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E L S E V I E R Behavioural Brain Research 85 (19 97) 27-35

BEH VIOUR LBR IN

RESE RCH

R e s e a r c h r e p o r tA nxie ty- and ac t iv i ty -re la ted e f fects o f d iazepam and chlordiazepox ide in

the rat l ight /dark and dar k/ l ight tes tsF . C h a o u l o f f , M . D u r a n d , P. M o r m ~ d e

G d n ~t iq u e d u S t r e s s I N S E R M C J F 9 4 -0 5 I N R A U n i v e rs i t~ B o r d e a u x I 1 1 4 6 r u e L ~ o S a i g n a t 3 3 0 7 6 B o r d e a u x C d de x F r a n c eReceiv ed 15 May 1996; revised 31 July 1996; accep ted 31 July 1996

Abstract

We have inves tiga ted, throu gh fac tor analysis, anxie ty- and ac t ivi ty-re la ted variables in ra ts p laced in the l ight /dark box. T hus ,vehic le- , d iazepam (DZ )- , a nd ch lordiazepoxide (CDP) -t rea ted ra ts were submit ted 30 min la ter to 5-min l ight /dark or dark/ l ighttests (initial placements in light or dark, respectively). Following this test, the animals were tested for 5 min in an automatedac t iv i ty mon i to r . Dos es o f D Z (0 . 75 -3 . 0 mg/kg) and C D P (2 . 5 -10 . 0 mg/kg) we re ba s ed on p re l imina ry evidence fo r 1 .5 mg/k gof DZ and 5 mg /kg of CD P b eing anxiolyt ic in the e levated plus-maze. In the l ight /dark test , D Z increased the num ber o f visi tsto and d ura t ion in the l igh t compar tmen t , and locom oto r a c tiv i ty in the da rk compar tmen t ; m oreove r , DZ dec reas ed the l a t encyto enter the l ight com partm ent . T hese effec ts were, how ever, s ignificant for the highes t dose only. Al though CD P yielded s imilarbehavio ura l e ffec ts, only the highes t dose had a s ignificant e ffect , namely, on la tency to en ter the l ight s ide . Converse ly , none ofthe oth er variables were benzodiazepine-sensi tive. Loc om otion in the ac t ivi ty cages was decreased by DZ and CD P, an effec ts ignif icant for the highes t doses of benzodiazepines (dark/ l ight tes t condi t ion only) . In both tes ts , fac tor analyses revealed ananxie ty-re la ted fac tor ( to w hich a ll variables re la ted to the vis its in the l ight and par t o f the locomotio n in the dar k con tr ibuted ) ,and an ac t iv i ty - re l a t ed fac to r (upon which the l a tency to en te r the da rk and pa r t o f the locomot ion in the da rk loaded) in thel ight /dark tes t only. I t i s sugges ted tha t a l though the l ight /dark and dark/ l ight tes ts capture an approach/avoidance dimens ion,DZ and CD P are mo re effec tive in the form er tes t. C om pared to the l ight /dark test , however, the plus-maze ma y be more sens i tiveto the anxiolyt ic e ffec ts of DZ and CDP.Keywords: Light/dark test; Dark/light test; Elevated plus-maze; Anxiety; Locomo tor activity; Factor (principal compo nent) analysis; Diazepam;Chlordiazepoxide; Rat

1 . I n t r o d u c t i o nA n i m a l m o d e l s o f a n x i e t y m a y b e r o u g h l y s u b d i v id e d

i n t o t w o c a t e g o r i e s , n a m e l y c o n d i t i o n e d a n d u n c o n d i -t i o n e d ( o r s p o n t a n e o u s / e t h o l o g i c a l ) t e s t s [ 2 6 ] .U n c o n d i t i o n e d t e st s, s u c h a s t h e e l e v a t e d p lu s - m a z e , t h el i g h t / d a r k b o x o r t h e s o c i a l i n t e r a c t i o n t e s t , h a v e b e e nt h e s u b j e c t o f a g r e a t d e a l o f w o r k , d u e t o t h e i r s i m p l i c it yo f u s e [ 1 7 ] . H o w e v e r , b e c a u s e t h e s e t e s ts r e l y u p o n t h ee x p l o r a t i o n o f a n o v e l e n v i r o n m e n t , t h e b e h a v i o u r a le f fe c ts o f t h e t r e a t m e n t s , w h e t h e r p h a r m a c o l o g i c a l o rp h y s i o l o g i c a l , m a y b e c o n t a m i n a t e d b y t h e i r i n t r i n s i ce f fe c ts u p o n l o c o m o t o r a c t i v it y [ 1 1 ,1 3 , 1 7 , 2 6 ] . I n a na t t e m p t t o u n d e r s t a n d t h i s p o s s i b l e e x p e r i m e n t a l c o n -* Corresponding author. Tel/fax: 33) 5757-1087;E-mail: [email protected]

f o u n d i n g , n u m e r o u s s t u d i e s h a v e a d d e d a n a n a l y s i s o ft h e s e l e ct iv e ef f ec t s o f t h e t r e a t m e n t s o n l o c o m o t o ra c t i v i t y ( e . g . , b y m e a n s o f a c t i v i t y c a g e s [ 9 ] ) . B e s i d e s ,m o r e r e c e n t w o r k s u g g e s t s t h a t f a c t o r ( o r p r i n c i p a lc o m p o n e n t ) a n a l y s i s m a y b e a n o t h e r m e a n s t o d e t e c tl o c o m o t i o n - d e p e n d e n t ( v s . l o c o m o t i o n - i n d e p e n d e n t )b e h a v i o u r s w i t h i n a t e s t [ 2 , 1 0 , 1 2 , 2 7 ] . T h i s f a c t o r i a la p p r o a c h r e li e s o n t h e g r o w i n g b o d y o f e v i d e n c e t h a tt h e r e s p o n s es o f a r o d e n t t o a n o v e l e n v i r o n m e n t d on o t b e l o n g t o a s i n g l e b e h a v i o u r a l d i m e n s i o n , t h u sl e n d i n g s u p p o r t t o t h e o r i g i n a l h y p o t h e s i s o f A r c h e r [ 1 ] .T h a t i s , w i t h i n o n e t e s t , s u c h a s t h e e l e v a t e d p l u s - m a z ew h e r e t h e r o d e n t m a y e x p l o r e ' u n s e c u r e ' o p e n a r m sa n d / o r ' s e c u r e ' d o s e d a r m s [ 2 0 ] , m u l t i f a c t o r i a l a n a l y s e sh a v e b e e n a b l e t o d e t e c t a t l e a st t w o o r t h o g o n a l c o m p o -n e n t s , o n e l i n k e d t o l o c o m o t o r a c t i v i t y a n d t h e s e c o n dl i n k e d t o a p p r o a c h / a v o i d a n c e c o n f l i c t s ( i . e . , a n x i e t y ) .

