blocking vta sept fr da rats

7/28/2019 Blocking VTA Sept FR DA Rats

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136 Brain Research, 406 (1987) 13~,-146ElsevierBRE 12428

C at echo lam ines an d con di t ioned b lock ing : e f fec t s o fvent ra l tegm ent a l , s ept a l and f ronta l6 - hyd roxyd opa m ine l e s ions in rats*

R.D. Oades , J . -M. R ive t , K . Taghzout i , M. Kharouby , H . Simon and M. Le M o a lPsychobiologie des Com porternents Adaptat i fs , L N .S .E .R .M . 2 59, Bordeaux (France)

(Accepted 5 August 1986)Key words : Dopamine; Noradrenaline; Ventral tegmental area; Septum; Frontal cortex;Attention; Conditioned blocking; Active avoidance

The performance of rats on the conditioned blocking test of learned inattention was measured in a two-way shuttle avoidance taskafter sham and dopamine (DA)-depleting lesions of the frontal cortex, septum and ventral tegmental area (VTA). Animals weretrained on two sessions with tone and/or light as conditioned stimuli. One group was trained with both stimuli on both sessions. A sec-ond group was trained on the first session with one stimulus and on the second with both stimuli. The blocking of conditioning to theadded stimulus (b) was tested by presenting the stimuli (a and b) separatelY and measuring the blocking ratio (avoidance to b/a + b)and response latencies. No deficits were recorded on tests of sensory and motor ability. The VTA group alone showed a hyperlocomo-tot response to apomorphine treatment and did not acquire the avoidance response. The appearance of blocking in the septal groupwas delayed until the end of the test session. Blocking was mildly attenuated in the frontal group. DA levels were depleted by about80% and noradrenaline (NA) levels by, respectively, 20 and 50% in frontal and septal areas. This suggests that the level of DA activityor the balance between the activity of DA and NA in frontal and limbic regions can contribute to efficient associative conditioningand/or the normal ability of rats n o t to attend to a redundant stimulus.

INTRODUCTIONIn animals as diverse as rodents and primates da-

mage to the septum and frontal cortex is associated(inter alia) with impairm ents of selective informati onpr oc es si ng 16,22,23,28,3t,32,47,65. Depletion of dopamine(DA), a major neuroregulator in these areas largelyfound in terminals of neurons that project from theventral te gmenta l area (VTA) 78, affects both learn-ing9,24,69 and adj unct ive be hav ior (e.g. schedu le-in-duced licking or d ri nk in g ) 62 '63'67"69. But specific testsfor a selective attention deficit after DA depletionhave not been used, except in studies of the basalgang lia 13,73,76. The re fo re we use d on e of t hese tests,conditioned blocking performance, after D A deple-

tion with 6-hydroxydopamine (6-OHDA) in the fron-tal cortex, sept um and VTA to investigate the contri-bution of mesolimbic and mesocortical D A activity toselective inform ation processing.

Conditioned blocking belongs to a group of'learned inatte ntion' tasks where performance hasbeen claimed to reflect the function of selective at-tention mechanisms3'41. If an ani mal is tra ine d to re-spond to the simulta neous prese ntati on of two stimulifrom the start of conditi oning, it will respond to thepresentation of either stimulus alone at the end ofconditioning. In a blocking task if one stimulus (e.g. alight) predicts reinfo rceme nt (e.g. a footshock) a ndhas started to control response (e.g. avoi dance), thenwhen a second stimulus is presented along with the

* Some of these results were communicated in preliminary form at the E.B.B.S.-S.F.E.C.A. workshop, Strasbourg, 1985 and theAustralian Neuroscience Meeting, Perth, 1986.Correspondence: R.D. Oades. Present address: Department of Physiology, Flinders Medical Centre, Bedford Park, S.A. 5042, Aus-

tralia.0006-8993/87/$03.50 1987 Elsevier Science Publishers B.V. (Biomedical Division)


