbury, 1 969 ) . As a r e s u l t o f t h i s r e l a t i o n between t he c u r r e n t i n t e n s i t y and t he c a u d a l s p r e a d o f t o n i c e x t e n s i o n , t h e e x t e n t o f t o n i c e x t e n s i o n has been t he most w i d e l y - u s e d measure o f MS s e v e r i t y ( P i n e l & J o n e s , 1973 ; Woodbury & D a v e n p o r t , 1952 ) . In t h e p r e s e n t e x p e r i m e n t s a s c o r e o f 0_ was a s s i g n e d i f no f o r e l i m b t o n i c e x t e n s i o n o c c u r r e d , 1 i f t h e r e was f o r e l i m b , b u t no h i n d l i m b e x t e n s i o n , 2^  i f h i n d l i m b e x t e n s i o n was o n l y p a r t i a l , and 3_~if t h e r e was c o m p l e t e h i n d -l i m b e x t e n s i o n w i t h b o t h l e g s e x t e n d i n g i n a c a u d a l d i r e c t i o n . Two o t h e r measures o f MS s e v e r i t y employed i n t he p r e s e n t e x p e r i -ment s , t he l a t e n c i e s t o f o r e - and h i n d l i m b t o n i c e x t e n s i o n , have a l s o been used i n p r e v i o u s e x p e r i m e n t s (Ramer & P i n e l , 1 975 ) . These l a t -e n c i e s were t i m e d f r om t h e s t i m u l u s o n s e t t o t he p o i n t when t h e l i m b s r e a c h e d c o m p l e t e c a u d a l e x t e n s i o n . A f o u r t h mea su re , t h e d u r a t i o n o f f o r e l i m b tonus .whas t r io tdbeenf f iu sed li 'nipKeiVtous.iexperiments, b u t d u r i n g 17 the c o u r s e o f p r e l i m i n a r y e x p e r i m e n t a t i o n , t h i s measure was f ound t o be b o t h r e l i a b l e and h i g h l y c o r r e l a t e d w i t h t h e o t h e r t h r e e mea su r e s . The d u r a t i o n o f f o r e l i m b tonus was t i m e d f r om t h e p o i n t a t w h i c h f u l l f o r e -l i m b e x t e n s i o n was r e a c h e d t o t he f i r s t j e r k o f t h e f o r e l i m b s d u r i n g t he e n s u i n g c l o n i c p h a s e . In each o f t h e f i v e e x p e r i m e n t s an a ve r a ge o f t h r e e a n i m a l s s u f f e r -ed f r o m E C S - i n d u c e d p a r a p l e g i a . These a n i m a l s were i m m e d i a t e l y s a c r i -f i c e d and t h e i r d a t a were n o t i n c l u d e d i n any o f t h e a n a l y s e s . A l c o h o l a d m i n i s t r a t i o n . In each e x p e r i m e n t t h o s e r a t s r e c e i v i n g a l c o h o l were i n i t i a l l y i n t u b a t e d w i t h a r e l a t i v e l y l o w , s t a n d a r d dose o f 1000 mg/kg o f a 20% e t h a n o l and w a t e r s o l u t i o n ( v / v ) . These s u b j e c t s were i n j e c t e d a t o t a l o f 42 t i m e s , once e v e r y 8 h r f o r 14 day s . F o r t he f i r s t 3 d a y s , t h e l e v e l o f i n t o x i c a t i o n was e s t i m a t e d 1 h r a f t e r each a d m i n i s t r a t i o n . T h e r e a f t e r , t h e l e v e l o f i n t o x i c a t i o n was a s s e s s e d a f t e r o n l y t h e s econd a d m i n i s t r a t i o n o f each day . T h i s p a r t i c u l a r method o f i n d u c i n g p h y s i c a l dependence t o a l c o h o l has been r e p o r t e d p r e v i o u s l y ( M u c h a , N P i n e l , & Van O o t , 1 975 ) , and s i m i l a r methods have been emp loyed by o t h e r s ( M a j c h r o w i c z , 1 973 ) . The l e v e l o f i n t o x i c a t i o n was r a t e d f o r each an ima l on t he b a s i s o f t h r e e b e h a v i o u r a l mea su re s ; 1) homecage a c t i v i t y , 2) a b i l i t y t o manoeu-v r e on a v e r t i c a l w i r e - m e s h c l i f f , and 3) g a i t . The f i r s t measure was an a s s e s smen t o f t he a c t i v i t y l e v e l o f t h e u n d i s t u r b e d a n i m a l . Thu s , an a n i m a l r e c e i v e d a s c o r e o f 0 i f he was u n c o n s c i o u s , 1_ i f c o n s c i o u s w i t h h i s head r e s t i n g on t h e f l o o r , 2 i f s i t t i n g s t i l l w i t h h i s head 18 h e l d up, o r 3_ i f he was mov ing abou t t he c age . Each s u b j e c t was then removed f r om h i s cage and p l a c e d a p p r o x i m a t e l y 15 cm away f r om t h e t o p edge o f a v e r t i c a l w i r e - m e s h c l i f f , 64 cm h i g h and 24 cm w i d e . I f t h e a n i m a l f a i l e d t o t a k e h o l d o f t h e c l i f f , he r e c e i v e d a s c o r e o f 0_; i f he h e l d , b u t t hen f e l l a t t e m p t i n g t o move, a s c o r e o f 1} i f he h e l d and managed t o c l i m b down, he r e c e i v e d a s c o r e o f 2_; o r i f he h e l d and -c l i m b e d up, a s c o r e o f 3_. F i n a l l y , each an ima l was p l a c e d on a f l a t , wooden s u r f a c e and r e c e i v e d a s c o r e o f 0_ f o r n o t m o v i n g , 1^ f o r s t a g -g e r i n g and f a l l i n g , 2_ f o r w a l k i n g v e r y s l o w l y , b u t s t e a d i l y , o r 3_ f o r w a l k i n g n o r m a l l y . I f an a n i m a l r e c e i v e d more than one s c o r e o f 2 o r 3 on any o f t h e s e t h r e e mea su r e s , s u b s e q u e n t doses o f a l c o h o l were i n c r e a s e d by 200 mg/kg, bu t i f t h e an ima l was j u d g e d t o be i n t o x i c a t e d , t he dose r e m a i n e d unchanged f o r s u b s e q u e n t a d m i n i s t r a t i o n s u n t i l t h e r e was e v i d e n c e o f t o l e r a n c e . The f i r s t i n t o x i c a t i n g doses s e r v e d as measures o f i n i t i a l t o l e r a n c e and t he l a s t i n t o x i c a t i n g doses s e r v e d as measures o f t h e f i n a l t o l e r a n c e o f t h e a n i m a l s t o a l c o h o l . The d i f f e r e n c e b e -tween t h e s e doses f o r each a n i m a l s e r v e d as a c o n v e n i e n t measure o f t he change i n t o l e r a n c e . Because o f t h e t endency o f some a n i m a l s t o l o s e w e i g h t when c h r o n i c a l l y e xpo sed t o a l c o h o l on t h i s r eg imen ( M u c h a e e t e a l . . ; 1976) a l l s u b j e c t s were w e i g h e d d a i l y . I f any s u b j e c t l o s t more t han 10 gm o f h i s p r e - a l c o h o l w e i g h t , a l c o h o l was s u b s e q u e n t l y a d m i n i s t e r e d i n s o l u t i o n w i t h M e t r e c a l r a t h e r t h a n w a t e r u n t i l normal w e i g h t was r e -g a i n e d . In t h i s way t h e w e i g h t s o f a l l o f t h e s u b j e c t s were h e l d f a i r l y 19 c o n s t a n t t h r o u g h o u t t h e f i v e e x p e r i m e n t s . C o n t r o l a n i m a l s n o t r e c e i v i n g a l c o h o l were i n t u b a t e d w i t h a 0 .9% s a l i n e s o l u t i o n i n volumes a p p r o x i m a t i n g t h e a v e r a g e amount o f a l c o h o l g i v e n t o t h e e x p e r i m e n t a l s u b j e c t s on a p a r t i c u l a r day . W i t h d r a w a l o b s e r v a t i o n . Commencing 9 h r a f t e r t h e l a s t a l c o h o l a d m i n i s t r a t i o n , each a n i m a l was o b s e r v e d e v e r y 4 h r f o r t e n c o n s e c u t i v e 1-min p e r i o d s . Fo r each p e r i o d , an e x p e r i m e n t e r unaware o f t h e a n i m a l ' s e x p e r i m e n t a l h i s t o r y , r e c o r d e d t h e p r e s e n c e o r ab sence o f each o f t he f o l l o w i n g s i x w i t h d r a w a l symptoms; 1) h y p e r r e a c t i v i t y t o h a n d l i n g , 2) e a r o r eye t w i t c h i n g , 3) j aw c l o n u s , 4) f a c i a l c l o n u s , 5) head n o d -d i n g , and/o r 6) body j e r k s . S i n c e t h e r e were f i v e , 10-min o b s e r v a t i o n s e s s i o n s i n a l l , t h e maximum s c o r e an a n i m a l c o u l d r e c e i v e f o r each symptom was 50 . These s i x measures have been f ound t o r e l i a b l y d i f -f e r e n t i a t e between a n i m a l s u n d e r g o i n g even v e r y m i l d w i t h d r a w a l and t h o s e w h i c h a r e n o t e x p e r i e n c i n g w i t h d r a w a l (Mucha elt a l _ . , 1975 ) . Each a n i m a l ' s s c o r e f o r a p a r t i c u l a r symptom was c o n v e r t e d t o a p e r c e n t -age o f t h e c o n t r o l g r o u p ' s mean s c o r e f o r t h a t symptom. T h u s , t h e mean o f t h e c o n t r o l a n i m a l s on each symptom was 100%. Fo r t h e pu rpo se s o f s t a t i s t i c a l c o m p a r i s o n t h e sum o f t h e s e i n d i v i d u a l symptoms was t a k e n and t h i s " c o m b i n e d " w i t h d r a w a l s c o r e was used f o r each a n i m a l . A l l c o m p u t a t i o n s were made r e l a t i v e t o t he group o f a n i m a l s w h i c h r e c e i v e d o n l y h a n d l i n g and a l c o h o l . In each o f t h e f o l l o w i n g e x p e r i -men t s , t h e a n i m a l s i n t h i s group w i l l be r e f e r r e d t o as t h e c o n t r o l s . 20 S t a t i s t i c a l a n a l y s i s . One-way a n a l y s e s o f v a r i a n c e were p e r f o r m e d on t h e d a t a o b t a i n e d f o r t h e comb ined w i t h d r a w a l s c o r e s , t h e t h r e e measures o f a l c o h o l t o l e r a n c e , and t h r e e o f t h e f o u r measures o f t h e E C S - i n d u c e d MS s e v e r i t y . The d a t a f rom t h e f o u r t h measure o f MS s e v e r i t y ( deg ree o f o v e r a l l t o n i c e x t e n s i o n ) were o r d i n a l , and t hu s r e q u i r e d n o n - p a r a m e t r i c a n a l y s i s . In t h i s c a s e , S i g n T e s t s and Mann-Wh i tney U t e s t s were used t o d e t e r m i n e t h e s i g n i f i c a n c e o f d i f f e r e n c e s w i t h i n and between g roups r e s p e c t i v e l y . Because t he number o f g roups i n each e x p e r i m e n t was g r e a t e r t han two , i t was n e c e s s a r y t o o b t a i n an o v e r a l l £ v a l u e f o r t h e a l c o h o l t o l e r a n c e measures and t he w i t h d r a w a l s c o r e s . I f t h i s o v e r a l l F_ was s i g n i f i c a n t , s ub sequen t i n d i v i d u a l c ompa r i s on s were made w i t h t he S c h e f f e t e s t . Because o f t h e s t r i n g e n c y o f t h i s t e s t , t h e s e i n d i v i d u a l a s s e s sment s were assumed t o be s i g n i f i c a n t a t an a l p h a l e v e l o f 0 .10 as s u g g e s t e d by S c h e f f e ( 1 9 5 9 ) . F o r a l l o t h e r c o m p a r i s o n s , howeve r , t he s i g n i f i c a n c e l e v e l was 0 . 0 5 . 