1976 - persinger, lafreniere & falter - psychopharmacology - oral taurine effects on inhibitory...

7/30/2019 1976 - Persinger, Lafreniere & Falter - Psychopharmacology - Oral Taurine Effects on Inhibitory Behavior - Respons

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Psychopharmacology49, 24 9-2 52 (1976) P s y ch ophhrmacology9 by Springer-Verlag1976

Oral Taurine Effects on Inhibitory Behavior"Response Trans ient s to S tep-Like Schedule ChangesM I C H A E L A . P E R S I N G E R , G Y S L A I N E F . L A F R E N It ~ R E, a n d H E R M A N F A L T E RPsychochemistry Laboratory, D epartments of Psycho logyand Chem istry, Laurentian Un iversity, Sudbury , Ontario, C anada

Abstract. R a t s h a b i t u a t e d t o D R L 6 -s s c h e d u le s t h a tr e q u i r e d r e s p o n s e i n h i b i t i o n i n o r d e r t o o b t a i n r e w a r dd i d n o t a l t e r t h e i r t o t a l r e s p o n s e s o r e f f i c ie n c y r a t i o s( r e s p o n s e / r e i n f o r c e m e n t ) w h e n p l a c e d a d l i b i tu m(ora l ly ) on 0 . 9 % tau r in e (1 .1 ___ 0 . 4 g /kg /2 4-h) re la t ivet o c o n t r o l s . I n t h r e e s e p a r a t e e x p e r i m e n t s , t a u r i n e -a d m i n i s t e r e d r a t s d i d s h o w s i g n if i ca n t ly p o o r e r a d -j u s t m e n t p r o f il e s ( h i g h e r r e s p o n s e / r e i n f o r c e m e n t r a -t i o s) d u r i n g t h e 1 5 m i n i m m e d i a t e l y f o l l o w i n g s te p -l i k e i n c r e a s e s i n i n h i b i t i o n t i m e d e m a n d t o D R L1 2 s . T h e e f f e c t w a s t r a n s i e n t a n d w a s n o t s i g n i f i c a n ti n s u b s e q u e n t s e ss io n s . T a u r i n e r a t s h a d b e e n h a b i t u a t -e d t o a D R L s c h e d u l e i n t e n d e d t o i n d u c e ' f r u s t r a t i o n 'b e f o r e t h e s t e p - c h a n g e d i d n o t d i f f e r f r o m t h e t a u r i n eg r o u p m a i n t a i n e d o n t h e n o r m a l D R L s c h e d u l e .N o s i g n if i ca n t d i ff e r e n c es w e r e n o t e d b e t w e e n t a u r i n ea n d c o n t r o l g r o u p s , e i t h e r b e f o r e o r a f t e r t a u r i n ea d m i n i s t r a t i o n o r b e f o r e o r a f t e r t h e s t e p - c h a n g ei n i n h i b i t i o n d e m a n d , w i t h r e s p e c t t o d e f e c a t i o n i nt h e t e st c h a m b e r , d a i l y f l u id c o n s u m p t i o n , b o d y w e i g h to r t o t a l r e s p o n s e s . W e c o n c l u d e d t h a t o r a l t a u r i n em a y i n h i b i t l e a r n i n g d u r i n g l a b il e p e r io d s o f a d j u st -m e n t f o l lo w i n g s u d d e n c h a n g e s o f in p u t d e m a n db u t d o e s n o t i n f l u e n c e a w e l l l e a r n e d o r e s t a b l i s h e dr e s p o n s e p a t t e r n . T h e s e r e s u l t s i m p l y t a u r i n e ' s r o l ei n t h e b r a i n a s a ' s t a b i l i z e r ' a g a i n s t s h o r t - t e r m i n p u tf l u c t u a t i o n s .Key words." R e s p o n s e i n h i b it i o n - T a u r i n e - D R Ls c h e d u l e - R a t - R e s p o n s e t r a n s i e n ts - D e f e c a t i o n- F r u s t r a t i o n - T e m p o r a l d i s c r i m i n a t i o n - S u d d e nr e i n f o r c e m e n t sc h e d u l e c h a n g e s.