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13 7f i rs t a f t e r t h e s t a r t o f t r a in i n g ( e . g . t o n e a n d l i g h t) ,e v e n i f it is p e r f e c t l y c o r r e l a t e d w i t h r e i n f o r c e m e n t ,t h e s e c o n d s t i m u l u s w il l n o t b e c o m e a s s o c i a t e d w i t hr e i n f o r c e m e n t . I n th i s e x a m p l e a n a n i m a l t e s t e d w i t ht h e t o n e a l o n e w i ll t e n d n o t t o s h o w a n a v o i d a n c e r e -s p o n s e . T h a t i s t o s a y t h e a s s o c i a t i o n b e t w e e n t o n ea n d f o o t s h o c k ha s b e e n ' b l o c k e d ' . A n a t t e n u a t io n o fb l o c k i n g ( c o n d i t i o n i n g t o t h e s e c o n d s t im u l u s ) i s o p -e r a t i o n a l l y c a l l e d a n im p a i r m e n t o f a t t e n t i o n .

I m p a i r e d p e r f o r m a n c e o n t as k s o f le a r n e d i n a t t en -t i o n h a s b e e n r e p o r t e d a f t e r n o n - s p e c i f i c d a m a g e a n de l e c t ri c a l s t i m u l a t io n o f th e s e p t u m a n d h i p p o c a m -pus 1 '12 '43 '57-59 '66 '72 ( c o n t r a s t r e f . 2 1 ) . E v i d e n c e f r o mp h a r m a c o l o g i c a l i n t e r v e n t i o n s s u g g e s t s t h a t t h e s ei m p a i r m e n t s m a y a r i s e f r o m i n t e r f e r e n c e w i t h t h e i n -n e r v a t i o n o f t h e s e o r r e l a t e d a r e a s b y b i o g e n i ca m i n e s s u c h a s a c e t y l c h o l i n e45'71, se ro to ni n 74,75 andposs ib ly noradrena l ine ( for re f s . 14 , 39 , 40 ; aga ins tr e f s . 2 , 1 9 , 8 0 ) . T r e a t m e n t s t h a t r e l e a s e D A o r i n -d u c e D A s u p e r s e n s i t i v i t y a r e a l s o c l a i m e d t o i m p a i rp e r f o r m a n c e o n s u ch t a sk s 1 5 ' 7 3 ' 7 6 ' 8 3 . B u t t h e o n l y a r e as t u d ie d p o s t m o r t e m f o r c h a n g e s o f D A a c ti v it y w a st h e n . a c c u m b e n s . U p t o n o w a n a t t e n t i o n a l i m p a i r -m e n t a s a re s u l t o f a b n o r m a l a c t i v it y i n t h e m e s o f r o n -t al o r m e s o s e p t a l D A s y s te m h a s o n l y b e e n i n f e r r e df r o m p e r f o r m a n c e o n a l t e r n a t i o n t a sk s 9,69, h o l e b o a r dlea rn ing 48'49 and inc reases of beh av ior co l l a t e ra l t ot a sk pe r fo rm anc e (e .g . rea r in g an d tu rn ing) 54,69.MATERIALS AND METHODS

D a t a f r o m 40 m a le S p r a g u e - D a w l e y r a ts ( 2 6 0 -3 2 0 g ) d i v i d e d b e t w e e n 4 t r e a t m e n t a n d t w o l e a r n i n gc o n d i t i o n s a r e c o n s i d e r e d . A n i m a l s w e r e h o u s e d i n -d iv idua l ly in a c l ima te -cont ro l l ed room on a 12-h l igh t -d a r k c y c l e (2 2 C , 0 8 . 0 0 - 2 0 . 0 0 h l i g h t) w i t h f o o d a n dw a t e r a d l i b i t u m . A l l a n i m a l s w e r e w e i g h e d a n dh a n d l e d d a i ly .Treatment

T w o w e e k s p r i o r t o t r a i n i n g e a c h r a t r e c e i v e d a b i-l a t e r a l i n f u s io n o f 6 - O H D A ( 1 / 4 c o n t a i n i n g 4 /~ g, c a l -c u l a t e d a s b a s e ) o r i t s v e h i c l e ( 0 . 2 m g / m l a s c o r b i ca c i d / s a l i n e s o l u t i o n ) u n d e r c h l o r a l h y d r a t e a n e s t h e -s ia ( 4 % , 1 0 m l /k g ) o v e r 4 m i n t o t h e V T A ( t o o t h b a r+ 5 m m : 3 . 2 m m p o s t e r i o r t o t h e b r e g m a , 0 . 5 l a te r a lt o t h e s i n u s, 8 . 8 v e n t r a l f r o m t h e s k u l l ), s e p t u m ( 1 . 5A , 0 . 7 L , 5 . 8 V ) a n d f r o n t a l c o r t e x ( 3 . 3 a n d 3 . 8 A , 0 . 5