0166-4328/97/$17.00 Copyr ight 1997 Elsevier ScienceB.V. All rights reservedP I I S0166-4328 (96 ) 00160-X


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28 F Chaou lof f et al . / Behavioural Brain Research 85 1997) 2 7-35For example, the number of entries in the closed arms,and, to a lesser extent, the number of total arm entriesbelong to the first dimension, whereas the percent ofopen arm entries and the percent of time spent thereinhave been shown to belong to the second dimension[10,12,22].

Another, complementary, paradigm is to test rodentssuccessively in different novel environments, with partic-ular attention paid to locomotor activity [2,12,21,27].For instance, such a procedure has confirmed that thenumber of closed arm entries in the elevated plus-mazeloads on one axis, together with locomotor activity fromother tests.

Besides the elevated plus-maze, the light/dark boxalso termed black and white box) has been widely usedwith mice [7-9,14,15,19,24,28], and to a lesser extentwith rats [4,5,16,18,25] for the evaluation o f anxiety.Thus, the apparatus consists of two connected compart-ments, one being large, white and brightly lit, and thesecond being small, black and dimly lit. The test is thusbased on the conflict between the exploration of thewhole apparatus and the aversion of the brightly litcompartment [8,9]. Some authors [7-9,14,15,18,19,24,28], but not all [16,25], have shown that this testis sensitive to benzodiazepines, i.e., benzodiazepines mayincrease the number of visits and/or the time spent inthe brightly lit area while decreasing [7] or not [24,28]the exploration of the dark compartment. In addition,repeated benzodiazepine treatment has been shown toincrease the percent of time spent by mice in the lightcompartment [23]. In keeping with the possibility thatthese behaviours are confounded by changes in locomo-tor activity, some authors have used the lack of effectof benzodiazepines either on total locomotion squarescrossed in light and dark) or on activity counts asevidence for an intrinsic anxiolytic effect of the benzo-diazepines [7-9,14,18,19,28]. However, the possibilitythat some of the aforementioned behaviours measuredin the light/dark test are partly or totally linked to thelocomotor effects of the benzodiazepines has never beenaddressed through factor analysis. This lack of informa-tion thus prompted us to dissect out anxiety- andactivity-related variables in the light/dark test.

A first series of experiments in the elevated plus-mazehelped to define the doses of each benzodiazepine to beused thereafter in the light/dark box, and to comparethereafter the sensitivity of these two tests to the benzo-diazepines. Then, we have examined the effects of diaze-pam DZ, 0.75-3.0 mg/kg) or chlordiazepoxide CDP,2.5-10.0mg/kg) on anxiety- and locomotion-relatedbehaviours by factor analysis. The assessment of thelocomotion-related axis was provided by testing the ratsin activity cages immediately after the light/dark boxtests. In addition, because some studies using thelight/dark box have involved the initial placement ofthe rats in the dark compartment instead of placing

them in the light one), a parallel experiment was run todetermine whether placing the rats initially in the lightcompartment referred to as light /dark tests) or in thedark comp artment referred to as dark/light tests) wouldaffect the distribution of the behavioural variablesamong putative orthogonal factor s).

2 . M a t e r i a l s a n d m e t h o d s2.1. Animals

Male Wistar rats IFF A CREDO, Les Oncins,France), weighing 180-200 g upon arrival, were used inthis study. Rats were housed 4 per cage in an animalquarter maintained at 22+ IC with a 12-h light-darkcycle lights on at 07.00 h) with food and water adlibitum. Rats weighed 200-220 g at the onset of theexperiments which were conducted between 14.00 and17.00 h). All rats were used on ly once, 10-14 days aftertheir arrival.2.2 . E levated p lus m aze

In the first series of experiments, the effects of1.5 mg/kg DZ and 5 mg/kg CDP were examined in theelevated plus-maze test. As already described [4,5], theapparatus was constructed of opaque Perspex, with fourelevated arms 66 cm from the floor, 45 cm long and10 cm wide). The arms were arranged in a cross, withtwo opposite arms being enclosed by 50-cm high walls.The two other arms were open, having at their intersec-tion a central 10 x 10 cm square platform giving accessto all arms. Because the floor surfaces were black andsmooth, 0.5-cm ridges bordering the open arms wereadded to provide an additional grip. The illuminationabove the central platform was 70 lux. Each rat wasplaced in the central square facing an open arm, andthe number onto and the time spent with the fourpaws) on each arm scored for 5 min by means of avideo-recording device.2.3. Light~dark and dark~light tests

The light/dark box, constructed of opaque Perspex,has been described previously [4, 5]. Briefly, the box wasdivided into two compartments, one 27 x 27 x 27 cmhigh, painted white and illuminated by a 60-W whiteincandescent bulb 900 lux), and the other27 x 18 x 27 cm high) painted black and lit by a 60-Wred incandescent bulb 70 lux). Both white and red

bulbs were located 37 cm above the floor. The twocompartments were connected by a small opening7 x 7 cm high). The white side floor was marked off innine 9 x 9 cm, squares, and the black side o f the floordivided into six 9 9 cm, squares. The box was placed


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30 F Cha oulof f et aL / Behavioural Brain Research 85 1997) 2 7-35

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IZ~]V e h i c l eI ~ ] D Z ( 1 . 5 m g / k g )~ C D P ( 5 m g /k g )

6 o453o15

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t he l a t e nc y to e n t e r t he da r k a f t e r p l a c e m e n t in t he l i gh t,w he r e a s on ly D Z inc r ea se d , i n a dose - de pe nde n t m a nn e r( H = 10 .9 , P = 0 . 01 3 ) , t he num b e r o f squa r e s c r o s se d i nthe da r k ( a l t hough a s im i la r t e nde nc y c ou ld be obse r ve din CDP- t rea ted ra ts ; Table 2) .

3 4 E f fec t s o f b en zo d ia zep in es in th e d a rk~ l ig h t t e s tN one o f t he be ha v iou r s e xa m ine d in t he da r k / l i gh tt e s t ( num be r o f e n t r i e s i n t he l i gh t , du r a t i on o f t he sevisi ts , la tency for the f i rs t v is it , loc om ot io n in the d a rk)proved sens i t ive to DZ or CDP (F ig . 2 , Tables 1 and 2) .