T a u r i n e h a s b e e n s u g g e s t e d b y s e v e r a l a u t h o r s ( e . g . ,D a v i d s o n a n d K a c z a m a r e k , 1 9 7 1 ) a s a n i n h i b i t o r yt r a n s m i t te r o r m o d u l a t o r c a n d i d a t e i n th e c e n t r al

n e r v o u s s y s t e m . I n g e n e r a l , t a u r i n e a d m i n i s t r a t i o nh a s b e e n r e p o r t e d t o i n h i b i t b e h a v i o r a l ( B a s k i n e t al .,1 9 7 4 ; P e r s i n g e r e t a l . , 1 9 7 6 ) a n d n e u r o e l e c t r i c a l( V a n G e l d e r , 1 9 7 2 ; M u t ~ n i e t a l . , 1 9 7 4 ) p r o c e s s e s .W e d e c i d e d t o e v a l u a t e t h e e f f e ct o f o r a l t a u r i n e( a t a c o n c e n t r a t i o n t h a t d i d n o t a l t e r n o r m a l f l u i di n t a k e ) u p o n a c o m p l e x b e h a v i o r r e q u i r i n g r e s p o n s ei n h i b i t i o n a n d l e a r n i n g . A l t h o u g h v e r y h ig h d o s e s( 21 m m o l e / k g ) i n j e c t e d i n t r a p e r i t o n e a l l y ( i . p .) h a v eb e e n a s s o c i a t e d w i t h d e c r e a s e s i n f i x e d - r a t i o r e s p o n d -i n g ( T h u t e t a l . , 1 9 7 6 ) , s u c h b e h a v i o r a l c h a n g e s m a yo n l y r e f l ec t r e a c t i o n s t o a c u t e c h e m i c a l c o n c e n t r a t i o n ss i n c e s i m i l a r r e s p o n s e p a t t e r n s w e r e p r o d u c e d b yh i g h c o n c e n t r a t i o n s o f o t h e r s u b s t an c e s .

I f ta u r i n e i s a n i n h i b i t o r s u b s t a n c e , t h e n o n e m i g h te x p e c t , s i m p l i s t i c al l y , a f a c i l i t a t i o n o f r e s p o n s e i n h i -b i t i o n . H o w e v e r , w e s u s p e c t e d t h a t t h e r e p o r t e de f f ic a c y o f t a u r i n e a s a n i n h i b i t o r o f b e h a v i o r a l o rn e u r o e l e c t r i c a l p r o c e s s e s m a y b e b a s e d o n i t s p r o p e n -s i ty t o r e t a r d l a b il e C N S c h a n g e s i n t h e p r o c e s s o fa c q u i s i t io n o r c o n s o l i d a t i o n . F r o m t h i s p o i n t o f v ie w ,t a u r i n e w o u l d b e a C N S ' s t a b i l i z e r ' a g a i n s t s h o r t -t e r m i n p u t f l u c t u a t i o n s . N e w l y a c q u i r e d b e h a v i o r so r r e c e n t d e v i a t i o n s f r o m n e u r o e l e c t r i c a l h o m e o s t a s i sw o u l d b e s i g n i f ic a n t ly a f f e c te d b y t a u r i n e a d m i n i s t r a -t i o n , o l d e r b e h a v i o r s w o u l d n o t b e i n f l u en c e d a s m u c h .T h e i m p l i c a t i o n o f th i s s t a t e m e n t i s m o s t p r o v o c a t i v ew i t h r e s p e c t t o t a u r i n e ' s t h e r a p e u t i c u s e : w h e r e a sr e c e n t C N S c h a n g e s m a y b e i n h i b i t e d , u n d e s i r a b l e a n dw e l l e s t a b l i s h e d b e h a v i o r s o r c o n g e n i t a l a b n o r m a l i -t ie s m a y n o t b e c o r r e s p o n d i n g l y i n h i b i te d b y t a u r i n et r e a t m e n t s .