L , 4 . 0 V ) . T h e 3 0 - g a u g e c a n n u l a s w e r e l e f t i n p l a c ea f t e r i n f u s i o n . A n i m a l s w e r e p r e t r e a t e d w i t h 2 0m g / k g d e s m e t h y l i m i p r a m i n e ( P e r t o f r a n , C i b a - G e i -g y ) to p r o t e c t n o r a d r e n e r g i c ( N A ) t e r m i n al s .

A f t e r 3 0 d a y s a n i m a l s w e r e d e c a p i t a t e d , t h e b r a i n sw e r e d i s s e c te d r a p i d l y o n i c e a n d t h e s a m p l e s s t o r e da t - 8 7 C . O n d i s s e c ti o n , c o r o n a l s l ic e s w e r e t a k e n a t1 - 2 m m 27'34 c o r r e s p o n d i n g t o K o n i g - K l i p p e l c o o r d i -n a t e s 1 1 , 0 5 0 - 1 0 , 3 0 0 ( f r o n t a l c o r t e x , F ) , 1 0 , 3 0 0 -8 , 3 8 0 ( n . a c c u m b e n s , A c c ) a n d 8 3 8 0 - 6 3 0 0 ( n e o s t r i a -t u m , S T R a n d s e p t u m , S ) . S a m p l e s f r o m e a c h s i de o ft h e b r a i n w e r e a n a l y z e d b y h i g h - p e r f o r m a n c e l iq u i dc h r o m a t o g r a p h y ( H P L C ) ( P e r k i n - E l m e r , 5 -/ ~ C - 18r e v e r s e p h a s e ) w i t h g l a s s y c a r b o n e l e c t r o c h e m i c a ld e t e c t i o n ( B i o a n a l y t i c a l S y s t e m s , L C 4 B , 7 2 0 m V ) .A f t e r s o n i c a t i o n a n d a l u m i n a s e p a r a t i o n s a m p l e sw e r e r u n i n 0 . 1 M p h o s p h a t e b u f f e r ( p H 4 ) a t 3 20 0 p s ia n d 1 m l / m i n . Q u a n t i f i c a t i o n w a s n o n - l i n e a r b e l o w2 0 p g . A n i m a l s w i t h l e s s t h a n 5 0 % b i l a t e r a l o r w i t hu n i l a t e r a l D A d e p l e t i o n w e r e e l i m i n a t e d f r o m t h eana lys is o f d a ta .Testing apparatus

L o c o m o t o r a c ti v i ty w a s m e a s u r e d i n a c ir c u l a r c o r -r i d o r 1 2 c m w i d e a n d 1 7 0 c m l o n g , e q u i p p e d w i t h 4p h o t o c e l l b e a m s , a n d c o u n t s w e r e r e c o r d e d a u t o m a -t ic a l ly f r o m a p r i n t - o u t c o u n t e r l o c a t e d o u t s i d e t h ete s t ing roo m 33.

T w o - w a y a c t i v e a v o i d a n c e c o n d i t i o n i n g t o o k p l a c ei n a m e t a l s h u t t l e b o x ( C a m p d e n , 4 9 x 2 1 x 2 0 c m )w i t h a 2 -c m e l e c t r i f i e d h u r d l e i n t h e m i d d l e a n d f l o o rb a r s ( 1 . 5 c m a p a r t ) t h a t c o u l d b e e l e c t r i f i e d b y as c r a m b l e d 1 . 0 - m A A C c u r r e n t . A l i g h t s t i m u l u s ( 6 0l u x ) w a s l o c a t e d o n e a c h s i d e a n d a l o u d s p e a k e r f o rt h e d e l i v e r y o f t h e s o u n d s t im u l u s ( 9 0 0 H z , 8 6 d B ) o no n e s i d e . T w o s u c h b o x e s w e r e p l a c e d i n n e i g h b o r i n ga i r c o n d i t i o n e d c h a m b e r s ( c o n s t a n t 6 6 - d B w h i t en o i se ) in a s o u n d - a t t e n u a t e d r o o m . T h e p r o g r a m f o rd e l i v e r y o f t h e c o n d i t i o n e d s t im u l i ( C S ) ( m a x . d u r a -t i o n 1 0 s f o l l o w e d b y u n c o n d i t i o n e d s t i m u l u s ( U S ) ,m a x . 1 5 s ) w a s c o n t r o l l e d b y a P D P 8 D i g i t a l c o m p u t -e r . S t i m u l i w e r e s w i t c h e d o f f b y a v o i d a n c e ( 5 s ) o r e s -c a p e r e s p o n s e s w h i c h w e r e a u t o m a t i c a l l y r e c o r d e d .I n t e r s t im u l u s i n t e r v a l s v a r i e d r a n d o m l y i n 1 5- s s t e p sf r o m 1 5 t o 9 0 s ( m e a n 3 0 s) .