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3 5 E f fec t s o f b en zo d ia zep in es in th e a c t iv i t y ca g esT h e n u m b e r o f b e a m b r e a k s w a s d e c r e a s e d b y D Zw he the r r a t s w e r e subm i t t e d 5 m in be f o r e ha nd tol ight /d a rk te s ts or da rk / l ight te s ts (Table 2) . How ever ,th is obse rva t ion reached s igni f icance in DZ- t rea ted ra tst h a t u n d e r w e n t t h e d a rk / l ig h t ( H = 1 2.9 , P = 0 . 0 0 5 ) , b u tno t t he l i gh t /da r k t e s t . I n t he C D P e xpe r im e n t s , r a tg r oups w e r e f ound to be d i f f e re n t , i nde pe nde n t ly o f t hen a t u r e o f th e t e s t in t h e l i g h t/ d a rk b o x ( H = 8 .2 , P =0 . 0 4 3 a n d H = 1 3 . 9 , P = 0 . 0 0 3 f o r t h e l i g h t / d a r k a n ddark / l ight te s ts , r e spec t ive ly) (Table 2) . P os t -hoc te s tsr e ve a l e d , how e ve r , t ha t on ly t he h ighe s t dose s o f D Za nd C D P a dm in i s t e r e d be fo r e t he da r k / l i gh t t e st s y ie lde dsignif icant results (Table 2) .

Fig. 1. Respective effects 30 min befor ehand) of diazepam DZ,0.75 mg/kg, i.p.) and chlordiazepoxide CDP, 5 mg/kg, i.p.) on thepercent of entries in the open arms, the percent of time spent in theopen arms, and the total open + closed) number of arm entries in ratssubmitted to a 5-min elevated plus-maze test. Values are themean +__SEM of 10 rats. *P < 0.05 and *** P < 0.001 for the com pari sonwith vehicle-injected rats.

3 3 E f fec t s o f b en zo d ia zep in es in th e lig ht~da rk te s tI n t he e x pe r im e n t s i nvo lv ing D Z a dm in i s t r a t i on , r a t sd i sp l a ye d a t r e a tm e n t e f fe c t on t he nu m b e r o f e n t ri e s int h e l i g h t ( H = 7 . 9 , P = 0 . 0 4 9 ) , t h e i r d u r a t i o n ( H = 8 . 3 ,P = 0 . 0 39 ) , a nd the l a t e nc y to e n t e r ( r etu r n ) in t he li gh t(H = 8 .2 , P = 0 .041 ) (F ig . 2 , Table 1 . Al th ou gh D Z t r ig-ge r e d dose - de pe nde n t c ha nge s i n t he a f o r e m e n t ione dbe ha v iou r s ( c om pa r e d t o ve h i c le ) , on ly 3 m g /kg o f D Zpro ved s igni f icant ly e f fec t ive (F ig . 2 , Table 1). In thee xpe r im e n t s invo lv ing C D P a dm in i s t r a t i on , t he pa t t e r n so f t he be ha v iou r a l r e sponses w e r e s im i la r t o t hose f o undw i th D Z; how e ve r , on ly t he l a t e nc y to e n t e r ( r e tu r n ) inthe l i gh t p r ove d se nsi t ive t o C D P ( H = 11 . 1 , P = 0 .011 )(Fig. 2, Table 1 .A s show n in Ta b le 1 , ne i t he r D Z no r C D P a f f e c t e d

3 6 Fa c to r a n a lyses o f va ria bles f r o m th e l ig h t~d a rk b o xa n d th e a c t iv i t y ca g es

A s show n in Ta b le 3 , be ha v iou r s m e a su r e d i n t hel i gh t /da r k t e s t a nd in t he da r k / l i gh t t e s t e m e r ge d m a in lyon two fac tors and one fac tor , r e spec t ive ly . Fac tor 1 ,c om m on to bo th t e s t s ( a nd w h ic h e xp la ine d 47 . 6 a nd59.6% of to ta l va r iances , r e spec t ive ly) , was re la ted toa nx ie ty (a s r e ve a l ed by t he a pp r oa c h /a vo ida n c e t ow a r dsthe l i gh t c om pa r tm e n t ) , w he r e a s t he s e c ond f a c to r(21.1% of the va r iance in the l ight /da rk te s t ) , was re la tedto l oco mo tor ac t iv i ty (as revea led by the ac t iv i ty cages) .In both te s ts , f ac tor 1 cor re la ted pos i t ive ly wi th thenum be r o f v is it s t o t he l i gh t c om p a r tm e n t a nd the i rdu r a t i on , a nd ne ga t ive ly w i th t he l a t e nc y f o r t he f i r s tv i si t to t he l i gh t c om pa r tm e n t ( Ta b le 3 ). M or e ove r , t hen u m b e r o f s q u a r e s c r o s s e d i n t h e d a r k c o m p a r t m e n tpa r t l y ( l i gh t /da r k t e s t ) o r t o t a l l y ( da r k / l i gh t t e s t ) p r o -j e c t e d upon the a nx ie ty d im e ns ion . A s f a r a s f a c to r 2 i sconcerned, th is ac t iv i ty- re la ted d imension rece ived s ig-n i f i ca n t c on t r i bu t ions f r om bo th t he l a t e nc y to e n t e r t hed a r k a n d t h e l o c o m o t i o n in t h e d a r k c o m p a r t m e n t ( inthe l ight /da rk te s t only) (Table 3) .


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F Cha oulof fet al. / Behavioural Brain Research 85 1997) 27 -35 31

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0 0DZ (mg/kg) CDP (mg/kg) DZ (mg/kg) CDP (mg/kg)0 075 15 3 0 25 5 10 0 075 15 3 0 25 5 10

F i g . 2 . R e s p e c t i v e e f f ec t s ( 3 0 m i n b e f o r e h a n d ) o f d i a z e p a m ( D Z , 0 . 7 5 - 3 . 0 m g / k g , i . p .) a n d c h l o r d i a z e p o x i d e ( C D P , 2 . 5 - 1 0 . 0 m g / k g , i . p. ) o n t h en u m b e r o f e n tr i e s in t h e l i g ht c o m p a r t m e n t i n r a t s s u b m i t t e d t o 5 - m i n li g h t / d a r k o r d a r k / l i g h t t e s ts . V a l u e s a r e t h e m e a n + S E M o f 1 0 ra t s .* P < 0 .0 5 f o r t h e c o m p a r i s o n w i t h v e h i c l e -i n j e c t ed r a ts .