T o t e s t t h i s h y p o t h e s i s , w e e x p o s e d r a t s t o a b e h a v -i o r a l s i t u a t i o n t h a t r e q u i r e d w e l l l e a r n e d i n h i b i t o r yr e s p o n s e s e q u e n c e s a s w e ll a s a d j u s t m e n t t o n e w p a t -t e r n s o f i n h i b it i o n . T h e t a s k s e l e c te d w a s a D R L( d i f fe r e n ti a l r e i n f o r c e m e n t o f l o w r a t e o f r e s p o n d i n g )s c h e d u le , w h e r e i n a s u b j e c t m u s t p o s t p o n e r e s p o n d i n gf o r a r e q u i r e d i n t e r v a l o f t i m e i n o r d e r t o r e c e iv e


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250 Psychopharmacology 49 (1976)a re w a r d . A l t h o u g h s t e a d y - s t a t e r e s p o n s e p a t t e r n st y p i c a l l y a r e a c q u i r e d o v e r t i m e f o r t h i s sc h e d u l e ,t r an s i e n t re s p o n s e p h e n o m e n a c a n b e e v o k e d w h e ns u d d e n c h a n g e s i n th e i n h i b i t i o n t i m e a r e i n s t i tu t e d .S u c h s h o r t - t e r m r e s p o n s e p a t t e r n s c a n d i f fe r e n t ia t es u b j e c t p o p u l a t i o n s t h a t m o r e s t a t ic s c h e d u le p r o c e -d u r e s c a n n o t ( H a l a s z e t a l. , 1 97 0 ; P e r s i n g e r e t a l. ,1 9 74 ). W e s u s p e c t e d t h a t t a u r i n e a d m i n i s t r a t i o nw o u l d n o t i n f l u e n c e w e ll l e a r n e d r e s p o n s e s t o s ta t i cs c h e d u l e s , b u t w o u l d e x h i b i t s h o r t - t e r m e f f e c ts d u r i n gt r a n s i e n t p e r i o d s o f a d j u s t m e n t t o n e w i n h i b i t o r yd e m a n d s .

H o w e v e r , i f r a ts r e c e i v i n g ta u r i n e w e r e t o d i s p l a yl es s i n h i b i t o r y r e s p o n d i n g o n l y d u r i n g t h e s h o r t p e r i o df o l l o w i n g a s c h e d u l e ch a n g e , t h e n a r g u m e n t s c o u l d b ep o s i t e d t h a t t a u r i n e f a c i l i t a te s ' f r u s t r a t io n ' o r e m o -t i o n a l r e s p o n d i n g t o t h e s e e x t i n c t io n - l i k e p r o c e d u r e s .S u c h a p o s s i b i l i ty is n o t i m p r o b a b l e i n v ie w o f t h ee x t r a o r d i n a r i l y h i g h c o n c e n t r a t i o n s o f t a u r i n e n e u r o -h y p o p h y s i s a n d p o s s i b ly v en t r a l h y p o t h a l a m u s ( G u i -d o t t i e t a l . , 1 9 7 2 ; C r a b a i e t a l. , 1 9 74 ) . O n t h e o t h e rh a n d , i f t a u r i n e a n i m a l s w e r e e x p o s e d t o a s c h e d u let h a t w a s s i m i l a r t o t h e s c h e d u l e a s s o c i a t e d w i t h t h es u d d e n c h a n g e , t h e y s h o u l d s h o w l e s s f a i l u r e s o f i n -h i b i t i o n d u e t o ~ f a c t o r s d u r i n g t h i sp e r i o d . T h i s s t i m u l u s o p e r a t i o n , i n a d d i t i o n t o t h eu s u a l m e a s u r e m e n t o f e m o t i o n a l b e h a v i o r , i .e . , d e f e -c a t i o n , w a s i n c l u d e d i n t h e p r e s e n t e x p e r i m e n t a ld e s i g n .