21 E x p e r i m e n t 1: ECS - I nduced I n t e n s i f i c a t i o n o f t h e  A l c o h o l W i t h d r a w a l Syndrome I n t r o d u c t i o n E x p e r i m e n t 1 had two m a j o r p u r p o s e s . The f i r s t was t o c o n f i r m and e x t e n d t h e i n i t i a l r e p o r t o f E C S - k i n d l i n g (Ramer & P i n e l , 1975 ) . Because o f t h e w i d e s p r e a d c l i n i c a l use o f ECS, a more d e t a i l e d i n v e s t i -g a t i o n o f t he p o s s i b i l i t y o f k i n d l i n g w i t h p e r i o d i c ECSs was w a r r a n t e d . The s e cond pu rpo se o f E x p e r i m e n t 1 was t o d e t e r m i n e w h e t h e r o r n o t t h e changes i n d u c e d by p e r i o d i c ECSs c o u l d p o t e n t i a t e t h e c o n v u l s i v e symp-toms p r o d u c e d by s ub sequen t a l c o h o l w i t h d r a w a l . Both E C S - k i n d l i n g and i t s p o t e n t i a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome were s t u d i e d a t two d i f f e r e n t c u r r e n t i n t e n s i t i e s . Methods F o l l o w i n g p o s t - s u r g i c a l r e c o v e r y , 33 o f t h e 45 s u b j e c t s r e c e i v e d t he f i r s t 15-mA t e s t ECS and were d i v i d e d i n t o t h r e e e q u a l g roups on t he b a s i s o f t h e i r r e s p o n s e t o i t . The s u b j e c t s i n two o f t h e s e g roups then r e c e i v e d a s e r i e s o f e i g h t t r e a t m e n t ECSs, one e v e r y 3 days a t e i t h e r 15 (n = 1 1 ) , o r 75 mA (n = 1 3 ) . The a n i m a l s i n the t h i r d g roup (n = 9) r e c e i v e d e i g h t p seudo -ECS s ; once e v e r y 3 days t h e e l e c t r o d e s were a t t a c h e d , b u t no c u r r e n t was p a s s e d . The a n i m a l s i n a l l t h r e e groups r e c e i v e d t he s econd 15-mA t e s t ECS, 3 days a f t e r t h e e i g h t h 22 t r e a t m e n t " s t i m u l a t i o n " . The 12 r e m a i n i n g a n i m a l s were c o n t r o l s w h i c h d i d n o t r e c e i v e e i t h e r o f t h e two t e s t ECSs o r any o f t h e t r e a t m e n t ECSs. Thu s , t he a n i m a l s i n each o f t h e two e x p e r i m e n t a l g roups r e -c e i v e d a t o t a l o f t e n ECS s ; t h o s e i n t he pseudo-ECS group r e c e i v e d two ; and t he c o n t r o l a n i m a l s , none. B e g i n n i n g t h e day a f t e r t h e s econd t e s t ECS, a l l 45 a n i m a l s were s u b j e c t e d t o t h e s t a n d a r d s e r i e s o f a l c o h o l i n t u b a t i o n s . A f t e r t h e f i n a l i n t u b a t i o n o f t h e s e r i e s , t he i n c i d e n c e o f o v e r t w i t h d r a w a l symptoms was a s s e s s e d i n each a n i m a l as p r e v i o u s l y d e s c r i b e d . R e s u l t s A t b o t h i n t e n s i t i e s , p e r i o d i c ECSs p r o d u c e d a k i n d l i n g - l i k e e f f e c t ; w i t h each s u c c e s s i v e s t i m u l a t i o n , t he e l i c i t e d MSs became p r o g r e s s i v e l y more s e v e r e . M o r e o v e r , t h e s e ECSs were f o u n d t o p o t e n t i a t e t he a l c o h o l w i t h d r a w a l s yndrome. E C S - i n d u c e d MSs. The p r o g r e s s i v e i n c r e a s e i n t he s e v e r i t y o f t h e MSs e l i c i t e d by t he p e r i o d i c ECSs was i l l u s t r a t e d , a t b o t h i n t e n s i t i e s , by s i g n i f i c a n t changes i n a l l f o u r measures o f s e i z u r e s e v e r i t y ( F i g u r e 1 ) . In each c a s e , t h e mean r e s p o n s e t o t h e s econd t e s t ECS was s i g -n i f r i i c an i t ' l y l y more s e v e r e t han t he mean r e s p o n s e t o t h e f i r s t . In r e -sponse t o t he s econd t e s t s t i m u l a t i o n , t h e s u b j e c t s i n bo th t h e 15- and 75-mA groups had s i g n i f i c a n t l y s h o r t e r l a t e n c i e s t o f o r e l i m b (15 mA, F_ ( 1 ,20 ) = 1 2 . 59 , p_<0.01; 75 mA, F ( 1 , 24 ) = 8 . 8 1 , p_<0.01) and h i n d l i m b 23 F i g u r e 1. The p r o g r e s s i v e i n c r e a s e i n MS s e v e r i t y p r o d u c e d by p e r i o d i c ECSs. A n i m a l s i n t h e e x p e r i m e n t a l g roups r e c e i v e d two 15-mA t e s t ECSs ( T j & T^) and e i g h t t r e a t m e n t ECSs a t e i t h e r 15 ( c i r c l e s ) , o r 75 mA ( s q u a r e s ) , p r e s e n t e d a t 3-day i n t e r v a l s . A n i m a l s i n a pseudo-ECS group ( t r i a n g l e s ) r e c e i v e d o n l y t h e two 15-mA t e s t ECSs. CONVULSION SEVERITY MEASURE Latency to H i nd l imb Ex tens ion ( sec) Latency to Forel imb Ex tens ion (sec) 3 g g g s g s g s- = s g s § I t U t b l l l l | I I • I 1 U ro 25 t o n i c e x t e n s i o n (15 mA, £ ( 1 , 20 ) = 6 . 6 8 , £ < 0 . 0 5 ; 75 mA, £ ( 1 , 24 ) = 5 . 3 0 , £ < 0 . 0 5 ) , s i g n i f i c a n t l y l o n g e r f o r e l i m b tonus (15 mA, £ (1 ,20 ) = 8.45 ; £ < 0 . 0 1 ; 75 mA, £ ( 1 ,24 ) = 6 . 2 6 , £ < 0 . 0 5 ) , and a s i g n i f i c a n t l y g r e a t e r e x t e n t o f t o n i c e x t e n s i o n (15 mA, S i g n T e s t , N = 5, x = 0 , £ < 0 . 0 5 ; 75 mA, S i g n T e s t , N = 5 , x = 0 , £ < 0 . 0 5 ) . In c o n t r a s t , t he r e s p o n s e s o f t h e pseudo-ECS a n i m a l s t o t h e s econd t e s t ECS were n o t s i g n i f i c a n t l y d i f f e r e n t t h a n t h e i r r e s p o n s e s t o t he f i r s t ( a l l £ ' s > 0 . 0 5 ) . The p r o g r e s s i v e i n c r e a s e i n the mean s e v e r i t y o f t h e c o n v u l s i v e r e s p o n s e was a l s o e v i d e n t i n t he p a t t e r n o f d i f f e r e n c e s between t he t h r e e t r e a t m e n t g r o u p s . S i n c e t h e s e t h r e e groups had been e q u a t e d on t he b a s i s o f t h e i r r e s pon se s t o t h e i n i t i a l 15-mA t e s t ECS, t h e r e were no s i g n i f i c a n t d i f f e r e n c e s i n t h e i r mean r e s p o n s e t o t h i s ECS, ( a l l £ ' s > 0 . 0 5 ) ; however , t h e MSs e l i c i t e d by t he s econd 15-mA t e s t ECS i n bo th t he 15- and 75-mA s u b j e c t s were s i g n i f i c a n t l y more s e v e r e t han t h o s e p r o d u c e d i n t he pseudo-ECS a n i m a l s . The re were s i g n i f i c a n t l y s h o r t e r l a t e n c i e s t o f o r e l i m b (15 mA, £ ( 1 , 1 8 ) , = 4 . 9 2 , £ < 0 . 0 5 ; 75 mA, £ ( 1 , 20 ) = 6 . 2 6 , £ < 0 . 0 5 ) and h i n d l i m b t o n i c e x t e n s i o n (15 mA, £ ( 1 , 18 ) = 5 . 74 , £ < 0 . 0 5 ; 75 mA, £ ( 1 ,20 ) = 6 . 2 6 , £ < 0 . 0 5 ) , a n d l o n g e r f o r e l i m b tonus (15 mA, £ ( 9 ,18 ) = 2 0 . 3 8 , £ < 0 . 0 1 ; 75 mA, £ ( 1 , 20 ) = 9 . 7 6 , £ < 0 . 0 l ) - However, t h e r e were no s i g n i f i c a n t d i f f e r e n c e s between t h e a n i m a l s o f any o f t h e t h r e e groups i n e x t e n t o f t o n i c e x t e n s i o n ( a l l £ ' s > 0 . 0 5 ) i n d u c e d by t h e s econd t e s t ECS. M o r e o v e r , t h e r e were no s i g n i f i c a n t d i f f e r e n c e s between t he mean r e s p o n s e s o f t h e 15- and 75-mA s u b j e c t s t o t he second t e s t ECS on any o f t he f o u r measures o f s e i z u r e s e v e r i t y ( a l l jp_'s> 0 . 0 5 ) . 26 E C S - k i n d l i n g was a l s o i l l u s t r a t e d by t h e p r o g r e s s i v e i n c r e a s e i n t h e i n t e n s i t y o f t h e r e s p o n s e s t o t h e e i g h t t r e a t m e n t ECSs. The MSs e l i c i t e d i n bo th t h e 15- and 75-mA groups by t he l a s t t r e a t m e n t ECS were s i g n i f i c a n t l y more s e v e r e than t h o s e e l i c i t e d : b y t he f i r s t on each o f t h e f o u r measures o f s e i z u r e s e v e r i t y ( a l l p _ ' s < 0 . 0 5 ) . D u r i n g t h i s phase o f t h e e x p e r i m e n t , t he 75-mA ECSs c o n s i s t e n t l y e l i c i t e d mean r e s p o n s e s more s e v e r e t han t h o s e d i s p l a y e d by t he 15-mA s u b j e c t s . How-e v e r , o n l y t he d i f f e r e n c e i n t he l a t e n c y t o f o r e l i m b t o n i c e x t e n s i o n was s i g n i f i c a n t ( £ ( 1 ,22 ) = 2 4 . 9 7 , p_<0.001). A l c o h o l t o l e r a n c e . The a n i m a l s w h i c h had p r e v i o u s l y been e xpo sed t o p e r i o d i c ECSs g e n e r a l l y t e n d e d t o r e q u i r e h i g h e r doses o f a l c o h o l t o i n i t i a l l y i n d u c e and s u b s e q u e n t l y m a i n t a i n i n t o x i c a t i o n t h r o u g h o u t t he a l c o h o l e x p o s u r e p e r i o d ( see A p p e n d i x I ) . O v e r a l l a n a l y s e s o f v a r i a n c e r e v e a l e d s i g n i f i c a n t d i f f e r e n c e s among t he f o u r g roups i n i n i t i a l t o l e r a n c e ( £ ( 3 ,41 ) = 8 . 0 2 , p_<0.01) , f i n a l t o l e r a n c e (F ( 3 ,41 ) = 6 . 4 3 , p_<0 .01 ) , and t h e change i n t o l e r a n c e (£_ ( 3 , 41 ) = 4 . 9 8 , p_<0.01 ) . A l t h o u g h t h e r e were s i g n i f i c a n t d i f f e r e n c e s between c e r t a i n g roups on each o f t h e s e mea su re s , t h e s e d i f f e r e n c e s appea red t o be l a r g e l y n o n -s y s t e m a t i c and s i n c e t h e y were n o t r e p l i c a t e d i n t h e r e m a i n i n g e x p e r i -ment s , t h e y were n o t p r e s e n t e d h e r e i n d e t a i l ( see A p p e n d i x I I ) . These d i f f e r e n c e s w i l l be d i s c u s s e d i n a more g e n e r a l c o n t e x t l a t e r i n t h e t h e s i s . W i t h d r a w a l syndrome. P e r i o d i c ECSs a t bo th 15-and 75 mA p o t e n t i a t e d 27 the a l c o h o l w i t h d r a w a l syndrome ( F i g u r e 2 ) . An o v e r a l l a n a l y s i s o f v a r i a n c e r e v e a l e d a s i g n i f i c a n t d i f f e r e n c e among t he f o u r g roups i n t h e combined w i t h d r a w a l s c o r e s (JF ( 3 , 41 ) = 3 . 0 9 , £ < 0 . 0 5 ) . Sub sequent i n -d i v i d u a l c o m p a r i s o n s a t t r i b u t e d t h i s d i f f e r e n c e e x c l u s i v e l y t o t h e s i g n i f i c a n t l y l e s s s e v e r e w i t h d r a w a l r e s p o n s e s o f t h e a n i m a l s i n t he c o n t r o l group t han t h o s e o f t he a n i m a l s i n the 15-mA (F_ ( 1 ,21 ) = 6 . 5 5 , £ < 0 . 1 0 ) and t he 75-mA, ECS groups ( £ ( 1 , 23 ) = 6 . 7 8 , £ < 0 . 1 0 ) . None o f t he d i f f e r e n c e s i n t he s e v e r i t y o f t he w i t h d r a w a l syndrome between t he c o n t r o l and pseudo-ECS g r o u p s , t he 15- and 75-mA g r o u p s , o r b e -tween t he pseudo-ECS and e i t h e r t h e 15- o r 75-mA groups were s i g n i f i -c a n t ( a l l £ ' s > 0 . 1 0 ) . D i s c u s s i o n The r e s u l t s o f E x p e r i m e n t 1 c o n f i r m and e x t e n d t h e i n i t i a l r e p o r t o f E C S - k i n d l i n g by Ramer and P i n e l ( 1 9 7 5 ) . In t he Ramer and P i n e l s i t udy , k i n d l i n g o c c u r r e d i n r e s p o n s e t o p e r i o d i c ECSs a t e i t h e r 15 o r 25 mA. A t bo th i n t e n s i t i e s l a t e n c i e s t o f o r e - and h i n d l i m b t o n i c e x t e n s i o n became p r o g r e s s i v e l y s h o r t e r , and t he e x t e n t o f t o n i c e x t e n -s i o n i n c r e a s e d . In E x p e r i m e n t 1, t h e s e same p a t t e r n s o f changes were o b s e r v e d . The r e s u l t s o f E x p e r i m e n t 1 e x t e n d t he f i n d i n g s o f Ramer and P i n e l (1975) i n t h r e e ways . F i r s t l y , t he p r o g r e s s i v e i n c r e a s e i n MS s e v e r i t y was a l s o r e f l e c t e d i n s y s t e m a t i c i n c r e a s e s i n t he d u r a t i o n o f f o r e l i m b t o n u s . S e c o n d l y , a l t h o u g h t he s t i m u l a t i o n s a t 75 mA were c o n s i d e r a b l y more i n t e n s e than t h o s e p r e v i o u s l y used by Ramer and P i n e l :' zhT.:\ :>-neral p a t t e r n o f k i n c ' - v . c ; i " . 28 F i g u r e 2. The i n c i d e n c e o f i n d i v i d u a l a l c o h o l w i t h d r a w a l symptoms i n the a n i m a l s o f E x p e r i m e n t 1. Each a n i m a l ' s s c o r e f o r a p a r t i c u l a r symp-tom was c o n v e r t e d t o a p e r c e n t a g e o f t he mean o f t h e c o n t r o l a n i m a l ' s s c o r e s f o r t h a t symptom. The s c o r e s f o r each group r e f l e c t t h e mean o f t h e s e c o n v e r t e d s c o r e s . 