T ab le 1R e s p e c t i v e e ff e c ts ( 3 0 m i n b e f o r e h a n d ) o f d i a z e p a m ( D Z , 0 . 7 5 - 3 . 0 m g / k g , i . p .) a n d c h l o r d i a z e p o x i d e ( C D P , 2 . 5 - 1 0 . 0 m g / k g , i . p. ) o n t h e t i m es p e n t a n d t h e l a t e n c y t o e n t e r t h e l i g h t (L ) c o m p a r t m e n t i n r a t s s u b m i t t e d t o 5 - m i n l i g h t / d a r k o r d a r k / l i g h t t e s t sT r e a t m e n t L i g h t / d a r k t e s t D a r k / l i g h t t e s t( m g / k g ) T i m e i n L L a t e n c y t o e n t e r D L a t e n c y t o e n t e r L T i m e i n L L a t e n c y t o e n t e r L(s) (s) (s) (s) (s)V e h i c le 5 . 5 + 5 . 5 ( 1 0 % ) 1 0. 1 + 3 . 4 2 6 3 + 1 9 1 6 . 3 + 6 . 5 ( 5 0 % ) 2 1 2 + 3 5D Z

0 . 75 1 . 9 + 1 .9 ( 1 0 % ) 1 3 . 2 + 3 . 7 2 6 4 + 2 5 3 . 8 + 2 . 6 ( 2 0 % ) 2 5 5 + 3 11.5 9. 7 ___5.2 (30 % ) 19.9 ___5.2 213 ___ 14 12.5 + 4.6 (60 %) 143 + 433 . 0 1 2 . 7 + 4 . 4 ( 7 0 % ) a 1 1 . 3 + 4 . 1 1 1 9 + 3 8 a 2 4 .1 + 8 . 5 ( 6 0 % ) 1 5 3 + 4 1

Veh ic l e 9 .1 + 4 . 9 ( 4 0 % ) 1 9 .1 + 5 . 5 1 9 7 + 3 3 1 7 .1 + 6 . 3 ( 5 0 % ) 1 9 4 + 3 9C D P

2 . 5 1 5 . 7 + 5 . 9 ( 5 0 % ) 1 1.8 +_ _3 .7 2 1 1 + 3 0 1 0 . 3 + 5 . 3 ( 3 0 % ) 2 2 7 + 3 75.0 22.9 + 8.6 (50 % ) 12.1 _ 3.4 173 _ 41 16.6 ___8.6 (40 %) 194 ___43

10.0 25.2 + 5.6 (90% ) 17.4 + 4.6 78 + 27 12.2 + 5.2 (60 %) 174 ___40T h e e f f e c t s o f D Z a n d C D P o n t h e l a t e n c y t o e n t e r t h e d a r k ( D ) w h e n r a t s w e r e i n it i a ll y p u t i n t h e l ig h t ( L ) ( l i g h t / d a r k t e s t ) a re a l s o s h o w n ; i nad d i t i o n , t h e p e r cen t a g es o f r a t s en t e r in g L a t l e a s t o n ce a r e i n d i ca t e d i n p a r en th e s e s . Va lu es a r e t h e m ea n __. SE M o f 1 0 r a t s.

P < 0 .0 5 f o r t h e c o m p a r i s o n w i t h v e h i c l e -i n j e c t ed r at s .

4 . Di scu ss io n

T h e p r e s e n t s t u d y h a s t r i ed , b y m e a n s o f d i ff e r e n td o s e s o f b e n z o d i a z e p i n e s a n d f a c t o r a n a l y si s : ( 1 ) t od e f i n e a n x i e t y - a n d l o c o m o t i o n - r e l a t e d b e h a v i o u r s i nt h e l ig h t / d a r k t e s t ; a n d ( 2 ) t o c o m p a r e t h e s e b e h a v i o u r sw i t h t h o s e r e c o r d e d i n t h e d a r k / l i g h t t e s t .4 1 Factor analyses o f l ight~dark test behaviours

A s u n d e r l i n e d i n t h e I n t r o d u c t i o n , t h e g r o w i n gi m p o r t a n c e o f u n c o n d i t i o n e d m o d e l s o f a n x i e t y h a s l edn u m e r o u s s t u d i e s t o d e f i n e t h e e x t e n t t o w h i c h l o c o -m o t o r a c t i v i ty m a y c o n t a m i n a t e t h e e st i m a t i o n o f

a p p r o a c h / a v o i d a n c e b e h a v i o u r s i n n o v e l e n v i r o n m e n t s .A s f a r a s t h e u n c o n d i t i o n e d l i g h t / d a r k t e s t o f a n x i e t y isc o n c e r n e d , t h e i n i t i a l o b s e r v a t i o n t h a t D Z o r C D P( a m o n g o t h e r b e n z o d i a z e p i n e s ) i n c r e a s e b o t h t h en u m b e r o f en t r ie s in t h e li g h t c o m p a r t m e n t a n d t o t a l( l i g h t + d a r k ) l o c o m o t i o n , b u t n o t l o c o m o t o r a c t i v i ty ina b a r e c a g e [ 8, 9 ] , h a s l e d t o t h e p r o p o s a l t h a t e x p l o r a t i o ni n th e l i gh t c o m p a r t m e n t i s i n d e p e n d e n t f r o m a n y g e n e r -a l i s ed motor e f fec t . In conf i rmat ion , more recent s tudiesi n m i c e [7 , 1 4 ] a n d r a t s [ 1 8 ] h a v e r e p o r t e d t h a t d o s e s o fD Z e n d o w e d w i t h a n x i o l y t i c e f f e c t s i n t h e l i g h t / d a r ktes t (a s a s ses sed by the number of v i s i t s in the l ight orthe i r dura t ion) a re ine f fec t ive on locomot ion in ac t iv i tycages . Bes ides these benzodiazepine - re l a t ed tool s ( the