O r a l a d m i n i s t r a t i o n o f ta u r i n e w a s u s e d s in c e ,u n l i k e o t h e r m o d e s , e . g ., i .p . i n j e c t i o n s , l e ss s tr e s sa n d h a n d l i n g a r t i f a c t s c o n f o u n d t h e d e s ig n . P a s s a g eo f ta u r i n e i n t o t h e a d u l t m a m m a l i a n b r a i n h a s b e e nd e s c r i b e d f o r th i s r o u t e ( U r q u h a r t e t a l ., 1 9 7 4) ,a n d m o s t i m p o r t a n t , i t w o u l d b e t h e m o s t l i k e l y r o u t eo f a d m i n i s t r a t i o n f o r h u m a n t r e a t m e n t . I n a d d i t i o n ,u n p u b l i s h e d d a t a f r o m o u r l a b o r a t o r y ( F a l t e r a n dP e r s i n g e r , 1 9 7 5) i n d i c a t e s i g n i f i c a n t l y e l e v a t e d f o r e -b r a i n a n d c e r e b e l l u m t a u r i n e l ev e ls ( + 1 1 G a n d+ 1 8 ~ , r e s p e c t i v e l y ) i n r a t s m a i n t a i n e d f o r 3 0 d a y s o n0 .9 ~ t a u r i n e s o l u t io n s d u r i n g D R L t r a in i n g .

M E T H O DIn three separate exper iments , 24 male Wistar s t rain rats (Rattusnorvegicus), 100, 150, or 230 days o f age when selected were usedas subjects (8 rats/experiment). Experim ents I, II , and III beganin June, September , and December , 1974, respectively. Beforetes ting, subjects had been m aintained in s ingle cages and grad ual lyreduced to 80 ~ f ree-feed body weight over a 21-day per iod. Subjectsin Exper iments I and I I I were maintained at this weight for therema inder of the s tudy ; weights of subjects in Exper iment I twere adjus ted for growth. Fol low ing three days o f cont inuousreinforcement t raining in s ingle-lever Lafay et te operan t chambers(housed in vent i lated masking noise .boxes) , the reinforcementschedule was changed to a DRL 6-s program. In this s i tuat ion,

the subject had to postp one lever responding at leas t 6 s in orderto receive a 35 mg N oyes foo d pel let reward. I f the t im e elapsedsince the la s t reward was less than 6 s when the next lever pressoccurred, then the next reward ava i labi l i ty was postpon ed anothe r6 s . Thi s s chedule w as maint a ined by automa t i c programmingequipment for the 2 tes t chambers used. H owever one o f thechambers was so constructed that 1 out of every 3 pel lets (anempir ical average) did not fal l into the del ivery through but fel lout of the subject 's reach b eneath the gr id f loor . This was cal led the'f rus t rat io n' DRL schedule. Four o f the subjects for each exper imentwere tes ted in this chamber .In al l 3 exper iments , subjects were maintained on the DRL6-s schedule for 24 to 26 consecutive daily 30-min sessions untils table basel ines were at tained for dai ly total rat ios of response(R )/tota l reinforcement (S+), i .e., R/S + ratios. A stable baselinewas def ined as not mo re than 10 ~ var iat ion over a 5-day per iodfor R/S rat ios between 2 and 3. Fou r of the animals in each ex-per ime nt (2 for each tes t chamber) were then given 0.9 ~ (0.07 M)taur ine solut ions in their graduated (ml) dr inking cyl inders . Pi lotdata indicated that this concentrat ion did not s ignif icant ly al terf luid consumption, a poten t ial ly imp ortant confounding v ar iablein food rew ard ope rant s tudies. W ith this concentration of taur ine,the average rat was expected to consume ab out lg/kg/24 h o ftaur ine. The other subjects received the vehicle ( tap water) . Theamount of ei ther taur ine solut ion or water consumed every daywas measured jus t before the dai ly tes t sess ion. Taur ine and w aterwere changed dai ly.