29 2000 J I t 400 O QC O o u QC 300 200 100 L _ J \ I I Contro l H Pseudo-ECS ELD 15-mA ECS EU 75-mA ECS 71 / 7 / m Hyper-Reactivity Ear - Eye Clonus Jaw Clonus I / / \ / / / \ / Facial Head Clonus Nods Body Jerks WITHDRAWAL SYMPTOMS 30 ( 1 9 7 5 ) , t he same g e n e r a l p a t t e r n o f k i n d l i n g o c c u r r e d . As i n t h e Ramer and P i n e l s t u d y , t he h i g h e r i n t e n s i t y ECSs were f ound t o p r oduce more s e v e r e r e s p o n s e s w i t h each a d m i n i s t r a t i o n . However , i n t h e p r e -s e n t e x p e r i m e n t , o n l y t he d i f f e r e n c e s i n f o r e l i m b e x t e n s i o n l a t e n c y were s i g n i f i c a n t . T h i r d l y , becau se t h e a n i m a l s o f b o t h g roups were g i v e n t e s t ECSs o f s t a n d a r d i n t e n s i t y b e f o r e and a f t e r k i n d l i n g , d i r e c t c ompa r i s on s c o u l d be made between t h e s e g r oup s . These t e s t ECSs made i t c l e a r t h a t a l t h o u g h t he h i g h e r i n t e n s i t y s t i m u l a t i o n s a p p e a r e d t o p roduce more s e v e r e MSs, t he deg ree o f k i n d l i n g p r o d u c e d was t h e same as t h a t p r o d u c e d by t he l o w e r i n t e n s i t y s t i m u l a t i o n s . The deve lopment o f t o l e r a n c e w i t h e x p o s u r e t o a l c o h o l and t h e s ub sequen t c o n v u l s i v e w i t h d r a w a l r e a c t i o n s were s i m i l a r t o t h o s e g e n e r a l l y r e p o r t e d by o t h e r i n v e s t i g a t o r s ( M a j c h r o w i c z , 1975 ) . In t h i s r e s p e c t , t he r e s u l t s o f E x p e r i m e n t 1 were a l m o s t i d e n t i c a l t o t h o s e p r e v i o u s l y r e p o r t e d by Mucha, e t al_. ( 1 975 ) . The Mucha e t al_. (1975) s t u d y used e x a c t l y t h e same methods as t h o s e used i n t he p r e s e n t e x -p e r i m e n t a n d , i n g e n e r a l , t h e same deg ree o f t o l e r a n c e , and t h e same t y p e o f w i t h d r a w a l r e a c t i o n werepprddu ' ced . The ma jo r f i n d i n g o f t h i s e x p e r i m e n t was t h a t p e r i o d i c ECSs can p o t e n t i a t e a s ub sequen t a l c o h o l w i t h d r a w a l s yndrome. Such p o t e n t i a t i o n i s c o n s i s t e n t w i t h o t h e r r e p o r t s t h a t p e r i o d i c a d m i n i s t r a t i o n o f one c o n v u l s i v e a g e n t can i n c r e a s e t h e s u s c e p t i b i l i t y o f t he an ima l t o t h e the c o n v u l s i v e e f f e c t s o f a n o t h e r a g e n t ( P i n e l , S k e l t o n , & Mucha, 1975; P i n e l & Van O o t , 1975 ) . A l t h o u g h t he r a t i o n a l e o f E x p e r i m e n t 1 was ba sed on t h e f a c t t h a t k i n d l i n g i n c r e a s e s t h e s e i z u r e s u s c e p t i b i l i t y .31 o f t he an ima l t h e r e b y i n c r e a s i n g t he s u s c e p t i b i l i t y o f t he an ima l t o t he c o n v u l s i v e e f f e c t s o f a l c o h o l w i t h d r a w a l , t h e r e s u l t s o f t h e p r e -s e n t e x p e r i m e n t o f f e r a n o t h e r p o s s i b l e i n t e r p r e t a t i o n . The f a c t t h a t h i g h e r doses o f a l c o h o l were r e q u i r e d t o i n i t i a l l y i n d u c e and t hen m a i n -t a i n i n t o x i c a t i o n i n t he e x p e r i m e n t a l a n i m a l s s u g g e s t s t h a t t he more s e v e r e w i t h d r a w a l syndrome e l i c i t e d i n t h e s e a n i m a l s m i g h t have been due t o t h e g r e a t e r amounts o f a l c o h o l t h e y r e c e i v e d . T h i s i m p l i e s t h a t t he r o l e o f r e p e a t e d ECSs was no t t o i n c r e a s e t he s u s c e p t i b i l i t y t o MSs p e r s e , b u t r a t h e r t o change t he a n i m a l ' s t o l e r a n c e o f a l c o h o l . By t h e methods o f a l c o h o l a d m i n i s t r a t i o n used i n t h i s e x p e r i m e n t , t h e s e more t o l e r a n t a n i m a l s w o u l d have been g i v e n g r e a t e r amounts o f a l c o h o l than t h e u n s t i m u l a t e d c o n t r o l s . T h i s h y p o t h e s i s o f t h e r e l a t i o n b e -tween p r i o r ECSs and a l c o h o l t o l e r a n c e was c o n s i d e r e d i n t h e r e m a i n i n g f o u r e x p e r i m e n t s o f t h i s t h e s i s . Bo th t h e E C S - k i n d l i n g e f f e c t and t h e E C S - i n d u c e d i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome have s e v e r a l i m p o r t a n t c l i n i c a l i m p l i c a t i o n s . F i r s t l y , t he f a c t t h a t spon taneous s e i z u r e s have " teen r e p o r t e d a f t e r a s e r i e s o f l o c a l b r a i n s t i m u l a t i o n s (Rovner & P i n e l , 1976;/ Wada & S a t o , 1973) as w e l l as a f t e r a s e r i e s o f c l i n i c a l ECS t r e a t m e n t s ( B l u m e n t h a l , 1955; F o l k s m a n , 1947; P a c e l l a & B a r r e r a , 1945; P o l l a c k , R o s e n t h a l , & Macey, 1963) s t r e s s e s t h e need f o r c l i n i c a l i n v e s t i g a t i o n o f t h e k i n d l i n g e f f e c t . S e c o n d l y , t h e t r a n s f e r o f t h e i n c r ea sed s s e i z . u ce r . s - . u s ee . p^ d, have haza rdou s consequences f o r c e r t a i n p a t i e n t s . U n t i l t he a p p r o p r i a t e t e s t s have been conducted^wn.:thhh;umanppatin ven.ts who have r e c e i v e d ECSs, 32 t he r e a c t i o n o f t h o s e p a t i e n t s t o d r u g s , o r t o d rug w i t h d r a w a l s h o u l d be c l o s e l y m o n i t o r e d . The re i s no r e a s o n t o s u s p e c t t h a t t h e i n c r e a s e d s e i z u r e s u s c e p t i b i l i t y i n d u c e d by r e p e a t e d ECSs i s s p e c i f i c t o a l c o h o l w i t h d r a w a l . T h i s i s a p a r t i c u l a r l y i m p o r t a n t p o i n t s i n c e p a t i e n t s r e c e i v i n g ECS t r e a t m e n t s a r e a l s o g i v e n a v a r i e t y o f drugs w h i c h can have c o n v u l s i v e e f f e c t s e i t h e r upon a d m i n i s t r a t i o n , o r upon w i t h d r a w a l (Goodman & G i l man, 1969; K a l i n o w s k y & H i p p i u s , 1969 ) . T h u s , e x t r eme c a r e s h o u l d be t a k e n n o t j u s t w i t h a l c o h o l , b u t w i t h t h e s e o t h e r drugs as w e l l . 33 E x p e r i m e n t 2: D u r a t i o n o f t h e I n t e r - E C S I n t e r v a l  and t h e I n t e n s i f i c a t i o n o f t h e A l c o h o l W i t h d r a w a l Syndrome I n t r o d u c t i o n One pu rpo se o f E x p e r i m e n t 2 was t o c o n f i r m t h e r e l a t i o n between i n t e r - E C S i n t e r v a l and t h e f a c i l i t a t i o n o r i n h i b i t i o n o f E C S - k i n d l i n g p r e v i o u s l y r e p o r t e d by Ramer and P i n e l ( 1 9 7 5 ) . They f ound t h a t when ECSs were p r e s e n t e d a t 3-day i n t e r v a l s , a k i n d l i n g e f f e c t was p r o d u c e d , bu t when ECSs were p r e s e n t e d a t 1-hr i n t e r v a l s , t h e r e was a p r o g r e s s i v e i n h i b i t i o n o f MSs. Thu s , i n t h e p r e s e n t e x p e r i m e n t , ECSs were p r e -s e n t e d a t 1 -hr o r 3 -day i n t e r v a l s and t he p r o g r e s s i v e e f f e c t s on MS s e v e r i t y were a s s e s s e d . A s e cond pu rpo se o f E x p e r i m e n t 2 was t o d e t e r m i n e t h e e f f e c t s o f i n t e r - E C S i n t e r v a l s on t he s ub sequen t i n t e n s i t y o f t he a l c o h o l w i t h d r a w a l syndrome. In a d d i t i o n t o p r o v i d i n g i m p o r t a n t p a r a m e t r i c i n f o r m a t i o n , t h i s e x p e r i m e n t compared t he e f f e c t s o f ECSs on t h e s e v e r i t y o f t h e a l c o h o l w i t h d r a w a l syndrome under two c o n d i t i o n s , one i n w h i c h ECSs p roduce MSs o f i n c r e a s i n g s e v e r i t y and t h e o t h e r i n w h i c h t h e y p r oduce MSs o f d e c r e a s i n g s e v e r i t y . The r e s u l t s o f Ramer & P i n e l (1975) p r o -v i d e d t he b a s i s f o r t h i s m a n i p u l a t i o n by c h a n g i n g t h e i n t e r v a l between s t i m u l a t i o n s . By u s i n g t h e s e two s c h e d u l e s o f ECS p r e s e n t a t i o n , t h e n e c e s s i t y o f k i n d l i n g pe r se i n t h e i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h -d rawa l syndrome m i gh t be d e t e r m i n e d . 34 Methods A l l 63 s u b j e c t s were i m p l a n t e d w i t h ECS e l e c t r o d e s b e f o r e random a s s i g n m e n t t o one o f t he s i x g r o u p s . The r a t s i n t h r e e o f t h e groups were i n t u b a t e d w i t h a l c o h o l i n t he s t a n d a r d manner a f t e r t e n , 15-mA ECSs p r e s e n t e d a t 3-day (n = 11) o r 1 -h r i n t e r v a l s (n = 1 0 ) , o r n o t a t a l l ( c o n t r o l ; n = 10 ) . Rat s i n t he r e m a i n i n g t h r e e groups were s t i m u -l a t e d a t t he same i n t e r v a l s (3 d a y s , n § ' 1 0 ; l rhr»; n §;>9!j3not" ia.t , aTl, n = 1 0 ) , b u t were s u b s e q u e n t l y i n t u b a t e d w i t h 0 .9% s o l u t i o n s o f s a l i n e . Those a n i m a l s n o t r e c e i v i n g ECSs were h a n d l e d t o t h e same deg ree as t h o s e r e c e i v i n g ECSs. A f t e r t h e l a s t i n t u b a t i o n , t he i n c i d e n c e o f w i t h d r a w a l symptoms was a s s e s s e d as b e f o r e . R'-R e s u l t s When ECSs were p r e s e n t e d a t 3-day i n t e r v a l s t h e r e was a p r o g r e s s i v e i n t e n s i f i c a t i o n o f t he E C S - i n d u c e d MSs, whereas i n t h e 1-hr c o n d i t i o n t h e r e was a p r o g r e s s i v e d e c l i n e i n t he s e v e r i t y o f t h e MSs. F u r t h e r -more, o n l y t h e ECSs w h i c h were p r e s e n t e d a t 3-day i n t e r v a l s p o t e n t i a t e d the a l c o h o l w i t h d r a w a l syndrome. E C S - i n d u c e d MSs. The re was a p r o g r e s s i v e i n c r e a s e i n t he s e v e r i t y o f t h e MSs e l i c i t e d by ECSs p r e s e n t e d once e v e r y 3 days ( F i g u r e 3 ) ; however , a p r o g r e s s i v e d e c r e a s e i n MS s e v e r i t y was o b s e r v e d i n t h e 1-hr c o n d i t i o n . The d a t a f o r t h e two g roups r e c e i v i n g ECSs once e v e r y 3 days and f o r t h e two g roups r e c e i v i n g ECSs a t 1 -hr i n t e r v a l s 35 F i g u r e 3. The p r o g r e s s i v e change i n MS s e v e r i t y i n r a t s r e c e i v i n g 15-mA ECSs a t 3-day ( s q u a r e s ) o r 1 -hr ( c i r c l e s ) i n t e r v a l s . CONVULSION SEVERITY MEASURE L a t e n c y to H i n d l i m b E x t e n s i o n ( s e c ) L a t ency to Fore l imb E x t e n s i o n (sec) M ' - j o> tn ^ w M ro ro -A -» o o o o o ' o L n w o c o c n w i k »—i i i I i i i ii i i \ I L / V 37 were comb ined f o r t he a n a l y s i s o f changes i n MS s e v e r i t y . A c o m p a r i s o n o f t h e s e v e r i t y o f t h e f i r s t and l a s t MSs o f t he 3-day group r e v e a l e d a s i g n i f i c a n t i n c r e a s e i n a l l f o u r measures o f MS s e v e r i t y ( a l l n _ ' s < 0 . 0 1 ) . The p r o g r e s s i v e d e c r e a s e i n t h e s e v e r i t y o f t h e MS e l i c i t e d a t 1 -hr i n t e r v a l s was i n d i c a t e d by s i g n i f i c a n t d e c r e a s e s i n t h r e e o f t h e measures o f s e i z u r e s e v e r i t y ; l a t e n c y t o f o r e l i m b t o n i c e x t e n s i o n ( £ ( 1 , 18 ) = 5 . 6 3 , £ < 0 . 0 5 ) , d u r a t i o n o f f o r e l i m b t o n u s , ( £ ( 1 ,18 ) = 8 . 5 1 , £ < 0 . 0 5 ) , and e x t e n t o f t o n i c e x t e n s i o n ( S i g n T e s t , N = 6 , x = 0 , j K O . 0 5 ) . The same p a t t e r n o f s i g n i f i c a n t changes was i l l u s t r a t e d by b e t w e e n -group c o m p a r i s o n s . The f i r s t MSs o f t h e a n i m a l s o f t h e 1-hr and 3-day groups d i f f e r e d s i g n i f i c a n t l y on o n l y t he l a t e n c y t o h i n d l i m b t o n i c e x t e n s i o n ( £ ( 1 , 23 ) = 6 . 8 3 , £ < 0 . 0 5 ) . However, t he l a s t MSs o f t h e a n i m a l s i n t h e 3-day group were s i g n i f i c a n t l y more s e v e r e t han t h o s e o f t h e a n i m a l s i n t he 1 -hr group on a l l f o u r measures o f MS s e v e r i t y ( a l l £ ' s < 0 . 0 2 ) . A l c o h o l t o l e r a n c e . U n l i k e t h e r e s u l t s o f E x p e r i m e n t 1, t h e r e were no s i g n i f i c a n t d i f f e r e n c e s between any two o f t h e t h r e e groups i n terms o f i n i t i a l t o l e r a n c e ( £ ( 2 , 32 ) = 0 . 2 7 , £ > 0 . 0 5 ) , f i n a l t o l e r a n c e ( £ ( 2 ,32 ) = 2 . 3 3 , £ > 0 . 0 5 ) , o r t h e change i n t o l e r a n c e ( £ ( 2 . 32 ) = 1 .35, £ > 0 . 0 5 ) . The mean r e s u l t s f o r each o f t h e groups a r e p r e s e n t e d i n A p p e n d i x 1. W i t h d r a w a l syndrome. The f a c t t h a t t he a l c o h o l w i t h d r a w a l s y n -dromes o f t h e a n i m a l s n o t expo sed t o a l c o h o l were s i g n i f i c a n t l y l e s s 38 s e v e r e t han t h o s e o f t h e a n i m a l s r e c e i v i n g a l c o h o l ( F i g u r e 4) c l e a r l y i l l u s t r a t e s t h e c o n v u l s i v e e f f e c t s o f a l c o h o l w i t h d r a w a l ( a l l p_ ' s<0.01). F u r t h e r m o r e , ECSs a l o n e had no e f f e c t on t he i n c i d e n c e o f t h e s e symptoms s i n c e t he g roups r e c e i v i n g ECSs b u t no t a l c o h o l d i d n o t d i s p l a y s i g n i -f i c a n t l y d i f f e r e n t i n c i d e n c e s o f t h e s e symptoms t han a n i m a l s r e c e i v i n g n e i t h e r a l c o h o l n o r ECSs ( a l l p _ ' s > 0 . 