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32 F. Chao ulof f et al . / Behavioural Brain Research 85 1997) 27-3 5Table 2Respective effects (30 min beforeh and) o f diazepam (DZ, 0.75-3.0 mg/kg, i.p.) and chlordiazepoxide (CDP , 2.5-10.0 mg/kg, i.p.) on the num berof squares crossed in the dark (D) com partment by rats sub mitted to 5-rain light/dark or dark/light tests, and on the num ber of beam breaksduring 5 -min trials in a ctivity cagesTreatmen t Light/dark test Dark/light test(mg/kg) Squares crossed in D Locom otor activity Squares crossed in D Loco motor activity(beam breaks) (beam breaks)~ h i cl e ~ 4 5 4 7 4 9 6 4 4 3D Z0 .75 56 3 a 47 6 48 3 52 61 .5 56 6 39 6 53 4 48 33 .0 68 4 b 36 8 67 7 30 4 b~ h i c l e 4 9 3 5 3 5 4 6 6 6 2 5CDP2 .5 55 3 61 3 55 6 63 85 .0 57 6 59 3 51 4 62 410.0 63 5 46 4 53 6 31 6 cValues are the mean +S EM of 9-10 rats.ap < 0.05, bp < 0.01, and cp < 0.001 for the co mparison w ith vehicle-injected rats.Table 3Factor (principal compon ent) analysis of the beha vioural variables measured in the light/dark and dark/light tests and in the activity cages(beam breaks)Variable Light/dark test Dark/light test

Factor 1 Factor 2 Factor 1 Factor 2(47.6%) (21.1%) (59.6%) (20.1%)Light/dark boxEntries in LTime in LLatency (D > L)Latency (L > D)Squares in DActivity cageBeam breaks

0.97 0.950.93 0.92- 0.92 - 0.90- 0 .800.44 0.45 0.630.63 0.99

For clarity, only factor loadings >0.2 are shown. L and D stand for light and dark, respectively.

v a l i d i t y o f w h i c h w i l l b e d i sc u s s e d i n m o r e d e t a i l b e l o w ) ,o t h e r s t u d i e s h a v e t r ie d , b y s u b m i t t i n g v a r i o u s s t r a i n so f m i c e [ 3 ] o r r a t s [ 2 1] t o d i f f e r e n t n o v e l e n v i r o n m e n t s( a m o n g w h i c h t h e l i g h t / d a r k t e s t ) , t o d r a w t h e r e la t i o n -s h i p s b e t w e e n a p p r o a c h / a v o i d a n c e - a n d l o c o m o t i o n -r e l a t e d b e h a v i o u r s . T o t h i s e n d , c o r r e l a t i o n m a t r i c e sf o l l o w e d b y f a c t o r a n a l y s e s w e r e p e r f o r m e d t h a tr e v e a le d t h a t t h e n u m b e r o f d a r k - t o - l ig h t t r a n s i ti o n si s t h e v a r i a b l e t h a t h a s t h e h i g h e s t l o a d i n g o n a na p p r o a c h / a v o i d a n c e - r e l a t e d f a c to r . I n t h e p r e s e n t s t u d y,f a c t o r a n a l y s i s c o n f i r m e d t h a t t h e n u m b e r o f v i s it s i nt h e l i g h t i s t h e s t r o n g e s t a n x i o l y s i s - r e l a t e d i n d e x . I na d d i t i o n , t h e t i m e s p e n t i n t h e l i g h t c o m p a r t m e n t a n dt h e l a t e n c y t o e n t e r i n t h e l i g h t b o t h l o a d e d o n t h i sl o c o m o t i o n - i n d e p e n d e n t f a c t o r . T h e o b s e r v a t i o n t h a tt h e t i m e s p e n t i n t h e l i g h t w a s n o t l i n k e d t o l o c o m o t i o na g r e e s w i t h o u r p r e v i o u s o b s e r v a t i o n i n d i f f e r e n t r a ts t r a i n s [ 2 1 ], b u t i s a t v a r i a n c e w i t h t h a t o f B e u z e n a n d

B e l z u n g [ 3 ] w h o d i d n o t f i n d a n y c l e a r - c u t o p p o s i t i o nb e t w e e n t h e t w o c o m p a r t m e n t s o f t h e li g h t / d a rk b o x .B e s i d e s s p e c i e s - r e l a t e d d i f f e r e n c e s , t h i s d i s c r e p a n c y i sp r o b a b l y d u e t o t h e r e s p e c t i v e d e s i g n o f t h e l i g h t / d a r kb o x e s , b ec a u s e t h e a p p a r a t u s u s e d b y B e u z e n a n dB e l z u n g [ 3 ] h a s b e e n m o d i f i e d s o th a t t h e l i g h t a n d d a r kc o m p a r t m e n t s a r e s e p a r a t e d b y a tu n n e l t h a t p r o v i d e sa t h i r d c o m p a r t m e n t .

T h e p r e s e n t s e ri e s o f e x p e r i m e n t s r e v e a l e d t h a t t h ei n i t i a l l a t e n c y t o e n t e r t h e d a r k c o r r e l a t e d t o l o c o m o t o ra c t iv i t y . I n k e e p i n g w i t h t h e o r t h o g o n a l i t y o f t h ea n x i e t y - a n d a c t i v i t y - r e l a t e d a x e s , t h i s o b s e r v a t i o n ,w h i c h p a r t l y a g r e e s w i t h t h e d a t a f r o m B e u z e n a n dB e l z u n g [ 3 ] , b u t o p p o s e s d a t a f r o m C o s t a l l e t a l . [ 7 ] ,i m p l i e s t h a t v i s i t s t o t h e l i g h t c o m p a r t m e n t a r e i n d e p e n -d e n t f r o m t h e t i m e i n i t i a l l y s p e n t o n p l a c e m e n t i n t h i sc o m p a r t m e n t . M o r e o v e r , l o c o m o t i o n in th e d a r k c o m -p a r t m e n t w a s e n d o w e d w i t h e q u i v a l e n t l oa d ri gs o n b o t h


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F Cha ouloffet al. / BehaviouralBrain Research 85 1997) 27-35 33a n x i e t y - a n d l o c o m o t i o n - r e l a t e d f a c t o r s , a n o b s e r v a t i o na t v a r i a n c e w i t h o u r p r e v i o u s f i n d i n g in i n b r e d r a t s t h a tlocomot ion in the da rk i s a s e l ec t ive anxie ty- re l a t edv a r i a b l e [ 2 1 ] . B e s i d e s p a r a d i g m - d e p e n d e n t d i f fe r e nc e s ,i t i s , h o w e v e r , n o t e w o r t h y t h a t i n o u r p a s t s t u d y t h i sb e h a v i o u r h a d a f a c t o r l o a d i n g ( 0 . 7 2 ) t h a t w a s t h el o w e s t a m o n g a l l a n x i e t y - r e l a t e d v a r i a b l e s . T a k e nt o g e t h e r , o u r p a s t a n d p r e s e n t f i n d i n g s i n d i c a t e t h a tl o c o m o t i o n i n t h e d a r k c a n n o t b e u s e d a l o n e t o r e v e a lanxie ty /anxio lys i s in the l ight /da rk t e s t .4 .2 . C om par i s on be tw e e n the l i gh t~dar k and dar k / l i g h ttes ts