T e s t s f o r s o u n d a n d s h o c k s e n s i t i v i t y w e r e c o n -d u c t e d i n t h e s h u t t le b o x a n d t h e r e s p o n s e t o s t r o n g -l ig h t il l u m i n a t io n i n a b o x w i t h t w o c o m p a r t m e n t s ( 2 5


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x 2 3 x 4 0 c m ) c o n n e c t e d b y a n 8 x 8 c m o p e n i n g w i tha 1 5 0 W b u l b 3 5 c m o v e r o n e s i d e 3 ,w . T h r e e t e s t s f o ra k i n e s i a w e r e c o n d u c t e d o n a n o p e n b e n c h ( l a t e n c yt o r e m o v e f o r e p a w s f r o m a 3 - c m b l o c k ; l a t e n c y t o r o -t a t e o n a 6 0 i n c l i n e d g r i d ; l a t e n c y t o m o v e 4 p a w s a f -t e r r e l e a s e f r o m c u p p e d h an d s1 8 '2 1) .T r a i n i n g a n d t e s t i n g

T h e 3 t e s t s f o r a k i n e s i a w e r e p e r f o r m e d i m m e d i a -t e ly p r io r t o o p e r a t i o n a n d a g a i n j u s t b e f o r e t h e s t a rto f p o s t o p e r a t i v e c o n d i t i o n i n g . M e a s u r e s o f l a t e n c yw e r e t a k e n f o r e a c h t e s t w i t h a m i n i m u m o f 2 m i n b e -t w e e n e a c h t r i al . T h e m e d i a n v a l u e f o r e a c h t es t w a st a k e n f o r a n a ly s i s. O n t h e p o s t o p e r a t i v e t e st t w oV T A a n i m a l s w i t h l a t e n c ie s c o n s i s t e n t l y l o n g e r b y af a c t o r o f 1 0 w e r e e l i m i n a t e d a n d n o t t e s t e d f u r t h e r .T e s t s f o r s e n s i t i v i t y t o t h e U S a n d C S w e r e p e r -f o r m e d t h e d a y a f t e r t e st s f o r c o n d i t i o n i n g ( p o s t o p e r -a t iv e d a y 1 9 o r 2 4 , d e p e n d i n g o n i n i ti a l w e i g h t g a i n s ) .A v e r a g e t h r e s h o l d s f o r fl in c h , j u m p a n d v o c a l i z a t i o nr e s p o n s e s w e r e d e t e r m i n e d o n a s c e n d i n g a n d d e -s c e n d i n g s e r i es o f 8 c u r r e n t i n t e n si t ie s ( 0 . 0 5 - 1 . 0m A ) p r e s e n t e d t o t h e a n i m a l c o n f i n e d to o n e s i d e o ft h e s h u t t l e b o x H . S e n s it iv i t y t o s o u n d w a s m e a s u r e di n t h e s h u t t l e b o x b y p r e s e n t i n g 4 t r ia l s e a c h a t 6 l e v -e l s o f s o u n d i n t e n s i t y ( 8 6 , 8 3 , 7 9 , 7 2 , 6 8 d B ) i n 3 d e -s c e n d i n g / a s c e n d i n g s e r ie s o f i n te n s i ti e s . O n l y t h eu s u a l C S i n t e n s i t y w a s r e i n f o r c e d . T h e l a t e n c y o fa v o i d a n c e , e s c a p e , o r i n th e c a s e o f n o n - c o n d i t i o n e d