1 0 ) . The m a j o r f i n d i n g o f t h e p r e s e n t e x p e r i m e n t was t h a t t h e a l c o h o l w i t h d r a w a l syndrome was s i g n i f i c a n t l y p o t e n t i a t e d by t he ECSs p r e s e n t e d once e v e r y 3 d a y s , b u t no t by t h o s e p r e s e n t e d a t 1-hr i n t e r v a l s ( F i g u r e 4 ) . An o v e r a l l a n a l y s i s o f v a r i a n c e p e r f o r m e d on t he w i t h d r a w a l s c o r e s r e v e a l e d a s i g n i f i c a n t d i f f e r e n c e among t h e s i x g roups ( £ ( 5 , 57 ) = 2 1 . 1 2 , p_<0.01) . Sub sequent i n d i v i d u a l c o m p a r i s o n s r e v e a l e d t h a t t h e w i t h d r a w a l syndrome o f t h e 3-day a n i m a l s was s i g n i f i c a n t l y more s e v e r e than t h a t o f e i t h e r t he 1-hr a n i m a l s ( £ ( 1 , 19 ) = 12 . 49 , p_<0.10) o r t h e c o n t r o l a n i m a l s ( £ ( 1 , 22 ) = 18 . 30 , p_<0.01). A l t h o u g h i t appea r s f r om F i g u r e 4 as though some p o t e n t i a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome may have been p r o d u c e d by t he ECSs a d m i n i s t e r e d a t 1 -hr i n t e r -v a l s , t h e d i f f e r e n c e between the a n i m a l s o f t h e 1-hr group and t he c o n t r o l a n i m a l s was n o t s i g n i f i c a n t (F_ ( 1 , 21 ) = 1 .33, p_>0.10) . D i s c u s s i o n The r e s u l t s o f E x p e r i m e n t 2 c o n f i r m e d Ramer and P i n e l ' s (1975) r e p o r t o f t h e r e l a t i o n between t he i n t e r - E C S i n t e r v a l and t he p r o g r e s -s i v e changes i n MS s e v e r i t y ; s t i m u l a t i o n s p r e s e n t e d once e v e r y 3 days 39 F i g u r e 4 . The i n c i d e n c e o f i n d i v i d u a l a l c o h o l w i t h d r a w a l symptoms i n t h e s i x g roups o f a n i m a l s o f E x p e r i m e n t 2 . Each a n i m a l ' s s c o r e f o r a p a r t -i c u l a r symptom was c o n v e r t e d t o a p e r c e n t a g e o f t h e mean o f t h e c o n t r o l a n i m a l s s c o r e s f o r t h a t symptom. The s c o r e s f o r each group r e f l e c t t h e mean o f t h e s e c o n v e r t e d s c o r e s . 40 400 300 o QC g 200 CJ QC L U 100 L. OL \ \ \ \ r\/ \/ 1 MED Hyper-Reactivity Control • 3-Day ISI. ETOH • 1-Hr ISI.ETOH • No ECS. No ETOH • 1-Hr ISI. No ETOH HI 3-Day ISI. No ETOH V J \ V Ear-Eye Clonus Jaw Clonus \ V \/ M \ V \ V \ \ \ \ \/ Facial Clonus Head Nods Body Jerks W I T H D R A W A L S Y M P T O M S 41 f a c i l i t a t e d k i n d l i n g whereas s t i m u l a t i o n s a t 1 -hr i n t e r v a l s i n h i b i t e d MSs. E x p e r i m e n t i2, howeve r , e x t e n d e d t h e s e f i n d i n g s by a l s o s how ing changes i n a f o u r t h measu re , t h e d u r a t i o n o f f o r e l i m b t o n i c e x t e n s i o n , w h i c h were c o n s i s t e n t w i t h t he changes i n t he o t h e r t h r e e measu re s . A s i m i l a r r e l a t i o n has been r e p o r t e d i n e x p e r i m e n t s i n w h i c h a n i m a l s have been k i n d l e d w i t h a m y g d a l o i d s t i m u l a t i o n s ; i n h i b i t i o n i s p r o d u c e d w i t h s h o r t i n t e r v a l s , whereas k i n d l i n g o c c u r s w i t h l o n g e r i n t e r v a l s . The main d i f f e r e n c e between EGSs and l o c a l b r a i n s t i m u l a t i o n s i n t h i s r e g a r d , however , appea r s t o be t h a t t he i n h i b i t o r y e f f e c t s o f s e i z u r e s e l i c i t e d by a m y g d a l o i d s t i m u l a t i o n a r e much l e s s e n d u r i n g than t h o s e p r o d u c e d by s e i z u r e s e l i c i t e d by ECSs. Fo r e x a m p l e , Goddard e t a l_. (1969) f o u n d t h a t k i n d l i n g c o u l d be p r o d u c e d w i t h a m y g d a l o i d s t i m u l a t i o n a t i n t e r v a l s o f 20 min o r more. I f s t i m u l a t i o n s were p r e -s e n t e d a t s h o r t e r i n t e r v a l s t h e y w o u l d e v e n t u a l l y f a i l t o e l i c i t MSs even i n k i n d l e d a n i m a l s . Ramer and P i n e l ( 1 9 7 5 ) , h o w e v e r , f o u n d t h a t E C S - k i n d l i n g was p r o d u c e d w i t h 3-day i n t e r v a l s and t h a t i f 1 -hr i n t e r -v a l s were used t he s e v e r i t y o f t h e MSs p r o g r e s s i v e l y d e c r e a s e d . U n l i k e E x p e r i m e n t 1, no s i g n i f i c a n t d i f f e r e n c e s between any o f t he groups i n i n i t i a l t o l e r a n c e , f i n a l t o l e r a n c e , o r t h e change i n t o l e r -ance were f o u n d . The r e s u l t s o f E x p e r i m e n t 1 s u g g e s t e d t h a t t h e i n -t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome was due t o changes i n the a n i m a l ' s t o l e r a n c e o f a l c o h o l w h i c h r e s u l t e d i n t he e x p e r i m e n t a l a n i m a l s r e c e i v i n g g r e a t e r amounts o f a l c o h o l t h a n t he u n s t i m u l a t e d a n i m a l s . However, i n the p r e s e n t e x p e r i m e n t , and i n a l l t h e r e m a i n i n g e x p e r i m e n t s , t h e r e were no d i f f e r e n c e s i n t he t o l e r a n c e o f t h e a n i m a l s 42 o f a l c o h o l . T h e r e f o r e , i t appea r s more l i k e l y t h a t t he p o t e n t i a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome was due t o an i n c r e a s e i n t h e a n i m a l ' s s u s c e p t i b i l i t y t o t h e c o n v u l s i v e e f f e c t s o f a l c o h o l w i t h d r a w a l p r o d u c e d by t h e p e r i o d i c ECSs. The f a c t t h a t t h e a l c o h o l w i t h d r a w a l syndrome was i n t e n s i f i e d o n l y when ECSs were p r e s e n t e d a t 3 - day , b u t n o t 1-hr i n t e r v a l s s u g g e s t s t h a t ECSs p e r se a r e n o t r e s p o n s i b l e ^ , f o r t h e i n t e n s i f i c a t i o n e f f e c t . The f i n d i n g s o f E x p e r i m e n t 2 s u g g e s t t h a t t h e same e f f e c t s w h i c h i n d u c e t h e p r o g r e s s i v e i n c r e a s e i n MS s e v e r i t y p r o d u c e d by p e r i o d i c ECSs a l s o f o rm t he b a s i s f o r t he i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l s yndrome. T h i s i n t e r p r e t a t i o n , w o u l d s u g g e s t t h a t t he i n h i b i t o r y e f f e c t s o f ECSs p r e s e n t e d a t 1 -hr i n t e r v a l s s h o u l d r e d u c e t he s e v e r i t y o f t h e a l c o h o l w i t h d r a w a l s yndrome. However , whereas t h e i n c r e a s e s i n s e i z u r e s u s -c e p t i b i l i t y a s s o c i a t e d w i t h k i n d l i n g w i t h o t h e r a gen t s have been shown t o be r e l a t i v e l y e n d u r i n g (Goddard e_t a l _ . , 1969; Mason and C o o p e r , 1972 ) , t h e i n h i b i t o r y e f f e c t o f s e i z u r e s have been shown t o be r e l a t i v e l y s h o r t - l i v e d (Mucha, P i n e l , & P h i l l i p s , 1976 ) . I t i s pe rhap s f o r t h i s reason, t h a t no d i m i n u t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome was o b s e r v e d i n t he a n i m a l s p r e s e n t e d w i t h ECSs a t 1 -hr i n t e r v a l s . 43 E x p e r i m e n t 3: Number o f ECSs and t h e  I n t e n s i f i c a t i o n o f t h e A l c o h o l W i t h d r a w a l Syndrome I n t r o d u c t i o n The pu rpo se o f E x p e r i m e n t 3 was t o d e t e r m i n e t he r e l a t i o n between the number o f ECSs and bo th t he deg ree o f E C S - k i n d l i n g and t he s u b s e -quen t i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome. Methods F o l l o w i n g p o s t - s u r g i c a l r e c o v e r y , t he 51 s u b j e c t s were r andomly d i v i d e d i n t o groups w h i c h r e c e i v e d 20 (n = 1 0 ) , 10 (n = 9 ) , 6 (n = 9 ) , 3 (n = 9 ) , o r no ECSs ( c o n t r o l ; n = 1 3 ) . The 15-mA ECSs were p r e s e n t e d once e v e r y 3 days as b e f o r e , b u t o n l y t he MSs o f t h e a n i m a l s r e c e i v i n g 20 s t i m u l a t i o n s were v i d e o t a p e d and a n a l y z e d . The o n s e t o f t he s t i m u -l a t i o n s was s t a g g e r e d so t h a t a l c o h o l e x p o s u r e t e r m i n a t e d on t he same day f o r a l l a n i m a l s . A l c o h o l a d m i n i s t r a t i o n s and w i t h d r a w a l o b s e r v a -t i o n s were as b e f o r e . R e s u l t s Bo th t he p r o g r e s s i v e i n t e n s i f i c a t i o n o f t h e E C S - i n d u c e d MSs and the i n t e n s i f i c a t i o n o f t he a l c o h o l w i t h d r a w a l syndrome were f ound t o be i n c r e a s i n g , n e g a t i v e l y - a c c e l e r a t e d f u n c t i o n s o f t h e number o f ECSs. 44 E C S - i n d u c e d MSs. As i n t h e p r e v i o u s e x p e r i m e n t s , t h e MSs grew p r o g r e s s i v e l y more s e v e r e i n r e s p o n s e t o each s u c c e s s i v e ECS ( F i g u r e 5 ) . A l t h o u g h t h e r e was some v a r i a b i l i t y i n t he c o u r s e o f t h e i n t e n s i f i c a t i o n o f t h e f o u r measures o f MS s e v e r i t y , i n g e n e r a l , t he s i x t h MSs were s i g n i f i c a n t l y more s e v e r e t han t he f i r s t i n te rms o f a l l f o u r measures o f MS s e v e r i t y ( a l l p _ ' s < 0 . 0 5 ) . An a n a l y s i s o f a l l f o u r measures o f MS s e v e r i t y i n d i c a t e d t h a t t he t e n t h MS was more s e v e r e than t h e f i r s t ( a l l p _ ' s < 0 . 0 5 ) . However, t h e 20 th MSs were n o t s i g n i f i c a n t l y more s e v e r e t han t he t e n t h on any o f t h e f o u r measu re s , ( a l l J D ' S > 0 . 0 5 ) . A l c o h o l T o l e r a n c e . As i n E x p e r i m e n t 2 , t h e r e were no s i g n i f i c a n t o v e r a l l d i f f e r e n c e s between t he groups i n i n i t i a l t o l e r a n c e ( £ ( 4 , 43 ) = 0 . 9 1 , p_>0 .05 ) , f i n a l t o l e r a n c e (F ( 4 ,43 ) = 0 . 9 2 , £ > 0 . 0 5 ) , o r t h e change i n t o l e r a n c e (_F ( 4 , 43 ) = 0 . 5 1 , £ > 0 . 0 5 ) . The mean v a l u e s f o r t h e s e t h r e e measures f o r each group a r e p r e s e n t e d i n A p p e n d i x I. W i t h d r a w a l syndrome. The s e v e r i t y o f t h e a l c o h o l w i t h d r a w a l s y n -drome was a f u n c t i o n o f t h e number o f ECSs ( F i g u r e 6 ) . An o v e r a l l a n a l y s i s o f v a r i a n c e i n d i c a t e d a h i g h l y s i g n i f i c a n t d i f f e r e n c e among t he a n i m a l s o f t he f i v e groups ( £ ( 4 ,43 ) = 1 7 . 55 , £ < 0 . 0 1 ) . S ub se -quen t i n d i v i d u a l c o m p a r i s o n s r e v e a l e d t h a t t h e i n c i d e n c e o f w i t h d r a w a l symptoms was s i g n i f i c a n t l y g r e a t e r i n t h e a n i m a l s o f t h e 20-ECS group than i n t h e a n i m a l s o f e i t h e r t he 6 -ECS , ( £ ( 1 , 17 ) = 7 4 . 0 3 , £ < 0 . 0 1 ) , 3-ECS (F (1 ,17 ) = 2 6 . 2 4 , £ < 0 . 0 1 ) o r c o n t r o l g roups ( £ ( 1 , 21 ) = 5 8 . 1 3 , £ < 0 . 0 1 ) . M o r e o v e r , t h e i n c i d e n c e o f w i t h d r a w a l symptoms was s i g n i f i -45 F i g u r e 5. The p r o g r e s s i v e i n c r e a s e i n MS s e v e r i t y p r o d u c e d by 2 0 , 15-mA ECSs p r e s e n t e d a t 3-day i n t e r v a l s . CONVULSION SEVERITY MEASURE Latency to Hindlimb Extension (sec) Latency to Forelimb Extension (sec) 47 F i g u r e 6. The i n c i d e n c e o f i n d i v i d u a l a l c o h o l w i t h d r a w a l symptoms i n t h e f i v e g roups o f a n i m a l s i n E x p e r i m e n t 3. Each a n i m a l ' s s c o r e f o r a part=-i c u l a r symptom was c o n v e r t e d t o a p e r c e n t a g e o f t h e mean o f t h e c o n t r o l a n i m a l ' s s c o r e s f o r t h a t symptom. The s c o r e s o f each group r e f l e c t t h e mean o f t h o s e c o n v e r t e d s c o r e s . 