Af t er 7 days of t aur ine or w ater t rea tment , on what w as ca ll edthe 's tep day ' , the schedule was suddenly changed half -way throughthe normal s es s ion f rom a DR L 6- s t o a DR L 12- s s chedule for t heremaining 15 min, for each rat . The number of responses andreinforcements d isplayed before and af ter the 's tep-c hang e' in re-quired inhib i t ion t ime was recorded. D uring the late r 10 to 14 dai lysess ions , the schedule rem ained at DR L 12 s. Subjects were alwaystes ted in the same chambers , in the same orde r and between 09: 00and 13:00. Post-sess ional m easurements o f defecat ion in the cham-ber were taken for each rat . Al l analyses were completed by anIBM 3 60 -40 computer and checked by hand ca l cula t ions .

R E S U L T SF o r a n a l y s is p u r p o s e s , t h e s u b j e c ts w e r e d i v i d e d i n t o4 g r o u p s ( 6 r a t s / g r o u p ) ' t a u r i n e - n o r m a l D R L s c h e d u l e( T N ) , ta u r i n e - ' f r u s t r a t i o n a l ' D R L s c h e d u l e ( T F ) ,c o n t r o l - n o r m a l D R L s c h e du l e ( C N ) , a n d c o n t ro l -' f r u s t r a t io n a l ' D R L s c h e d u l e ( C F ) . T h e m e a n R / S +r a t io s a n d t h e i r s t a n d a r d d e v i a t i o n s f o r t h e T N , T F ,C N , a n d C F g r o u p s f o r th e 5 d a y s b e f o r e a n d 5 d a y sa f t e r t a u r i n e ( o r w a t e r ) a d m i n i s t r a t i o n a r e s h o w n i nF i g u r e 1. A 2 - w a y a n a l y s i s o f v a r ia n c e ( A N O V A )i n d i c a t e d n o s t a t i s t ic a l l y s ig n i f i c a n t d i ff e r e n c e s b e -t w e e n s c h e d u l e s o r t r e a t m e n t s ( F < 1 , d f = 1 / 2 0 ) .T h e m e a n changes in ratios a n d t h e i r s ta n d a r d d e v i a -t i o n s , c a l c u l a t e d b y d i v i d i n g t h e m e a n R / S + r a t i o sf o r e a c h s u b j e c t a f t e r th e t a u r i n e o r w a t e r t r e a t m e n t b yt h e m e a n R / S + r a t io s b e f o r e t h e t r e a t m e n t f o r t h eT N , T F , C N , a n d C F g r o u p s , w e r e 0 .9 0 _+ 0 .0 9 ,0 . 9 7 + 0 . 1 6 , 0 . 8 1 _ 0 . 2 5 , 0 . 9 8 + 0 . 1 2 , r e s p e c t i v e l y .H o w e v e r a 2 - w a y a n al y s i s o f v a r i a n c e ( A N O V A )i n d i c a t e d n o s t a t i s ti c a l l y s i g n i f ic a n t d i f f e re n c e s b e -t w e e n t r e a t m e n t s ( F < 1 ) n o r s c h e d u l e s ( F = 3 . 0 2 ;