T o o u r k n o w l e d g e , t h e p r e s e n t s t u d y i s t h e f i r s t t or e p o r t a f a c t o r a n a l y s i s o f t h e b e h a v i o u r s m e a s u r e d i nthe da rk / l ight t e s t . Bes ides , a compar i son wi th thel ight /da rk t e s t revea l s no major d i f fe rences regard ingt h e p r o j e c t i o n s o f t h e d i ff e r e n t b e h a v i o u r s u p o n t h ea p p r o a c h / a v o i d a n c e - r e l a t e d a xi s. T h e s o l e d i f fe r e n c ec o n c e r n e d t h e l o c o m o t i o n - r e l a t e d a x i s w h i c h d i d n o tr e c e i v e a n y c o n t r i b u t i o n f r o m t h e d a r k / l i g h t t e s t ,whereas in the l ight /da rk t e s t , t he l a t ency to en te r thed a r k ( w h i c h is u n i q u e t o t h i s t e st ) a n d p a r t o f t h el o c o m o t o r a c t i v i t y i n t h e d a r k c o n t r i b u t e d t o t h e l o c o -m o t o r a c t i v i t y - r e l a t e d a x i s . T a k e n t o g e t h e r , o u r d a t as h o w t h a t b o t h t e s ts a l l o w t h e r e c o g n i ti o n o f an x i e t y -re l a t ed behaviours , bu t the l igh t /da rk t e s t a l so a l lows ,t h r o u g h t h e a s s e s sm e n t o f th e l a t e n c y t o e n t e r t h e d a r k ,t h e r e c o g n i t io n o f lo c o m o t i o n - d e p e n d e n t v a r i a b le s .H o w e v e r , t h e c o m p a r i s o n b e t w e e n v e h i c l e - i n j e c t e d r a t s( w h i c h t e n d e d t o e n t e r m o r e o f t e n i n t h e l i g h t c o m p a r t -m e n t w h e n p l a c e d i n i t i a l l y i n t h e d a r k , c o m p a r e d t othose p laced in i t i a l ly in the l ight ) sugges t s tha t thel i g h t / d a r k t e s t m a y b e m o r e a v e r s i v e t h a n t h e d a r k / l i g h tt e s t ( a l t h o u g h t h e f o r m e r r e s p o n d s b e t t e r t h a n t h e l a tt e rt o D Z a n d C D P t r e a tm e n t s : s e e b e l o w ) .

A l t h o u g h b o t h t e s ts a l lo w t h e r e c o g n i t io n o f o n ea n x i e t y - r e l a t e d f a c t o r a n d o n e a c t i v i t y - r e l a t e d f a c t o r ,t h e c r u c i a l p o i n t w h i c h d e s e r v e s f u r t h e r i n v e s t i g a t i o nl i e s in to the poss ib i l i ty tha t the a forement ioned anxie ty-r e l a t e d d i m e n s i o n i s n o t c o m m o n t o b o t h t e s t s . A sa l r e a d y r e p o r t e d b y m e a n s o f o t h e r e n v i r o n m e n t a lm o d e l s [ 1 2 ] , d i f f e r e n t t e s t c o n d i t i o n s m a y l e a d t od i f fe r e n t a n x ie t y d i m e n s i o n s . T h e n , w e c a n n o t e x c l u d ethe poss ib i l i ty tha t in t e r - t e s t d i f fe rences in the l ight /d a rkb o x ( b a s e l in e b e h a v i o u r s , r e s p o n s e / l a c k o f r e s p o n s e t ob e n z o d i a z e p i n e s ) a r e d u e t o t h e d i f fe r e n t a n x i e ty d i m e n -s i o n s g e n e r a t e d b y t h e r e s p e c t i v e e x p e r i m e n t a lcondi t ions .4 . 3 . E f f e c t s o f be nz od iaz e p ine s in the li gh t~dar k t e s t:c o m p a r i s o n w i t h t h e e l e v a t e d p l u s - m a z e

T r e a t m e n t s w i t h D Z o r C D P i n c r e a s e d , d o s e - d e p e n -d e n t ly , t h e n u m b e r o f v i si ts in t h e l i g h t a n d / o r t h e i r