V T A a n i m a l s , b e h a v i o r a l r e s p o n s e s ( e . g . l o o k u p ,m o v e , r e a r ) w e r e r e c o r d e d . R e s p o n s i v e n e s s t o l ig h tw a s r e c o r d e d i n t e rm s o f t h e l a t e n c y t o e s c a p e f r o ma n d r e t u r n t o t he l i gh t c o m p a r t m e n t o f th e t w o - c h a m -b e r b o x i n w h i c h t h e a n i m a l h a d b e e n c a r e f u l ly p l a c e df a c in g a w a y f r o m t h e e n t r a n c e t o t h e d a r k s i d e . S e p a -r a t e m e a s u r e s f o r e n t r y l at e n c i e s w i th t w o a n d 4 p a w sw e r e t a k e n .

T h e c o n d i t i o n i n g p r o c e d u r e , m o d i f i e d a ft e r C r i d -e r 15, l a s t e d 6 d a y s s t a r t i n g o n p o s t o p e r a t i v e d a y 1 2 o r1 7 ( d e p e n d i n g o n w e i g h t ) ( T a b l e I ) . A n i m a l s w e r eb r o u g h t t o t h e t e s t r o o m e a c h d a y i n t h e i r h o m e c a g e .T w o a n i m a l s w e r e t e s t e d a t t h e s a m e t i m e . T h e o n ew o u l d b e g i v e n th e b l o c k i n g p r o c e d u r e , t h e o t h e rw o u l d b e a le a r n i n g c o n t r o l . O n d a y 1 o f th e p r o c e -d u r e b o t h a n i m a l s w e r e g i v e n 1 . 5 -h e x p l o r a t i o n e x p e -r i e n c e o f t h e s h u t tl e b o x w i t h o u t C S o r U S . O n d a y s 2a n d 3 o n e a n i m a l s t a r t e d t r a i n i n g w i t h t h e s i n g l e C S' a ' w h il s t t h e o t h e r c o n t i n u e d w i th f r e e e x p l o r a t i o n o ft h e b o x . B o t h r e c e i v e d t r a i n i n g w i t h t h e c o m p o u n dC S ' a b ' ( l ig h t a n d t o n e ) o n d a y s 4 a n d 5 . T h e l e a r n i n gc r i t e r i o n w a s 8 / 1 0 a v o i d a n c e s o n 3 s u c c e s s i v e b l o c k so f 1 0 t r ia l s . O n a t t a i n i n g c r i t e r i o n t h e s e s s i o n w o u l db e t e r m i n a t e d t o a v o i d t h e e f fe c t s o f o v e r t r a i n in g .T h e p r o g r e s s o f a s e s s io n w a s m o n i t o r e d o u t s i d e t h et es t r o o m o n t h e c o m p u t e r p r in t o u t . T h e r e w a s am a x i m u m o f 1 0 0 t r ia l s /d a y a n d a m i n i m u m o f 1 0 0 t ri -a l s i n 2 d a y s . O n d a y 6 t h e b l o c k i n g t e s t f o l l o w e d a ni n i ti a l s e s s io n o f 2 0 r e m i n d e r t r ia l s . T h e t e s t c o n s i s t e d

T A B L E ISumm ary: be havioural training and testing (conditioned blocking )

D ay 1Stage 1Day 2 Day 3

Stage 2 Stage 3Day 4 Day 5 Day 6

Blocking Explore/ CS a CS a CS ab CS ab CS abgroup habituation 100 trials 100 trials 100 trials 100 trials 20 trials reinforcedreinforced reinforced or reinforced or reinforced or thento criterion to criterion to criterion CS a(rain 50) (min 50) 20 trialsnon-reinforcedCS b20 trialsnon-reinforcedan dControl Explore/ Explore and Explore and CS ab CS ab CS abgroup habituation habituation habituation 100 trials 100 trials 12 trials reinforcedreinforced reinforced or sequence : a, b,to criterion a, ab, b, a, b, ab(min 50)


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o f 20 n o n - r e i n f o r c e d p r e s e n t a t io n s o f e a c h s t i m u l u sa l o n e , i n t e r s p e r s e d w i t h r e i n f o r c e d p r e s e n t a t i o n s o ft h e c o m p o u n d C S ( e . g . a , b , a , a b , b , a , b , a b , a) .