48 500 L 400 O DC 300 O O o DC 200 100 \ \ \/ \/ \/ \/ V Control • 20ECSs • 10 ECSs LUI 6 ECSs • 3 ECSs f f l \/ \/ \/ \/ Hyper -Reactivity Ear-Eye Clonus Jaw Clonus Facial Clonus Head Nods Body Jerks W I T H D R A W A L S Y M P T O M S 49 c a n t l y g r e a t e r i n t he a n i m a l s o f t he 10-ECS group t han t h a t o f t he a n i -mals o f t h e 6-ECS ( £ ( 1 ,16 ) = 1 5 . 0 3 , p_<0 .0 l ) and c o n t r o l g roups ( £ ( 1 ,20 ) = 11 .86 , p_<0.05). None o f t he o t h e r d i f f e r e n c e s between groups were s i g n i f i c a n t ( a l l p_'s> 0 . 1 0 ) . D i s c u s s i o n As i n t h e p r e v i o u s e x p e r i m e n t s 10 ECSs s i g n i f i c a n t l y p o t e n t i a t e d the a l c o h o l w i t h d r a w a l syndrome. E x p e r i m e n t 3 a l s o c o n t r i b u t e d t o t h e f i n d i n g s o f t h e two p r e v i o u s e x p e r i m e n t s by documen t i n g t h e r e l a t i o n between t h e number o f ECSs and t h e deg ree o f s e v e r i t y o f t h e a l c o h o l w i t h d r a w a l syndrome. In E x p e r i m e n t 3 , s i x - ' o r r f e w e r C E C S s - - w e r e : n o t ' ' s u f f i -c i e n t t o s i g n i f i c a n t l y i n t e n s i f y t h e a l c o h o l w i t h d r a w a l s ynd rome, whereas 10 o r more w e r e . The p r e s e n t r e s u l t s s u g g e s t t h a t i n s u b s e -quen t a t t e m p t s t o d e t e r m i n e w h e t h e r o r n o t t h e s u s c e p t i b i l i t y t o a l c o h o l w i t h d r a w a l i s i n c r e a s e d by c l i n i c a l ECS t r e a t m e n t s , a t t e n t i o n s h o u l d be d i r e c t e d t o w a r d t h o s e p a t i e n t s who have had l a r g e numbers o f ECSs. The r e s u l t s o f E x p e r i m e n t 3 have a l s o shown t h a t t h e degree o f MS s e v e r i t y i s d i r e c t l y r e l a t e d t o t h e number o f ECSs i n a s e r i e s . A l t h o u g h each measure o f MS s e v e r i t y d e v e l o p e d a t i t s own r a t e , i n g e n e r a l MS s e v e r i t y was more s e v e r e a f t e r l a r g e numbers o f ECSs. How-e v e r , as can be seen f r o m F i g u r e 5, t he deg ree o f i n t e n s i f i c a t i o n appea r s t o be a s y m p t o t i c by a p p r o x i m a t e l y t h e t e n t h ECS; t h e r e was a s l i g h t , b u t n o n - s i g n i f i c a n t i n c r e a s e i n t h e s e v e r i t y o f each o f t h e f o u r measures o f MS s e v e r i t y f r o m t h e t e n t h t o t h e 20 th MSs. I t w o u l d 50 appea r f rom t h e s e d a t a t h a t t h e c o u r s e o f E C S - k i n d l i n g i s c o m p l e t e a f t e r 10 s t i m u l a t i o n s . However , i t i s d i f f i c u l t t o r u l e o u t t he p o s s i b i l i t y t h a t i m p o r t a n t deve lopment s i n e p i l e p t o g e n e s i s m i gh t o c c u r w i t h a d d i t i o n a l ECSs. T h i s p o s s i b i l i t y i s i l l u s t r a t e d by t he d e v e l o p -ment o f s pon taneou s s e i z u r e s w i t h l o c a l e l e c t r i c a l b r a i n s t i m u l a t i o n s . In t he m a j o r i t y o f k i n d l i n g s t u d i e s v e r y few s t i m u l a t i o n s have been commonly u s e d , l a r g e l y because l o c a l b r a i n s t i m u l a t i o n s p r oduce MSs w h i c h i n t e n s i f y and d e v e l o p v e r y q u i c k l y . However, r e c e n t s t u d i e s have r e v e a l e d t h a t s t r i k i n g changes can be o b s e r v e d a f t e r 200 t o 300 s t i m u l a t i o n s i n t he fo rm o f i n t e r i c t a l s p i k i n g and t h e deve l opment o f spon taneous s e i z u r e s ( P i n e l & R o v n e r , 1976; Wada & S a t o , 1974 ) . Some c l i n i c a l e v i d e n c e even e x i s t s t h a t w i t h a l a r g e number o f ECSs s p o n -taneous s e i z u r e s m i gh t o c c u r ( P a c e l l a & B a r r e r a , 1945; P o l l a c k " , R o s e n t h a l , & Macey, 1963 ) . Thu s , i t may be p rematu re t o r u l e o u t t h e p o s s i b i l i t y t h a t E C S - k i n d l i n g does n o t c o n t i n u e t o p r o g r e s s w i t h more t han 10 s t i m u l a t i o n s . 51 E x p e r i m e n t 4 : Permanence o f t h e ECS - I nduced  I n t e n s i f i c a t i o n o f t h e A l c o h o l W i t h d r a w a l Syndrome I n t r o d u c t i o n In each o f t h e p r e v i o u s t h r e e e x p e r i m e n t s p e r i o d i c ECSs i n t e n s i f i e d the a l c o h o l w i t h d r a w a l syndrome. The pu rpo se o f E x p e r i m e n t 4 was t o a s s e s s t h e permanence o f t h i s e f f e c t . Methods Of t h e 49 s u b j e c t s , 36 r e c e i v e d t e n 15-mA ECSs a t 3-day i n t e r v a l s . These a n i m a l s were randomly d i v i d e d i n t o f o u r g roups w i t h d e l a y s o f 10 weeks (n = 7 ) , 6 weeks (n = 1 0 ) , 3 weeks (n = 1 0 ) , o r 2 weeks (n = 9) between t he l a s t ECS and t h e t e r m i n a t i o n o f a l c o h o l e x p o s u r e . The r e m a i n i n g 13 a n i m a l s ( c o n t r o l s ) were a l s o i n t u b a t e d w i t h a l c o h o l b u t r ema i ned u n s t i m u l a t e d . The o n s e t o f t he ECS a d m i n i s t r a t i o n s was a g a i n s t a g g e r e d so t h a t each a n i m a l was w i t h d r a w n f r om a l c o h o l on t he same day. S i n c e t h e E C S - k i n d l i n g e f f e c t i n i t i a l l y r e p o r t e d by Ramer and P i n e l (1975) was r e p l i c a t e d i n each o f t h e f i r s t t h r e e e x p e r i m e n t s o f t h i s t h e s i s , t he E C S - k i n d l i n g e f f e c t was n o t a s s e s s e d as t h o r o u g h l y i n t h i s e x p e r i m e n t . However, i n t h i s e x p e r i m e n t , t he e x t e n t o f h i n d l i m b e x t e n s i o n was m o n i t o r e d t o c o n f i r m t h e deve l opment o f p r o g r e s s i v e l y more s eve revMS s . 52 R e s u l t s As i n E x p e r i m e n t s 1, 2 , and 3, E C S - k i n d l i n g o c c u r r e d i n r e s p o n s e t o t h e p e r i o d i c ECSs. A l t h o u g h t he same deg ree o f t o l e r a n c e was d i s -p l a y e d i n a l l g r o u p s , t h e a n i m a l s w h i c h r e c e i v e d ECSs s u f f e r e d a more s e v e r e w i t h d r a w a l syndrome. However , t h e degree o f i n t e n s i f i c a t i o n o f t he w i t h d r a w a l syndrome was i n v e r s e ! y y r e l a t e d t o t h e d e l a y between t he l a s t ECS and t h e t e r m i n a t i o n o f a l c o h o l e x p o s u r e . A s i g n i f i c a n t deg ree o f i n t e n s i f i c a t i o n l a s t e d up t o 3 weeks a f t e r t h e l a s t ECS. E C S - i n d u c e d MSs. To t h e e x t e n t t h a t i t was mea su red , t he p r o -g r e s s i v e i n c r e a s e i n t he s e v e r i t y o f MSs was l a r g e l y t he same as t h a t o b s e r v e d i n t h e p r e v i o u s e x p e r i m e n t s . In r e s p o n s e t o t h e f i r s t ECS a p p r o x i m a t e l y 40% o f t h e a n i m a l s d i d n o t d i s p l a y maximal h i n d l i m b e x t e n s i o n , w h e r e a s , i n r e s p o n s e t o t he l a s t s t i m u l a t i o n , a l l a n i m a l s d i s p l a y e d f u l l e x t e n s i o n . A l c o h o l t o l e r a n c e . As i n E x p e r i m e n t s 2 and 3, t h e r e were no s i g n i f i c a n t d i f f e r e n c e s between t h e groups i n t h e i r t o l e r a n c e t o a l c o h o l . The re were no s i g n i f i c a n t d i f f e r e n c e s i n t h e i r i n i t i a l t o l -e r a n c e (F ( 4 , 4 4 ) = 1.52, p_>0 .05 ) , t h e i r f i n a l t o l e r a n c e (F_ ( 4 , 44 ) = 1.26, p_>0.05), o r t h e i r change i n t o l e r a n c e ( £ ( 4 ,44 ) = 1.58, p_>0 .05 ) . The means o f each group f o r t h e s e measures a r e p r e s e n t e d i n A p p e n d i x I. W i t h d r a w a l syndrome. The deg ree o f i n t e n s i f i c a t i o n o f t h e a l c o h o l 53 w i t h d r a w a l syndrome was i n v e r s e l y r e l a t e d t o t h e l e n g t h o f t h e d e l a y between t he l a s t ECS and t h e t e r m i n a t i o n o f a l c o h o l e x p o s u r e ( F i g u r e 7 ) . As i n E x p e r i m e n t s 1, 2 , and 3, t e n p e r i o d i c ECSs s i g n i f i c a n t l y i n t e n s i -f i e d t h e r e a c t i o n o f t h e a n i m a l s t o a l c o h o l w i t h d r a w a l 2 weeks l a t e r . However, when the d e l a y between t h e l a s t ECS and t h e t e r m i n a t i o n o f a l c o h o l e x p o s u r e was l o n g e r t h e s e v e r i t y o f t he s ub sequen t a l c o h o l w i t h -d rawa l syndrome was l e s s . R e l a t i v e t o t h e c o n t r o l s , t h e i n c i d e n c e o f combined w i t h d r a w a l symptoms was s i g n i f i c a n t l y h i g h e r i n t h e a n i m a l s o f t he 2-week ( £ ( 1 ,20 ) = 1 5 . 3 1 , £ < 0 . 0 1 ) and 3-week d e l a y groups ( £ ( 1 ,21 ) = 1 0 . 55 , £ < 0 . 0 5 ) . However, a n i m a l s t h a t were t e s t e d a t l o n g e r i n t e r -v a l s d i d n o t d i f f e r s i g n i f i c a n t l y f r om t h e c o n t r o l s ( a l l £ ' s > 0.-10). The i n v e r s e r e l a t i o n between t h e d e l a y and t h e s e v e r i t y o f t h e w i t h d r a w a l syndrome was a l s o i l l u s t r a t e d by d i f f e r e n c e s between t h e e x p e r i m e n t a l g r o u p s . The i n c i d e n c e o f combined w i t h d r a w a l s c o r e s was s i g n i f i c a n t l y g r e a t e r i n t he a n i m a l s o f t h e 2-week d e l a y g roup t han t h a t i n t h e a n i m a l s o f t h e 6-week ( £ ( 1 , 17 ) = 1 7 . 2 9 , £ < 0 . 0 1 ) and 10-week d e l a y g roups ( £ ( 1 , 21 ) = 1 1 . 9 5 , £ < 0 . 0 5 ) . However , t h e i n c i d e n c e o f comb ined w i t h d r a w a l s c o r e s i n t he a n i m a l s o f t h e 3-week d e l a y g roup was s i g n i f i -c a n t l y g r e a t e r t h a n t h a t i n t he a n i m a l s o f t he 6-week d e l a y group o n l y ( £ ( 1 ,18 ) = 1 0 . 73 , £ < 0 . 0 5 ) . D i s c u s s i o n The i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome by p r i o r ECS appea r s t o be a d e c r e a s i n g f u n c t i o n o f t h e d e l a y between t he l a s t ECS and a l c o h o l w i t h d r a w a l . Under t h e c o n d i t i o n s o f t h e p r e s e n t e x -p e r i m e n t , t h e i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome was n o t o b s e r v e d a f t e r d e l a y s o f 6 weeks o r more. 54 F i g u r e 7. The i n c i d e n c e o f i n d i v i d u a l a l c o h o l w i t h d r a w a l symptoms i n t he a n i m a l s o f E x p e r i m e n t 4 . Each a n i m a l ' s s c o r e f o r a p a r t i c u l a r symptom was c o n v e r t e d t o a p e r c e n t a g e o f t h e mean o f t h e c o n t r o l a n i m a l ' s s c o r e f o r t h a t symptom. The s c o r e s f o r each group r e f l e c t t he mean o f t h e s e c o n v e r t e d s c o r e s . 55 C] Control E l 2-wk delay 0 3-wk delay 6"wk delay B 10-wk delay Hyper Ear-Eye Jaw Facial Head Body Reactivity Clonus Clonus Clonus Nods Jerks W I T H D R A W A L S Y M P T O M S 400 L 300 \/ 56 ECSs have been shown t o have b i o c h e m i c a l and n e u r o p h y s i o l o g i c a l e f f e c t s w h i c h f o l l o w a t i m e c o u r s e s i m i l a r t o t h a t r e p o r t e d i n t h e p r e -s e n t e x p e r i m e n t f o r t h e i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome. F o r e x a m p l e , i n c r e a s e s i n monoamine o x i d a s e a c t i v i t y have been r e p o r t e d t o l a s t 6 weeks a f t e r a s e r i e s o f 42 ECSs i n r a t s ( P r y p r & O t i s , 1970 ) . M o r e o v e r , a f t e r a c ompa rab l e number o f ECSs , a d v e r s e e f f e c t s on normal g rowth p a t t e r n s i n young r a t s have been r e -p o r t e d t o l a s t more t han 2 weeks ( P r y o r , 1974).. McGaugh (1974) a l s o f ound t h a t , depend i n g on t he p a r a m e t e r s o f t he ECS p r e s e n t a t i o n , r e t r o -grade amnes ia i n a n i m a l s can l a s t f r om 12 h r t o 1 month. In humans, i n d i c a t i o n o f EEG s l o w i n g a f t e r a p p r o x i m a t e l y 15 ECSs has ? been r e p o r t e d t o l a s t up t o 2 o r 3 months ( S m a l l , 1974 ) . The r e l a t i o n o f t h e t i m e c o u r s e o f t h e s e e f f e c t s and t he i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h -d rawa l syndrome d e s c r i b e d i n t he p r e s e n t e x p e r i m e n t l e a d s one t o s p e c -u l a t e t h a t one o f t h e changes u n d e r l y i n g t h e s e e f f e c t s m i gh t a l s o be t he b a s i s o f t h e i n t e n s i f i c a t i o n e f f e c t . I n d e e d , a t t e m p t s have a l r e a d y been made t o e s t a b l i s h t he e f f e c t s o f t h e i n t e r a c t i o n o f ECS and v a r i o u s n e u r o t r a n s m i t t e r s on t h e s e i z u r e s u s c e p t i b i l i t y o f o r g a n i s m s ( O t t o s o n , 1960; K a r c z m a r , 1974 ) . However , t o e s t a b l i s h t h e r e l a t i o n between t h e s e e f f e c t s and t h e E C S - i n d u c e d i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h -d rawa l s yndrome, s t u d i e s u s i n g c o n d i t i o n s compa rab l e t o t h o s e used i n t he p r e s e n t e x p e r i m e n t s w i l l have t o be c o n d u c t e d . 