d u r a t i o n . H o w e v e r , d u e t o t h e h i g h h e t e r o g e n e i ty o f t h eda ta , on ly those an imal s rece iv ing the h ighes t dose ofDZ proved s igni f i cant ly d i f fe rent f rom the i r cont ro l s . Ink e e p i n g w i t h t h e o b s e r v a t i o n t h a t m i d d l e - r a n g e d o s e so f D Z a n d C D P m a r k e d l y i n c re a s ed t h e p e r c e n t o f t im es p e n t o n t h e o p e n a r m s o f t h e e le v a t e d p l u s - m a z e ( t h u sindicat ing effect ive anxiolyt ic effects ; for a review inra t s : s ee [20] ) , i t i s l i ke ly tha t under our exper imenta lc o n d i t i o n s , t h e l i g h t / d a r k t e s t w a s m o r e a v e r s i v e t h a nthe p lus -maze t e s t . Thus , marked d i f fe rences in l igh ti n te n s it ie s b e t w e e n c o m p a r t m e n t s i n t h e l ig h t / d a r k b o x( 7 0 0 l u x / 7 l u x ) s u r e l y a c c o u n t f o r t h e l o w n u m b e r s o fa n i m a l s r e s p e c ti v e ly e n te r i n g t h e l i gh t c o m p a r t m e n t a n dr e s p o n d i n g t o D Z a n d C D P . R e g a r d i n g t h e d i f f e r e n c e sbe tween the e f fec t s of benzodiazepines in the two t es t s ,i t i s re l evant to add tha t Kshama e t a l . [16] and Santucc ie t a l . [25] were ab le to obse rve anxio ly t i c e f fec t s of 1 .5a n d 2 .5 m g / k g d o s e s o f D Z i n r a t s t e st e d i n t h e p l u s-m a z e , b u t n o t i n t h e l i g h t / d a r k b o x ( a s r e v e a l e d b y t h enum ber of en t r ie s in the light ) . In t e res t ingly , i t has beenr e p o r t e d t h a t s u b c h r o n i c t r e a t m e n t w i t h D Z a t a d o s et h a t i n c r e a s e d t h e p e r c e n t o f o p e n a r m v i s i ts a n d t h ep e r c e n t o f t im e s p e n t o n t h e s e a r m s b y m i c e p r o v e dinef fec t ive aga ins t the num ber of l igh t - to-da rk t rans -i t ions in the l ight /da rk box [23] ; however , t h i s reg imenincreased the pe rcen t of time spe nt in the l ight, t he reb ysugges t ing tha t th i s va r i ab le should be inc luded in fu tures t u d ie s . I n t h e p r e s e n t s t u d y , a c o m p a r i s o n o f t h evar i ab i l i t i e s (a s a s ses sed by means of the respec t ivevar i ances ) of the d i f fe rent anxie ty- re l a t ed responses inthe p lus -maze and the l ight /da rk t e s t s t rongly sugges t st h a t t h e l a t t e r t e st p r o m o t e s h i g h ly h e t e r o g e n e o u s b e h a v -i o u r a l r e s p o n s e s . O n t h e o t h e r h a n d , o n e c o u l d s u g g e s tt h a t a n y c o m p a r i s o n b e t w e e n t h e s e t e s t s i s u s e l e s sbecau se these t e s t s e i the r re f lec t d i f fe rent anx ie ty s t a t es ,a s shown for the soc ia l in t e rac t ion t e s t vs . t he e l eva tedp l u s - m a z e t e s t [ 1 2 , 2 1 ] , o r a r e m o d e r a t e l y l i n k e d o n e t oano ther (a t l eas t in mice [2] ) . Thi s i s , how ever , un l ike ly ,b e c a u s e i n r a ts , b o t h t h e p e r c e n t o f t i m e i n t h e o p e na r m s o f th e p l u s - m a z e a n d t h e n u m b e r o f v is it s t o t h el ig h t c o m p a r t m e n t o f t h e li g h t / d a r k t e s t p r o j e c t t o o n eunique anxie ty- re l a t ed fac tor [21] .T h a t D Z ( a n d C D P ) i n c r e a s e d , i n a d o s e - d e p e n d e n tm a n n e r , t h e n u m b e r o f l ig h t - t o - d a r k t r a n s i t io n s i s i na g r e e m e n t w i t h p a s t d a t a i n m i c e [ 7 - 9 , 1 4 , 1 5 , 1 9 ] a n dr a t s [ 1 8 ]. I t i s n o t e w o r t h y , h o w e v e r , t h a t m o s t o f t h e s es t u d i e s f o u n d a n x i o l y t i c e f f e c t s o f D Z a t d o s e s l o w e rthan 3 mg /kg, poss ib ly re f l ec ting species -, i l l umina t ion- ,a n d n y c t h e m e r e - r e l a t e d d i f f e r e n c e s b e t w e e n p r o t o c o l s .M o r e o v e r , t h e u s e o f a b l a c k b o x i n t h e c o r n e r o f awhi t e open f i e ld [18] , ra the r than the mode l in i t i a l lyd e s c r i b e d b y C r a w l e y a n d G o o d w i n [ 9 ] , m a y a l s oa c c o u n t f o r t h i s c o n t r a d i c t io n . B e s i de s , w e w e r e n o t a b l et o c o n f i r m p r e v i o u s d a t a [ 7 , 2 4 , 2 8 ] s u g g e s t i n g t h a t t h et ime spent in the l ight a rea may be a be t t e r anxio lys i s -r e l a te d i n d e x a s c o m p a r e d t o t h e n u m b e r o f v is it s t o


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34 F. Chaouloff et al. / Behavioural Brain Research 85 199 7) 27- 35l igh t . Ac tua l ly , i n ou r hands , the num ber of v is i ts in thel ight , t he i r dura t ion , and the l a t ency for the f i r s t en t ryin the l ight had equiva lent informat ive va lues .I n t er e s ti n g l y , t h e n u m b e r o f p o s i ti v e r e s p o n d e r s s e e m e da l so to be a good tool to a s ses s the anxio ly t i c e f fec t s ofD Z a n d C D P i n t h e l i g h t / d a r k b o x . T h i s r e s u l t i s a tv a r i a n c e w i t h t h a t o f t h e p l u s - m a z e w h e r e t h e p e r c e n t a g eo f p o s i t iv e r e s p o n d e r s ( i. e ., t h o s e e n t e r i n g o p e n a r m s a tl eas t once) was s imi la r in vehic le - and benzodiazepine -t rea ted ra t s . Thi s d i f fe rence sugges t s tha t the l igh t /da rkb o x m a y b e m o r e a v e r s i v e , t h e r e b y p o s s i b l y l e a d i n g ( a si n t h e D Z e x p e r i m e n t s ) t o a n a l l - o r - n o n e r e s p o n s e . A se v i d e n c e d f o r m a n y y e a r s [ 1 7 , 2 6 ] , t h e s id e e f fe c ts o fb e n z o d i a z e p i n e s , s u c h a s h y p e r l o c o m o t i o n [ 11 ] , a n d f o rh i g h d o s e s , m y o r e l a x a t i o n a n d / o r s e d a t i o n [ 1 3 ] , c o n -fou nd the i r anxio ly t i c e ffec t s in uncon di t ion ed t e s ts .H o w e v e r , t h i s p o s s i b i li t y m a y b e r e j e c te d h e r e in b e c a u s et h e r e w a s n o c o r r e l a t i o n b e t w e e n t h e n u m b e r o f e n t r i e si n t h e l i gh t a n d l o c o m o t o r s c o r e s i n a c t iv i t y c ag e s ( n o n -p a r a m e t r i c S p e a r m a n c o r r e l a t i o n c o e f f i c i e n t : r = 0 . 0 9 ,P = 0 .23) , an obse rva t ion in l ine wi th the ra t b id imens io-na l (anxie ty- and ac t iv i ty- re l a t ed) reac t iv i ty , a s revea ledby fac tor ana lys i s .

pro tocol - re l a t ed d i f fe rence regard ing the e f fec t s of theb e n z o d i a z e p i n e s u p o n l o c o m o t o r s c o r e s i n t h e a c t i v i t yc a g e s in d i c a te s t h a t t h e p o s i t iv e e ff e c t o f D Z a n d C D Pin the l ight /da rk t e s t , bu t not in the da rk / l ight t e s t , i si n d e p e n d e n t o f a n y c h a n g e i n b e n z o d i a z e p in ep h a r m a c o k i n e t i c s .