B i o c h e m i c a l d a t a w e r e a n a l y z e d w i th S t u d e n t ' s t -t e s t . B e h a v i o r a l d a t a w e r e s u b j e c t e d t o a n a l y s i s o fv a r i a n c e f o r r e la t e d s a m p l e s ( e . g . p r e - a n d p o s t o p e r -a t iv e te s t s; F r i e d m a n ) o r f o r i n d e p e n d e n t s a m p l e s( e .g . c o n d i t i o n e d b l o c k i n g ; K r u s k a l - W a l l i s ) b e f o r ep o s t h o c p a i r e d t es t in g ( M a n n - W h i t n e y ) , u n l es so t h e r w i s e s t a t e d .R E S U L T S

A n i m a l s w e r e n o t t e s te d u n ti l th e y h a d r e g a i n e dt h e i r p r e o p e r a t i v e w e i g h t . T h e r e w a s a 1 2 - o r 1 7 - d a yr e c o v e r y p e r io d a s s o m e a n i m a l s w i t h V T A l e si o n sw e r e s l o w t o r e g a i n w e i g h t .M o t o r t e s t s

T h e l a t e n c ie s o f r e s p o n s e o n t h e 3 te s t s o f a k in e s i af o r a n i m a l s t h a t c o n t i n u e d w i t h t h e c o n d i t i o n i n g p r o -c e d u r e ( n = 1 0 p e r g r o u p ) a r e s h o w n i n T a b l e I I .T a k i n g i n t o a c c o u n t p r e o p e r a t i v e r e s p o n s e l a t e n c ie st h e r e w e r e n o c o n s i s t e n t d i f f e r e n c e s b e t w e e n t h eg r o u p s a c r o s s t e s t s ( d r = 7 , Z2 = 1 1 , P 0 . 1 > 0 . 2 ) .S t i m u l u s s e n s i t i v i t y

T h e r e w e r e n o c o n s i s t e n t d i f f e r e n c e s b e t w e e ng r o u p s a c r o s s t h e c u r r e n t t h r e s h o l d s t h a t e l i c i t e d v o -c a l iz a t i o n , j u m p o r f l in c h r e s p o n s e s ( e . g . f l in c h ;m e a n c u r r e n t t h re s h o l d + S . E . M . : C , 0 .2 8 + 0 . 0 8 ;V T A , 0 . 3 3 + 0 . 0 7 ; S , 0 . 2 4 + 0 . 0 3 ; a n d F , 0 .2 4 + 0 . 0 5mA).

A v o i d a n c e s , o r b e h a v i o r a l r e s p o n s e s in t h e V T A

T A B L E I I IMe an la te nc y ( s ) to e x i t and re turn to an i l luminate d c hambe r( S . E . M . )Four lesion groups; C, sham control ; VTA, ventral tegmentalarea; S, septum; F, frontal cortex. S ee text for further de tails.

G r o u pC V T A S F

Exit 16.8 4.7 42 .5 9 .3 12 .0 2 .9 38 .8 9.7Return 37.2 6 .1 31.0 8 .8 65 .6 27.9* 39.5 16.8* Includes one example a t maximum latency (recording period300 s).

g r o u p ( e . g . s t o p a n d l o o k ) , w e r e r e c o r d e d a t t h e l o w -e s t s o u n d s e n s it i v it y o f 6 8 d B ( w h i t e n o i s e 6 6 d B ) f o ra ll an i m a ls e x c e p t o n e f r o m t h e V T A g r o u p , o n e s e p -t a l a n d t w o s h a m - c o n t r o l a n i m a l s . F u r t h e r a n a l y s i s o fr e s p o n s e l a t e n c i e s r e v e a l e d n o c o n s i s t e n t d i f f e r e n c e sb e t w e e n g r o u p s . A m e a s u r e o f t h e r e a c t iv i t y t o l ig h tw a s p r o v i d e d b y th e l a t e n c i e s t o l e a v e a n d r e t u r n t o ab r ig h t ly i l lu m i n a t e d c h a m b e r ( T a b l e I I I ) , r e c o r d e da f t e r a v o i d a n c e c o n d i t i o n i n g . N e i t h e r a n a n a l y s i s f o rt h e 4 l e s io n g r o u p s ( Z2 = 5 . 4 ) n o r o n e t a k i n g i n t o a c -c o u n t t h e d i f f e r e n t c o n d i t i o n i n g e x p e r i e n c e ( d f = 7 ,Z2 = 2 . 6 ) s h o w e d t h e r e t o b e a n y i n t e r g r o u p d i f f e r -e n c e s .L e a r n i n g