57 E x p e r i m e n t 5: Drug P r e t r e a t m e n t s and ECS - I nduced  I n t e n s i f i c a t i o n o f t he A l c o h o l W i t h d r a w a l Syndrome I n t r o d u c t i o n The pu rpo se o f t h i s f i f t h and f i n a l e x p e r i m e n t was t o a s s e s s t h e e f f e c t s o f a s e r i e s o f d rugs r o u t i n e l y a d m i n i s t e r e d i n c o n j u n c t i o n w i t h c l i n i c a l ECS t r e a t m e n t s on t he E C S - i n d u c e d i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome. Because o f c e r t a i n h a z a r d s a s s o c i a t e d w i t h ECS t r e a t m e n t s , p a t i e n t s t y p i c a l l y r e c e i v e t h r e e d i f f e r e n t d rugs p r i o r t o each t r e a t m e n t ; a t r o p i n e s u l f a t e , a b a r b i t u r a t e , and s u c c i n y l - c h o l i n e , ( F i n k , 1974; F r a n k e l , 1973 ) . P a t i e n t s r e c e i v i n g s e v e r a l ECS a d m i n i s t r a t i o n s f r e -q u e n t l y c o m p l a i n o f s e v e r e a n x i e t y b e f o r e and a f t e r each ECS. B a r b i t u r -a'teses have been f ound t o r e d u c e t h i s a n x i e t y . A t r o p i n e s u l f a t e , on t he o t h e r s h a n d y has been f ound t o be e f f e c t i v e i n r e d u c i n g t h e p r o b -lems o f apnea and b r a d y c a r d i a w h i c h somet imes o c c u r a f t e r an E C S - i n d u c e d MS. One o f t h e most common c o m p l a i n t s and h a z a r d s a s s o c i a t e d w i t h ECS a d m i n i s t r a t i o n s i s t h a t o f bone f r a c t u r e s o r d i s l o c a t i o n s p r o -duced by t h e MS. S u c c i n y l - c h o l i n e has been f ound v e r y e f f e c t i v e i n r e d u c i n g t h e s e h a z a r d s by b l o c k i n g musc l e c o n t r a c t i o n s . In some ca se s oxygen i s a l s o a d m i n i s t e r e d t o r e d u c e t h e p rob lems a s s o c i a t e d w i t h a n o x i a somet imes o c c u r r i n g as a r e s u l t o f t h e e l i c i t e d c o n v u l s i o n s . Thu s , i n E x p e r i m e n t 5 each o f t h e s e f o u r a g e n t s was g i v e n t o t h e e x p e r i m e n t a l a n i m a l s p r i o r t o each ECS t o a s s e s s t he e f f e c t s o f t h e s e 58 d rugs on t h e E C S - i n d u c e d i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome. Methods The 39 s u b j e c t s were randomly d i v i d e d i n t o f o u r g r o u p s , one r e c e i v i n g t h e s e r i e s o f d rugs p r i o r t o each ECS (n = 1 0 ) , a n o t h e r r e c e i v i n g t h e d r u g s , b u t no ECSs (n = 8 ) , a t h i r d r e c e i v i n g o n l y t h e ECSs (n = 1 2 ) , and a f o u r t h r e c e i v i n g n e i t h e r t h e d rugs n o r t he ECSs ( c o n t r o l ; n = 9 ) . Those a n i m a l s n o t r e c e i v i n g ECSs r e c e i v e d c o n t r o l h a n d l i n g . Thus , t h e d e s i g n was a 2x2 f a c t o r i a l w i t h t h e two v a r i a b l e s b e i n g ECS a d m i n i s t r a t i o n s and d rug p r e t r e a t m e n t s w i t h a l l t h e a n i m a l s r e c e i v i n g a l c o h o l . P r i o r t o each s c h e d u l e d ECS, t h e " d r u g " s u b j e c t s r e c e i v e d j_.p_. i n j e c t i o n s o f a t r o p i n e s u l f a t e (0 .036 mg/kg) , s od ium p e n t o b a r b i t a l (50 mg/kg) , and s u c c i n y l - c h o l i n e (10 mg/kg). The c o n c e n -t r a t i o n s o f each aqueous d r u g s o l u t i o n were a d j u s t e d so t h a t each a n i m a l r e c e i v e d abou t 0.2 c c o f s o l u t i o n p e r i n j e c t i o n . The a t r o p i n e , b a r b i t u r a t e and s u c c i n y l - c h o l i n e were a d m i n i s t e r e d 3 0 , 1 5 , and 3 m i n u t e s p r i o r t o each ECS r e s p e c t i v e l y . Each a n i m a l was t h e n o x y g e n a t e d f o r 30 s e c i m m e d i a t e l y p r i o r t o each ECS i n a l o w - p r e s s u r e oxygen chamber (45x45x90 cm). A f t e r e ach ECS, any a n i m a l d i s p l a y i n g b r e a t h i n g d i f f i -c u l t i e s p r o d u c i n g marked c y a n o s i s o f t h e h i n d l i m b s was r e t u r n e d t o t h e oxygen chamber f o r 1 m i n . However , i f an a n i m a l c e a s e d b r e a t h i n g a l -t o g e t h e r , i t was r e s u s c i t a t e d on a H a r v a r d S m a l l - A n i m a l R e s u s c i t a t o r u n t i l normal b r e a t h i n g r e t u r n e d . On l y e i g h t o f t h e 18 a n i m a l s w h i c h 59 r e c e i v e d drugs r e q u i r e d a d d i t i o n a l o x y g e n a t i o n a t some t i m e d u r i n g t he e x p e r i m e n t , b u t o n l y 3 o f t h e 8 r e q u i r e d r e s u s c i t a t i o n . The re was no r e l a t i o n between t h e s e t r e a t m e n t s and l a t e r r e s p o n s e s t o a l c o h o l o r a l c o h o l w i t h d r a w a l . As u s u a l , 1 day a f t e r t h e l a s t ECS, a l c o h o l was a d m i n i s t e r e d f o r 14 d a y s . A f t e r t h i s a l c o h o l i n t u b a t i o n p e r i o d t he s e v e r i t y o f t h e a l c o h o l w i t h d r a w a l syndrome was a s s e s s e d . a s b e f o r e . R e s u l t s A l t h o u g h t h e d rug t r e a t m e n t s e l i m i n a t e d any o v e r t c o n v u l s i v e r e s pon se s t o t h e ECSs , t he u sua l E C S - i n d u c e d i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome was n o t s i g n i f i c a n t l y r e d u c e d by t h e s e p r e t r e a t m e n t s . E C S - i n d u c e d MSs. The drugs a d m i n i s t e r e d p r i o r t o each ECS r e n d e r e d the a n i m a l s c o m p l e t e l y a t a x i c , and s e d a t e d . W i th t he a p p l i c a t i o n o f c u r r e n t , a m i l d j e r k o r t r e m o r r an t h r o u g h t he body w h i c h d i d n o t o u t -l a s t t he d u r a t i o n o f t he s t i m u l a t i o n . W i t h i n 20 min o f each ECS, a l l a n i m a l s were awake and b e h a v i n g n o r m a l l y w i t h no a p p a r e n t a f t e r - e f f e c t s . A l c o h o l t o l e r a n c e . As i n t h e c a s e o f t h e p r e v i o u s t h r e e e x p e r i -ments no s i g n i f i c a n t d i f f e r e n c e s between any o f t h e groups were f ound on i n i t i a l t o l e r a n c e ( £ ( 3 ,35 ) = 1.56, n_>0.05), f i n a l t o l e r a n c e ( £ ( 3 , 35 ) = 1.12, p_>0.05) o r t h e change i n t o l e r a n c e ( £ ( 3 , 35 ) = 2 . 3 9 , 60 p_>0.05) . A l l means a r e a g a i n p r e s e n t e d i n A p p e n d i x I. T hu s , as i n t he p r e v i o u s t h r e e e x p e r i m e n t s , t h e ECSs had n o ' e f f e c t on t he t o l e r a n c e o f t h e a n i m a l o f a l c o h o l . W i t h d r a w a l syndrome. As i n t he p r e v i o u s e x p e r i m e n t s , an i n t e n s i -f i c a t i o n o f t he a l c o h o l w i t h d r a w a l syndrome was o b s e r v e d i n s u b j e c t s r e c e i v i n g 10 ECSs ( F i g u r e 9 ) . M o r e o v e r , t h i s i n t e n s i f i c a t i o n o c c u r r e d i n a n i m a l s w h e t h e r o r n o t t h e i r MSs had been p h a r m a c o l o g i c a l l y b l o c k e d . An o v e r a l l a n a l y s i s o f v a r i a n c e r e v e a l e d s i g n i f i c a n t d i f f e r e n c e s among the f o u r g roups i n t h e comb ined w i t h d r a w a l s c o r e s ( £ ( 3 , 35 ) = 11 . 89 , p_<0.01). Sub sequen t i n d i v i d u a l c o m p a r i s o n s r e v e a l e d t h a t t h e s u b j e c t s r e c e i v i n g ECSs e i t h e r a l o n e o r a f t e r t he d rug p r e t r e a t m e n t s d i s p l a y e d a h i g h e r i n c i d e n c e o f comb ined w i t h d r a w a l symptoms than d i d t he r a t s i n e i t h e r the c o n t r o l ( £ ( 1 ,19 ) = 18 . 54 , p_<0.01, and £ ( 1 , 17 ) = 14 .57 , p_<0.01, r e s p e c t i v e l y ) o o r d d r u g r : n o E E 6 S c c o r i : d i t i ' o n s ( ( £ ( 1 , 18 ) = 14 .67 , p_<0.01, and £ ( 1 ,16 ) = 1 0 . 8 9 , p_< 0 . 0 2 5 , r e s p e c t i v e l y ) . The d rug t r e a t m e n t s t h e m s e l v e s had no s i g n i f i c a n t e f f e c t on t h e w i t h d r a w a l s c o r e s r e g a r d l e s s o f w h e t h e r t h e y were a d m i n i s t e r e d i n c o n j u n c t i o n w i t h ECSs ( £ ( 1 ,20 ) = 4 . 2 2 , p_>0.10) o r n o t ( £ ( 1 ,15 ) = 1.48, p_>00.10). D i s c u s s i o n The r e s u l t s o f E x p e r i m e n t 5 thus c o n f i r m t h o s e o f t he o t h e r f o u r e x p e r i m e n t s o f t h i s t h e s i s ; an i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h -d rawa l syndrome was p r o d u c e d by 10 p e r i o d i c ECSs . More i m p o r t a n t l y , 61 F i g u r e 8. The i n c i d e n c e o f i n d i v i d u a l a l c o h o l w i t h d r a w a l symptoms f o r t h e f o u r g roups o f a n i m a l s i n E x p e r i m e n t 5. Each a n i m a U s s c o r e f o r a p a r t i -c u l a r symptom was c o n v e r t e d t o a p e r c e n t a g e o f t h e mean o f t h e c o n t r o l a n -i m a l s f o r t h a t symptom. The s c o r e s f o r each group r e f l e c t t h e mean o f t h e s e c o n v e r t e d s c o r e s . 62 400 22 < O dc 300 o ° 200 o DC °- 100 L Control • ECS ECS + Drugs 0 Drugs R \4i Hyper-Reactivity \ \ \ "/ \ \ \ \ \ \ \ \ 7 I I L \ Y r \ - h i t \ \ \ \ \ \ A 71 A Ear-Eye Clonus Jaw Clonus Facial Clonus Head Nods Body Jerks W I T H D R A W A L S Y M P T O M S 63 however , was t he f i n d i n g t h a t t h e e l i c i t a t i o n o f MSs t y p i c a l l y p r o -duced by ECSs i s n o t n e c e s s a r y f o r i n c r e a s i n g t he s e v e r i t y o f t h e w i t h -d rawa l syndrome. T h i s i s c o n s i s t e n t w i t h t he r e p o r t t h a t p e r i o d i c a m y g d a l o i d s t i m u l a t i o n s can i n c r e a s e t h e s e v e r i t y o f a s ub sequen t a l c o h o l w i t h d r a w a l s yndrome, even when t he s t i m u l a t i o n i n t e n s i t i e s a r e t oo low t o e l i c i t MSs ( P i n e l , Van Oot & Mucha, 1975 ) . In t he s t u d y by P i n e l e_t a l_. ( 1 9 7 5 ) , a m y g d a l o i d s t i m u l a t i o n s wh i ch were n o t i n t e n s e enough t o e l i c i t MSs, p r o d u c e d a p o t e n t i a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome w h i c h was s l i g h t l y , bu t n o t s i g n i f i c a n t l y l e s s t h a n t h a t p r oduced by s t i m u l a t i o n s w h i c h r e l i a b l y e l i c i t e d MSs. T h i s same r e l a t i o n was a l s o o b s e r v e d i n t he f i n d i n g s o f E x p e r i m e n t 5. Thu s , p e r i o d i c ECSs can p o t e n t i a t e t he a l c o h o l w i t h d r a w a l syndrome even when the MSs a r e p h a r m a c o l o g i c a l l y b l o c k e d . The e l i c i t a t i o n o f MSs, however , does appea r t o c o n t r i b u t e t o t h e degree o f i n t e n s i f i c a t i o n i n some way. 64 D i s c u s s i o n In t he p r e s e n t e x p e r i m e n t s p e r i o d i c ECSs were f ound t o i n t e n s i f