5. ConclusionsT h e p r e s e n t s t u d y s h o w s t h a t f a c t o r a n a l y s e s o f th e

b e h a v i o u r s r e c o r d e d i n t h e l i g h t / d a r k a n d d a r k / l i g h tt e s ts a l l o w t h e r e c o g n i t io n o f a n x i e t y - r el a t e d b e h a v i o u r st h a t a r e n o t c o n f o u n d e d b y l o c o m o t o r a c t i v i t y . I naddi t ion , th i s s tudy sugges t s tha t a l though the l ight /da rkt e s t m a y b e m o r e a v e r s i v e t h a n t h e d a r k / l i g h t t e s t , t h ef o r m e r m a y b e m o r e s e n s i t i v e t o t h e a n x i o l y t i c e f f e c t so f b e n z o d ia z e p i n e s . H o w e v e r , c o m p a r e d t o t h e w i d e l yu s e d e l e v a t e d p l u s - m a z e o f a n x i e ty , t h e l i g h t / d a r k t e s ty i e l d s m u c h m o r e h e t e r o g e n e o u s r e s p o n s e s ( b o t h i nc o n t r o l s a n d b e n z o d i a z e p i n e - t r e a t e d a n i m a l s ), a c h a r a c -t e ri s ti c t h a t m a y l i m i t i ts u s e i n p s y c h o p h a r m a c o l o g y .

4 4 E f fec t s o f b en zo d ia zep in es in th e d a rk~ l ig h t t e s t :co m p a r iso n wi th th e l ig h t /d a rk te s tF o r a n u n k n o w n r ea s on , l o w do s e s o f D Z a n d C D P

d e c r e a s e d t h e p e r c e n t o f ra t s e n t e r in g t h e l i g ht c o m p a r t -m e n t , a s c o m p a r e d t o t h e c o n t r o l s . A n o b s e r v a t i o n o ft h e e f f e c t s o f t h e s e l o w d o s e s o n b e h a v i o u r s l o a d i n ghighly on the anxie ty- re l a t ed ax i s conf i rmed th i s pa ra -d o x i c a l e f f e c t . O n t h e o t h e r h a n d , d o s e s t h a t p r o v e def fec t ive in the l igh t /da rk t e s t were dev oid o f s igni f i cante f fec ts in the da rk / l igh t t e s t, t he reb y sugges t ing tha t th el i g h t / d a r k t e s t m a y a l l o w a b e t t e r r e c o g n i t io n o f t h ea n x i o l y t ic e f f ec t s o f b e n z o d i a z e p i n e s t h a n t h e d a r k / l i g h tt e s t , a l though base l ine l eve l s ( s ee above) a l so sugges ttha t the da rk / l ight t e s t may be l e s s avers ive . Thed i f fe r e n ti a l ef f e ct o f D Z a n d C D P a c c o r d i n g t o t h en a t u r e o f th e t e s t c o n t r a s t s w i t h d a t a f r o m C o l p a e r te t a l . [6] and Cos ta l l e t a l . [7] . Thus , the former s tudyf o u n d t h a t 2 . 5 - m g / k g d o s e s o f D Z a n d C D P i n cr e a se dt h e n u m b e r o f d a r k - t o - li g h t t r a n s it i o n s i n r a t s p l a c e din i t i a l ly in the da rk . However , i n th i s s tudy: (1) thea p p a r a t u s w a s a b l a c k b o x p l a c e d i n a w i d e o p e n f i e l d ,the l a t t e r be ing d imly i l lumina ted; (2) the t e s t was 10m i n l o ng ; a n d ( 3 ) d o s e s b e l o w a n d a b o v e 2 .5 m g / k gwere ine f fec t ive . Cos ta l l e t a l . [7] repor t ed tha t a1 .2 5 m g / k g d o s e o f D Z i n c re a s ed t h e d u r a t i o n ( b u t n o tthe nu mb er) o f the v i s it s in the light , whe the r m ice wereplaced in i t i a l ly in the l ight or da rk . However , Cos ta l le t a l . [7] used mice p laced under a reversed l ight /da rkc y c le , a p a r a d i g m t h a t m a y u n d e r l ie t h e h i g h n u m b e r o fl i g h t - to - d a r k t r a n s it i o n s ( > 1 0 ) o b s e r v e d i n t h e c o n t r o l s.A s f a r a s t h e p r e s e n t s t u d y i s c o n c e r n e d , t h e l a c k o f a

AcknowledgementT h e a u t h o r s w i s h t o t h a n k D r . J e a n - L u c M o r e a u

( H o f f m a n - L a R o c h e , B a s e l , S w i t z e r l a n d ) f o r t h e k i n dg i ft o f D Z a n d C D P , D r . B y r o n J o n e s ( P e n n S t a t eU n i v e r s i ty , P A , U S A ) f o r c o r r e c t i n g t h e s t y l e /g r a m m a r ,a n d Y a n n i c k M e l l e r in f o r t a k i n g c a r e o f t h e a n i m a l s .

References[ 1 Archer , J . , Tests of em otionali ty in ra ts and mice: a review, AnimalBehav., 21 (1973) 205-235.[2] Belzung, C . and Le Pape, G . , Com parison o f d ifferent behaviora ltes t s i tua t ions in psychopharmacology for measurement of anxi-ety, Physiol. Behav., 56 (1994) 623-628.[3] Beuzen, A. and Belzung, C. , Link between emotional memoryand anxie ty s ta tes : a s tudy by principal com ponent analysis , Phy-siol. Behav., 58 (1995) 111-118.[4] C haouloff , F. , Fa i lure to f ind behavioural d ifferences between leanand obese Zucker ra ts submitted to novel environments , Int. J.Obesity, 18 (1994) 780-782.[5] Chaouloff , F. , K ulikov, A. , Sarr ieau , A. , Castan on, N. andMorm 6de, P. , Male Fischer 344 and Lewis ra ts d isp lay d ifferences

in locomotor react iv i ty , but not in anxie ty-re la ted behaviours:re la t ionships with the h ippocampal sero tonergic system, BrainRes., 693 (1995) 169-178.[6] Colpaert , F .C. , M eert , T.F. , Niem egeers , C.J .E. and Janssen ,P.A.J . , Behaviora l and 5-HT antagonis t effec ts of r i tanserin : apure and se lec tive antagonis t of LSD discr imination , Psychophar-macology, 86 (1985) 45-54.[7] Costa l l , B. , Jones, B.J . , Kelly , M.E. , Naylor , R.J . and Tomkins,D.M., Explora t ion of mice in a b lack and white tes t box: val ida-t ion as a model of anxie ty , Pharmacol. Biochem. Behav. , 32(1989) 777-785.[8] Crawley, J .N. , N europh arma cologic specif ic i ty o f a s imple animal


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