N o a n i m a l w i t h V T A d a m a g e a c q u i r e d a c o n d i -t i o n e d a v o i d a n c e . S e v e r a l a n i m a l s i n t h is g r o u ps h o w e d b u t o n e a v o i d a n c e r e s p o n s e i n 2 0 0 t r i a l s .T h e r e w e r e n o 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 r a t e o fa v o i d a n c e a c q u i s i t i o n b e t w e e n a n i m a l s w i t h s h a m ,

T A B L E I IAk in e s ia t e st s: me a n la te nc y ( s ) to r e mov e fore paw s f ro m a b loc k ( fore paw) , to ro ta te 18IT on an inc l ine d gr id ( ro ta t ion) an d to in i tia tel o c o m o t io n ( m o v e) p r e - a n d p o s t o p er a t iv e l y ( S . E . M . )Four lesion groups: C , sham co ntrol ; VTA , ventral tegmentai a rea; S, septum; F , frontal cortex. S ee text for further detai ls .

G r o u pC V T A S FP r e P o s t P r e P o s t P r e P o s t P r e P o s t

~ r e p a w 1 . 8 0 . 3 2 . 7 0 . 6 1 . 7 0 . 2 2 . 9 0 . 6 1 . 3 0 . 2 2 . 2 0 . 9 1 . 8 0 . 8 1 . 6 0 . 3R o ta ti on 1 1 . 5 2 . 3 7 . 4 0 . 9 8 . 2 1 . 8 1 0 . 3 1 . 8 8 . 2 1 . 9 6 . 0 1 . 2 1 0 . 7 2 . 3 6 . 4 1 . 2M o ve 4 . 8 1 . 0 3 . 2 0 . 5 5 . 7 0 . 8 4 . 5 1 . 1 2 . 7 0 . 6 1 . 6 0 . 5 3 . 8 0 . 6 2 . 1 0 . 5


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E ~ a b t r a i n i n ga / a b t r a i n i n g

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T

1Fig. 1. A: mean number of blocks of 10 tria ls to atta in 8/10avoidance responses to a s ingle CS (shaded column) or thecompound light/tone CS (open column) in a two-way shuttlebox . B: mean (+ S .E .M .) avo idance responses to CS b /a + b(blocking ratio) after training in the blocking condition (CSa /ab : (open co lumn)) o r in the norm al lea rn ing condi t ion withCS ab (shaded column), n = 10 per grou p, 5 per conditio n. C,sham control; S, septal group; F, f rontal group: *P < 0.05.

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a b a / a b a b a / a b a b a / a bG r o u p C S F

Fig. 2. The mean response latencies for the firs t (1-3) and last(17-20) 3 te s t p resen ta t ions o f the non-re in forced CS b wereca lcu la ted fo r an imals t ra ined in the b lock ing (a /ab) and lea rn-ing con tro l cond i tions (ab) . The medians o f these la tenc ies a reshown for con tro l (C) , sep ta l (S) and fron ta l (F) an imal g roupsin each condition. In each column are shown the response la-tenc ies to the mos t recen t 3 re in forced p resen ta tions o f CS ab .Median o f the mean te s t avo idance la tenc ies to CS a a f te r aband a/ab training were: C , 3.4, 4.6; S, 3.6, 4.4; and F , 4.7, 4.8 s.*P < 0.05, **P < 0.02.

s e p t a l o r f r o n t a l l e s i o n s , b u t a c q u i s i t i o n w a s f a c i l i -t a t e d f o r a n i m a l s p r e s e n t e d w i t h t h e c o m p o u n d C S ' a b 'w i t h r e sp e c t t o t h o s e p r e s e n t e d w i t h o n l y t h e t o n e o rt h e l i g h t at t h e s t a r t o f c o n d i t i o n i n g ( Z2 = 16 .8 , P

blocking vta sept fr da rats

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