y an a n i m a l ' s r e a c t i o n t o s u b s e q u e n t ECSs and t o p o t e n t i a t e t he c o n v u l s i v e symptoms o f a l c o h o l w i t h d r a w a l . The i n t e n s i f i c a t i o n o f MSs by p e r i o d i c ECSs ( E C S - k i n d l i n g ) was shown t o be a f u n c t i o n o f t h e s i n t e i j - E C S i n t e r v a l and t he number o f ECSs , b u t was f ound n o t t o be a f f e c t e d by c u r r e n t i n t e n s i t y . F u r t h e r m o r e , when ECSs were a d m i n i s t e r e d a t 3-day i n t e r v a l s , t he e l i c i t e d MSs became p r o g r e s s i v e l y more s e v e r e ; whereas w i t h 1 -h r i n t e r v a l s , t h e MSs became p r o g r e s s i v e l y l e s s s e v e r e . When e l i c i t e d once e v e r y 3 d a y s , t he MSs i n c r e a s e d i n i n t e n s i t y w i t h each s u c c e s s i v e ECS; however , t h e r e were o n l y m i n o r i n c r e a s e s a f t e r t h e t e n t h s t i m u -l a t i o n . F i n a l l y , t h e magn i tude o f t h e change i n MS s e v e r i t y was t h e same a t e i t h e r 15 o r 75 mA even though t h e h i g h e r i n t e n s i t y c u r r e n t c o n s i s t e n t l y a p p e a r e d t o e l i c i t more s e v e r e MSs. These same v a r i a b l e s i n f l u e n c e d t he degree t o w h i c h p e r i o d i c ECSs p o t e n t i a t e d t h e r e a c t i o n t o s ub sequen t a l c o h o l w i t h d r a w a l ; ECSs a d m i n i s t e r e d a t 3-day i n t e r v a l s i n c r e a s e d t he i n c i d e n c e o f w i t h d r a w a l symptoms, whereas t h o s e p r e s e n t e d a t 1 -hr i n t e r v a l s d i d n o t . The i n t e n s i f i c a t i o n o f t h e a a l i c b h o T w i t h d r a w a l syndrome a l s o became more marked w i t h g r e a t e r numbers o f ECSs and was f ound t o be e q u a l l y as s e v e r e a f t e r ECSs o f e i t h e r 15 o r 75 mA. Two a d -,d . i t ibna i l l v a r i a b l e s were i n v e s t i g a t e d w i t h r e g a r d t o t h e E C S - i n d u c e d p o t e n t i a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome. Under t h e c o n d i t i o n s used i n t h e s e e x p e r i m e n t s s u b j e c t s were r e n d e r e d more s u s c e p t i b l e t o t he c o n v u l s i v e e f f e c t s o f a l c o h o l w i t h d r a w a l f o r a p e r i o d o f s e v e r a l 65 weeks a f t e r t h e l a s t o f a s e r i e s o f t e n ECSs. A l s o , t h i s i n t e n s i f i c a t i o n was f ound t o o c c u r even though t he MSs t y p i c a l l y e l i c i t e d by ECSs had been p h a r m a c o l o g i c a l l y b l o c k e d . The re a r e a number o f s i m i l a r i t i e s between t h e p r o g r e s s i v e changes i n MS s e v e r i t y o b s e r v e d d u r i n g t h e c o u r s e o f t h e p r e s e n t i n v e s t i g a t i o n s and t h o s e p r o d u c e d by a s e r i e s o f l o c a l b r a i n s t i m u l a t i o n s ( k i n d l i n g ) . F i r s t l y , i n bo th ca se s t h e r e i s a p r o g r e s s i v e i n c r e a s e i n t he s e v e r i t y o f t h e e l i c i t e d MSs. In t h i s r e g a r d , k i n d l i n g w i t h n e o c o r t i c a l s t i m u -l a t i o n s i s more l i k e k i n d l i n g p r o d u c e d w i t h r e p e a t e d ECSs; MSs a r e t y p i c a l l y e l i c i t e d on t he f i r s t s t i m u l a t i o n and become p r o g r e s s i v e l y more s e v e r e w i t h s ub sequen t s t i m u l a t i o n s . I t may be r e c a l l e d t h a t w i t h s u b c o r t i c a l s t i m u l a t i o n s , t h e r e a r e no b e h a v i o u r a l r e s p o n s e s t o t h e f i r s t few s t i m u l a t i o n s . S e c o n d l y , f o r b o t h E C S - k i n d l i n g , and k i n d l i n g w i t h a m y g d a l o i d s t i m u l a t i o n s , k i n d l i n g p r o g r e s s e s more r a p i d l y a t l o n g i n t e r v a l s , w i t h s h o r t i n t e r v a l s i n h i b i t i n g MSs. The c r i t i c a l i n t e r v a l s f o r p e r i o d i c ECSs seems t o be l o n g e r , h o w e v e r . A l t h o u g h a n i m a l s k i n d l e e f f e c t i v e l y a t 1-hr i n t e r v a l s w i t h a m y g d a l o i d s t i m u l a t i o n s ( R a c i n e , e_t a l _ . , 1 973 ) , w i t h ECSs i n t e r v a l s o f g r e a t e r than a day a r e r e q u i r e d . When ECSs a r e p r e s e n t e d a t 1-hr i n t e r v a l s , t h e r e i s a p r o g r e s -s i v e d e c r e a s e i n t he s e v e r i t y o f MSs. T h i r d l y , e i t h e r p e r i o d i c ECSs o r p e r i o d i c a m y g d a l o i d s t i m u l a t i o n s p roduce i n c r e a s e s i n s e i z u r e s u s -c e p t i b i l i t y w h i c h a r e n o t s p e c i f i c t o t h e a g e n t u s e d . T h u s , a n i m a l s k i n d l e d w i t h e i t h e r a gen t may be r e n d e r e d more s u s c e p t i b l e t o t he e f f e c t s o f o t h e r c o n v u l s i v e a gen t s as w e l l . In a d d i t i o n t o t h e e f f e c t s p r oduced by p e r i o d i c ECSs on t he a l c o h o l w i t h d r a w a l syndrome documented §6 h e r e , a n t e c e d e n t , p e r i o d i c ECSs have a l s o been f ound t o i n t e n s i f y t h e c o n v u l s i v e e f f e c t s o f f l u o r o t h y l ( P r i c h a r d , G a l l a g h e r , & G l a s e r , 1969 ) . P e r i o d i c a m y g d a l o i d s t i m u l a t i o n s , on t he o t h e r h a n d , have been r e p o r t e d t o i n t e n s i f y t h e c o n v u l s i v e r e s p o n s e t o a l c o h o l w i t h d r a w a l ( P i n e l , Van O o t , & Mucha, 1975) and m e t r a z o l ( P i n e l & Van O o t , 1975 ) . A f o u r t h a p p a r e n t s i m i l a r i t y between k i n d l i n g w i t h p e r i o d i c ECSs and a m y g d a l o i d s t i m u l a t i o n s i s t h a t t he e f f e c t s o f bo th a r e r e l a t i v e l y e n d u r i n g . Because o f t h e d i f f e r e n c e s i n t he measures u s e d , howeve r , i t i s d i f -f i c u l t t o make p r e c i s e c o m p a r i s o n s between t h e s e two a g e n t s . In t h e p r e s e n t i n v e s t i g a t i o n s , a f t e r t e n ECSs , t h e a l c o h o l w i t h d r a w a l syndrome was s i g n i f i c a n t l y i n t e n s i f i e d 3 week s , bu t n o t 6 weeks a f t e r t h e l a s t ECS. Goddard e t al_. (1969) used a s a v i n g s measure t o a s s e s s t he permanence o f a m y g d a l o i d k i n d l i n g and f o u n d a s a v i n g s o f 90% i n t h e number o f s t i m u l a t i o n s r e q u i r e d t o e l i c i t MSs a f t e r a 12-week s t i m u -l a t i o n - f r e e p e r i o d . A f i f t h and f i n a l s i m i l a r i t y i s t h a t t h e d e v e l o p -ment o f s p o n t a n e o u s l y r e c u r r i n g s e i z u r e s has been r e p o r t e d w i t h bo th p e r i o d i c ECSs ( E s s i g , e t a l_. , ( 1 9 6 1 ; P a c e l l a & B a r r e r a , 1945; P o l l a c k , R o s e n t h a l and Macey, 1963) and l o c a l b r a i n s t i m u l a t i o n s (Rovner & P i n e l , 1976; Wada & S a t o , 1974; Wada e t a l _ . , 1975 ) . These f i v e s i m i -l a r i t i e s s u g g e s t t h a t s i m i l a r mechanisms may u n d e r l i e k i n d l i n g w i t h t h e s e two a g e n t s . Thus i n s i g h t s i n t o t h e mechanisms u n d e r l y i n g t h e k i n d -l i n g phenomenon i t s e l f m i g h t be o b t a i n e d by a c o m p a r i s o n o f k i n d l i n g w i t h t h e s e two a g e n t s . M o r e o v e r , a t t e m p t s t o e x p l a i n t h e k i n d l i n g phenomenon must now a c c o u n t f o r more than t he f e a t u r e s o f a m y g d a l o i d k i n d l i n g . , e x c l u s i v e l y . 67 A l t h o u g h t h e r e s u l t s o f t h e p r e s e n t i n v e s t i g a t i o n s c anno t be a p -p l i e d d i r e c t l y t o c l i n i c a l s i t u a t i o n s , t h e y do s u g g e s t t h a t t h e u s ua l h a z a r d s o f t h e a l c o h o l w i t h d r a w a l syndrome m i gh t be p o t e n t i a t e d i n humans a f t e r a s e r i e s o f ECSs. The r e s u l t s a l s o s u g g e s t t h a t t h i s e f f e c t m i gh t be more marked a f t e r many ECSs have been a d m i n i s t e r e d a t r e l a t i v e l y l o n g i n t e r v a l s and t h a t t he e f f e c t m i gh t a l s o l a s t s e v e r a l weeks a f t e r t h e t e r m i n a t i o n o f t h e t r e a t m e n t s . F i n a l l y , t he f i n d i n g s s u g g e s t t h a t t h i s i n t e n s i f i c a t i o n m i g h t o c c u r even when t h e MSs o f t he ECSs have b e e n o p h a r m a c o l o g i c a l l y b l o c k e d . A l t h o u g h t h e s e e x p e r i -ments do n o t p r o v e t h a t such haza rdou s i n t e r a c t i o n s a r e a s s o c i a t e d w i t h c l i n i c a l ECS t r e a t m e n t s , t h e y do s t r e s s t h e need f o r r e s e a r c h c o n d u c t e d i n a c l i n i c a l s e t t i n g . A l t h o u g h t he a l c o h o l w i t h d r a w a l syndrome was t h e o n l y a g e n t m o n i t o r e d i n t he p r e s e n t i n v e s t i g a t i o n s , t h e r e i s n o t r ea son t o b e l i e v e t h a t t h e e f f e c t s o f t h e i n c r e a s e i n s e i z u r e s u s c e p t i b i l i t y i n d u c e d by p e r i o d i c ECSs a r e s p e c i f i c t o a l c o h o l w i t h d r a w a l . Many o f t h e d rugs f r e q u e n t l y a d m i n i s t e r e d t o p a t i e n t s u n d e r g o i n g ECS t r e a t m e n t s have m i l d l y c o n v u l s i v e e f f e c t s e i t h e r upon a d m i n i s t r a t i o n o r w i t h d r a w a l (Goodman & G i l m a n , 1969 ) . I t i s , t h e r e f o r e , p o s s i b l e t h a t a s e r i e s o f ECSs c o u l d p o t e n t i a t e t h e c o n v u l s i v e e f f e c t s o f one o f t h e s e a g e n t s . For e x a m p l e , t h e w i t h d r a w a l r e a c t i o n a f t e r a b r u p t d i s c o n t i n u a t i o n o f any one. o f t h e commonly -used d i b e n z a z e p i n e s (e_.c[. i m i p r a m i n e o r amy-t r i p t y l i n e ) c o u l d be i n t e n s i f i e d o r pe rhaps t he c o n v u l s i v e e f f e c t s o f h i g h doses o f t h e MAO i n h i b i t o r s (e_.£. i p r o n i a z i d e o r p a r g y l i n e ) m i g h t be p o t e n t i a t e d . Thu s , p o t e n t i a l l y c o n v u l s i v e a g e n t s w h i c h a r e r e l a t i v e l y 68 s a f e when a d m i n i s t e r e d i n s m a l l doses may, i n f a c t , e l i c i t o v e r t c o n v u l s i v e symptoms when a d m i n i s t e r e d f o l l o w i n g p e r i o d i c ECSs. The use o f t h e s e p o t e n t i a l l y c o n v u l s i v e d rugs s h o u l d , . t h e r e f o r e , be c a r e -f u l l y c o n t r o l l e d and m o n i t o r e d a f t e r a s e r i e s o f p e r i o d i c ECS a d m i n i -s t r a t i o n s . Even though a l l d rug t r e a t m e n t s a r e t y p i c a l l y d i s c o n t i n u e d d u r i n g t h e c o u r s e o f ECS t r e a t m e n t s , becau se t he e f f e c t s o f E C S - k i n d l i n g a r e r e l a t i v e l y e n d u r i n g s t h e p o t e n t i a l l y haza rdou s e f f e c t s o f p e r i o d i c ECSs may l a s t i n t o t h e n e x t d rug a d m i n i s t r a t i o n p e r i o d . An e x a m i n a t i o n o f t he c l i n i c a l ECS l i t e r a t u r e r e v e a l s s e v e r a l i n t e r e s t i n g p a r a l l e l s between t he c o n d i t i o n s d e s c r i b e d i n t h i s t h e s i s f o r maximal i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome by ECS and t h o s e w h i c h a r e assumed t o p r oduce o p t i m a l t h e r a p e u t i c e f f e c t s . F i r s t l y , i n E x p e r i m e n t 1 i t was f ound t h a t t he deg ree o f t h e i n t e n s i f i c a t i o n o f the a l c o h o l w i t h d r a w a l syndrome was the same a f t e r p e r i o d i c ECSs o f two d i f f e r e n t s u p r a t h r e s h o l d c u r r e n t i n t e n s i t i e s . I t i s g e n e r a l l y a c c e p t e d t h a t t h e t h e r a p e u t i c e f f e c t s o f c l i