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+

18

16

14

12

I0

8

6

4

2

18

16

14

12

I0

8

6

4

2

A9 Tau r ine ~ n= 6O C o n t ro l n = 6

B A S E L I N E J -S E S S I O N S

B9 T a u r in e n = 6O C o n t ro l n = 6

\

P O S T S T E P

Fig. 1. Mean total response/to tal reinforcement ratios (R/S +)from the separate experiments for rats that were maintained ontaurine or water orally during: pre-step DRL 6 s baseline sessions,the sudden mid-session step (.s-) from DR/_, 6 s to DR L :12 s, andpost-step (DRL 12 s) sessions. Animals in A (TN, CN) had beenexposed to normal DRL 6-s schedules while those in B (TF, CF)had been exposed to DRL 6-s schedules intended to induce'frustration'. Vertical bars indicate standard deviations

d f = 1 / 2 0 ; P < 0 .1 0 ). A 3 - w a y A N O V A w i t h o n em e a s u r e r e p e a t e d f o r t o t a l r e s p o n s e s e m i t t e d b e f o r ea n d a f t e r tr e a t m e n t a p p l i c a t i o n s h o w e d n o s i gn i fi c a n td i ff e re n c e s o n a n y f a c t o r. D e f e c a t i o n i n t h e c h a m b e rb e f o r e a n d a f t e r ( + 5 d a y s ) t a u r i n e o r w a t e r a d m i n i s -t r a t i o n a ls o w a s f o u n d b y 3 - w a y A N O V A n o t t o b es i g n i f i c a n t a t a n y l e v e l o f a n a l y s i s . R a t i o s o f d a i l yw a t e r c o n s u m p t i o n f o r t h e 5 d a y s b e f o r e a n d a f t e rt r e a t m e n t f o r t h e T N , T F , C N , a n d C F g r o u p s w e r e1.09 __ 0.17, 1.13 0.15, 1.12 _+ 0.27, an d 1.0 1 0 .05 . These d i f f e r ences were no t s i gn i f i can t . S i nce t her a t s d r a n k 2 5 - 5 0 m l o f f l u i d /d a y , c a l c u l a ti o n s de -m o n s t r a t e d t h e t a u r i n e s u b j e c t s w e r e c o n s u m i n g1 .1 0 . 4 g o f t a u r i n e / k g o f b o d y w e i g h t / 2 4 h .

T h e m e a n s a n d S . D . s f o r t h e R / S + r a t io s f o r d i f -f e r e n t g r o u p s b e f o r e a n d d u r i n g t h e 1 5 r a i n a f t e r th e

s u d d e n s c h e d u l e c h a n g e ( 5 ) o n t h e s in g l e s t e p s e s s i o na n d f o r p o s t - s t e p s e s s i o n s a r e s h o w n a l s o i n F i g u r e 1 .A 2 - w a y A N O V A i n d i c a te d o n l y a s i gn i fi c a n t t r e a t-m en t e f fec t (F = 7 .23 ; d f = 1/20, P < 0 .01 ; how eve r ,t h e h o m o g e n e i t y o f v a r i a n c e t e s t w a s s i g n i f i c a n t( P < 0 .0 1) . G r o u p v a r i a n c e t e st s i n d i c a t e d s i g n i fi c a n td i f f e re n c e s b e t w e e n t h e T N a n d T F g r o u p s ( F = 1 2.4 8,d f = 6 / 6 , P < 0 , 0 1 ) , a n d b e t w e e n t h e C N a n d C Fgrou ps (F = 176.80 , d f = 6 / 6 , P < 0 .001) , bu t no tb e t w e en th e T N a n d C N o r T F a n d C F g r ou p s .T h e 1 2 f r u s t r a t i o n c o n d i t i o n r a t s h a d s i g n i f i c a n t l yg rea t e r (F = 35 .48 , d f = 12/12, P < 0.001) g ro upv a r i a n c e t h a n t h e 1 2 n o r m a l c o n d i t i o n r a t s . W h e nc o m p a r i s o n s w e r e m a d e o n l y be t w e e n t h e c o n t r o la n d t a u r i n e g r o u p s ( w i t h h o m o g e n e i t y o f va r i a n ce )t e s t e d i n t h e n o r m a l D R L s c h e d u l e , m o r e s i g n i f i c a n td i f f e r ences were no t ed ( t = 11 .05 ; d f = 1/10, P

1976 - persinger, lafreniere & falter - psychopharmacology - oral taurine effects on inhibitory...

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