n i c a l ECSs l i e i n t h e e p i l e p t i f o r m e l e c t r o g r a p h i c d i s c h a r g e s and do n o t depend on t he l e v e l o f t h e c u r r e n t as l o n g as t h e s e ECSs e l i c i t s e i z u r e s ( c f . F i n k , 1974 ) . K a l i n o w s k y and H i p p i u s (1969) and O t t o s o n ( 1 9 6 0 ) , f o r e x a m p l e , have a r gued t h a t ECSs a t i n t e n s i t i e s w h i c h do n o t e l i c i t e l e c t r o g r a p h i c s e i z u r e s do n o t p roduce t h e r a p e u t i c e f f e c t s whereas a number o f d i f -f e r e n t s u p r a - m a x i m a l i n t e n s i t i e s ECSs do n o t d i f f e r i n t h e i r t h e r a p e u t i c e f f e c t s . S e c o n d l y , i n E x p e r i m e n t 2 t he i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome was p r o d u c e d o n l y when a n i m a l s r e c e i v e d ECSs p r e -s e n t e d a t 3-day i n t e r v a l s whereas ECSs p r e s e n t e d a t s h o r t e r i n t e r v a l s 69 p r o d u c e d no o b s e r v a b l e e f f e c t s on the w i t h d r a w a l syndrome. S e v e r a l a u t h o r s have recommended t h a t , f o r o p t i m a l t h e r a p e u t i c e f f e c t s , ECSs S h o u l d be p r e s e n t e d f r o m two t o t h r e e t i m e s p e r week (Abrams & F i n k , 1972; F r a n k e l , 1973; K a l i n o w s k y & H i p p i u s , 1969 ) . Abrams and F i n k ( 1 9 7 2 ) , f o r e x a m p l e , c o n c l u d e d t h a t t he i n t e r v a l s n e c e s s a r y f o r t h e g r e a t e s t b e h a v i o u r a l e f f e c t s a r e f r o m 3 t o 9 days w i t h a t l e a s t 24 t o 48 h r between each ECS. When ECSs a r e p r e s e n t e d a t i n t e r v a l s o f l e s s t han 1 h r , a v e r y t r a n s i e n t s t a t e o f " r e g r e s s i o n " i s p r o d u c e d i n w h i c h a g e n e r a l i n h i b i t i o n o f bo th t h e MSs and spon taneous b e h a v i o u r s i n g e n e r a l , i s p r o d u c e d ( K a l i n o w s k y & H i p p i u s , 1 9 6 9 ) , and t h e t h e r a -p e u t i c e f f e c t s a s s o c i a t e d w i t h d i s t r i b u t e d ECSs a r e a p p a r e n t l y a b s e n t (Abrams & F i n k , 1 972 ) . T h i r d l y , i n E x p e r i m e n t 3 , t h e deg ree o f t h e i n -t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome was f ound t o be an i n c r e a s i n g , n e g a t i v e l y - a c c e l e r a t e d f u n c t i o n o f t h e number o f a n t e c e d e n t ECSs. In c l i n i c a l p r a c t i c e , i t i s g e n e r a l l y a c c e p t e d t h a t t h e l a r g e r t h e number o f ECSs , t h e g r e a t e r t h e t h e r a p e u t i c e f f e c t s even though t h e e x a c t number o f s t i m u l a t i o n s i s assumed t o depend on the p a r t i c u -l a r p a t i e n t and d i s o r d e r ( c f . F i n k , 1974 ) . Foafc|fi:ly,S*herres"uTts'o6f E x p e r i m e n t 4 d e m o n s t r a t e d t h a t t he i n c r e a s e d s u s c e p t i b i l i t y t o c o n v u l s i v e w i t h d r a w a l symptoms p e r s i s t e d f o r s e v e r a l week s . Most c l i n i c a l r e p o r t s c l a i m t h a t t he t h e r a p e u t i c e f f e c t s o f r e p e a t e d ECSs a r e a l s o r e l a t i v e l y e n d u r i n g . F i n a l l y , i n E x p e r i m e n t 5, p h a r m a c o l o g i c a l p r e t r e a t m e n t d i d n o t s i g n i f i c a n t l y r e d u c e t he i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome. F r a n k e l (1973) and K a l i n o w s k y and H i p p i u s (1969) have a r g u e d t h a t t he same s e r i e s o f d rug p r e t r e a t m e n t s does n o t a l t e r t h e t h e r a -70 p e u t i c e f f e c t s o f r e p e a t e d ECSs. These f i v e p a r a l l e l s s u g g e s t t h a t t h e c o n d i t i o n s w h i c h p r oduce o p t i m a l t h e r a p e u t i c e f f e c t s a r e a l s o t h o s e w h i c h max im i ze t he h a z a r d s a s s o c i a t e d w i t h t he E C S - k i n d l i n g e f f e c t . M o r e o v e r , t h e p a r a l l e l s s u g g e s t t h a t t h e t h e r a p e u t i c and k i n d l i n g e f f e c t s may have a common b a s i s . However , u n t i l d i r e c t c o m p a r i s o n s a r e made between t h e s e two e f f e c t s and on t he p a r a m e t e r s t h a t i n f l u e n c e them, t h i s p o s s i b i l i t y i s l i t t l e more t han s p e c u l a t i o n . The re a r e two m a j o r i s s u e s c o n c e r n i n g t h e mechanisms u n d e r l y i n g the E C S - i n d u c e d i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome. The f i r s t i s w h e t h e r x the f i EeS shd i l r e S t l y i t nc f ce .a sen t thea se i zu re s u s c e p t i b i l i t y o f t h e a n i m a l o r w h e t h e r t h e i n t e n s i f i c a t i o n o f t he a l c o h o l w i t h d r a w a l syndrome i s m e d i a t e d by a change i n a l c o h o l t o l e r -a n c e . In o t h e r w o r d s , i s t h e a l c o h o l w i t h d r a w a l syndrome i n t e n s i f i e d because t h e a n i m a l s a r e more s u s c e p t i b l e t o t h e c o n v u l s i v e e f f e c t s o f a l c o h o l w i t h d r a w a l o r do t h e y s u f f e r more s e v e r e w i t h d r a w a l because t h e y r e c e i v e g r e a t e r amounts o f a l c o h o l ? The r e s u l t s o f E x p e r i m e n t 1 seemed t o s u p p o r t t he l a t t e r h y p o t h e s i s . In E x p e r i m e n t 1 a n i m a l s w h i c h r e c e i v e d ECSs were more t o l e r a n t q<f a l c o h o l and t hu s r e q u i r e d g r e a t e r amounts o f a l c o h o l t o p r oduce t he r e q u i r e d deg ree o f i n t o x i -c a t i o n . T h u s , i t was n o t s u r p r i z i n g when t h e s e a n i m a l s d i s p l a y e d more s e v e r e w i t h d r a w a l t h a n a n i m a l s r e c e i v i n g l e s s a l c o h o l . However , i n t he r e m a i n i n g f o u r e x p e r i m e n t s t h i s r e l a t i o n between a l c o h o l t o l e r a n c e and ECSs was n o t r e p l i c a t e d , i t w o u l d seem t h a t t h i s h y p o t h e s i s c o n -c e r n i n g t h e b a s i s o f t h e i n t e n s i f i c a t i o n e f f e c t i s v e r y u n l i k e l y . T h u s , a t t h i s p o i n t , t he most r e a s o n a b l e h y p o t h e s i s i s t h a t r e p e a t e d ECSs 71 d i r e c t l y i n c r e a s e t h e s u s c e p t i b i l i t y o f t he a n i m a l s t o t he c o n v u l s i v e e f f e c t s o f a l c o h o l w i t h d r a w a l . A s e cond m a j o r i s s u e c o n c e r n i n g t h e mechanisms u n d e r l y i n g t h e E C S - i n d u c e d i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome i s w h e t h e r t h i s e f f e c t i s a p r o d u c t o f k i n d l i n g p e r se o r r a t h e r a p r o d u c t o f o n l y t h e r e p e a t e d ECSs. The re a r e two f i n d i n g s i n t he p r e s e n t e x p e r i m e n t s w h i c h s u g g e s t t h a t k i n d l i n g may be t h e b a s i s o f t he i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome. In E x p e r i m e n t 2 , two groups o f a n i m a l s r e c e i v e d t he same number o f s t i m u l a t i o n s a t two d i f f e r e n t i n t e r v a l s and had the same number o f MSs, b u t o n l y t h e a n i m a l s i n t he g roup w h i c h d i s p l a y e d k i n d l i n g a l s o d i s p l a y e d an i n t e n s i -f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome. In E x p e r i m e n t 3, o n l y t h o s e a n i m a l s i n t he g roups w h i c h r e c e i v e d a number o f ECSs s u f f i c i e n t t o p r oduce a s i g n i f i c a n t deg ree o f E C S - k i n d l i n g d i s p l a y e d a s i g n i f i c a n t deg ree o f i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome. I f t h e h y p o t h e s i s was t r u e t h a t t h e i n t e n s i f i c a t i o n o f t h e a l c o h o l w i t h -d rawa l syndrome was a p r o d u c t o f E C S - k i n d l i n g , t h e n i t s h o u l d a l s o have been t r u e t h a t t h e a n i m a l s i n an ECS group w h i c h were k i n d l e d s h o u l d have been more r e s p o n s i v e t o a l c o h o l w i t h d r a w a l t han t h o s e a n i m a l s , i n t he same groups w h i c h d i d n o t k i n d l e . However , w i t h i n - g r o u p a n a l y s e s f a i l e d t o c o n f i r m t h i s p r e d i c t i o n . No s i g n i f i c a n t c o r r e l a t i o n s were f ound between any o f t h e measures a s s o c i a t e d w i t h E C S - i n d u c e d MSs and e i t h e r t he t o l e r a n c e o r w i t h d r a w a l m e a s u r e s , o r between any o f t h e t o l e r a n c e and w i t h d r a w a l - r e l a t e d measures ( a l l p _ ' s > 0 . 0 5 ) . T h u s , a t t h i s t i m e , i t i s u n c l e a r what t h e r o l e o f E C S - k i n d l i n g i s i n t he i n t e n s i -72 f i c a t i o n o f t h e a l c o h o l w i t h d r a w a l syndrome. These f i v e e x p e r i m e n t s have c l e a r l y e s t a b l i s h e d t h a t p e r i o d i c ECSs can p r oduce k i n d l i n g - l i k e e f f e c t s , and t h a t t h e s e p e r i o d i c ECSs can i n t e n s i f y t h e a l c o h o l w i t h d r a w a l s yndrome. However , t h e mechanisms u n d e r l y i n g t h e s e e f f e c t s a r e n o t y e t f u l l y u n d e r s t o o d . The r e s u l t s o f t h e s e f i v e e x p e r i m e n t s do p r o v i d e , g u i d e l i n e s f o r f u r t h e r i n v e s t i -g a t i o n s o f t he k i n d l i n g e f f e c t and t he i n t e r a c t i o n o f p e r i o d i c ECSs w i t h o t h e r " c o n v u l s i v e " a g e n t s . 73 R e f e r e n c e L i s t Abrams, R. M u l t i p l e ECT: what have we l e a r n e d ? In M. 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P h y s i o l . , 1962, 2 0 3 , 197 -200 . 78 A p p e n d i x I_ Mean V a l u e s f o r t h e A l c o h o l - t o l e r a n c e Measures f o r each Group r e c e i v i n g A l c o h o l i n each E x p e r i m e n t Group d I n i t i a l F i n a l T o l e r a n c e T o l e r a n c e Change i n T o l e r a n c e E x p e r i m e n t 1 C o n t r o l (12) Pseudo-ECS (9) 15-mA ECS (11) 75-mA ECS (13) 1.80 2.80 1.90 2 .70 2 .20 3.10 2 .30 2 .90 0.97 0.80 0.84 0.62 E x p e r i m e n t 2 C o n t r o l (13) 3 - d a y , ETOH (12) 1 - h r , ETOH (10) 2 .10 3.20 2 .10 3.30 2 .60 3 .10 1.15 1.22 1.06 E x p e r i m e n t 3 C o n t r o l (13) 20 ECSs (8) 10 ECSs (9) 6 ECSs (9) 3 ECSs (9 ) 2 .10 3.20 2 .30 3.20 2 .20 3.20 1.90 3.10 2 .00 3;oo 1.15 0 .98 0.96 1.02 1.04 E x p e r i m e n t 4 C o n t r o l (13) 2 - week d e l a y (9) 3 - week d e l a y (10) 6-week d e l a y (10) 10-week d e l a y (7) 2 .08 3.23 2 .20 3.16 2.36 3.44 2 .14 3.22 1.94 2 .97 1.15 0.96 0 .78 1.08 1.03 E x p e r i m e n t 5 C o n t r o l (9) ECS (12) ECS + Drugs (10) Drugs (8 ) 2.22 2.89 1.90 3.05 2 .23 3.21 2 .18 3.08 0.67 1.15 0 .90 0 .90 N o t e . V a l u e s a r e e x p r e s s e d i n g r a m s / k i l o g r a m . Numbers i n p a r e n t h e s e s a r e t h e number o f a n i m a l s p e r g r oup . 79 A p p e n d i x I I T a b l e o f S c h e f f e V a l u e s f o r t he I n d i v i d u a l , Be tween -g roup Compar i sons o f t he T o l e r a n c e - r e l a t e d Measures o f E x p e r i m e n t I Group Pseudo-•ECS 15-mA ECS 75-mA ECS I n i t i a l T o l e r a n c e 3 G o n t r o l Pseudo-ECS 15-mA ECS ( 1 , 19 ) = 2.17 ( 1 , 21 ) = 1 7 . 0 5 3 ( 1 , 18 ) = 4 .65 ( 1 , 23 ) = 1,20 = ( 1 , 22 ) = rt 1 9 . 2 2 9 6.83 0.52 F i n a l T o l e r a n c e 3 C o n t r o l Pseudo-ECS 15-mA ECS ( 1 ,19 ) = 0 .20 ( 1 , 21 ) = 1 5 . 7 6 a ( 1 ,18 ) = 1 6 . 2 1 a ( 1 , 23 ) = ( 1 , 20 ) = ( 1 , 22 ) = 4 . 33 4 .91 1.77 Change i n T o l e r a n c e 3 C o n t r o l Pseudo-ECS 15-mA ECS ( 1 ,19 ) = 2.87 ( 1 , 21 ) = 1.74 ( 1 , 18 ) = 0.11 ( 1 , 23 ) = ( 1 ,20 ) = ( 1 , 22 ) = 1 4 . 4 9 a 3.64 5.24 N o t e . Numbers i n p a r e n t h e s e s i n d i c a t e t h e deg ree s o f f reedom a £ < 0 . 0 1 . 

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