Effects of phencyclidine, N-allyl-N-normetazocine (SKF-10,047), and verapamil on performance in a radial maze

Effects of phencyclidine, N-allyl-N-normetazocine (SKF-10,047), and verapamil on performance in a radial maze

Pharmatoloe~ Bu~then:t~trv & Behattor, Vol 24 pp 187-191 1986 ' Ankho International lnc Printed m the U S A 0091-3057/86 $3 00 + 00 Effects of Phenc...

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Pharmatoloe~ Bu~then:t~trv & Behattor, Vol 24 pp 187-191 1986 ' Ankho International lnc Printed m the U S A

0091-3057/86 $3 00 + 00

Effects of Phencyclidine, N-Allyl-N-Normetazocine (SKF- 10,047), and Verapamil on Performance in a Radial Maze DAVID

J

McCANNANDJ

C

WINTER

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D e p a r t m e n t o f P h a r m a ~ o l o g y a n d Therapeutl~ s, S~ h o o l o f Medt~ m e S t a t e U n t v e r s l t y o f N e w Yotl, at B u f f a l o , B u f f a l o , N Y 14214 Received

3 January

1985

McCANN, D J AND J C WINTER l=~letts oJ phem v¢ hdmc, N-all~l-N-m,rmeta:ot the (SKF-IO 047) and ~eraparml on perJormam e ira tl radml maze PHARMACOL BIOCHEM BEHAV 24(2) 187-191, 1986 - - T w o groups of eight rats were trained to obtain food pellets m an 8-arm radml maze Stable performance was assumed to be present when a criterion of 89~ efhc~ency, l e , all arms entered wathm 9 arm entraes was reached m 5 consecuttve sessaons The effects of phencychdme (PCP) and N-allyl-N-normetazocme (SKF-10,047) were then evaluated m Group 1 The mteractaon between verapamd and PCP was examined m Group 11 Both PCP (6 mg/kg, IP, 15 man before testing) and SKF-10,047 (30 mg/kg, IP, 30 mln) decreased effaoency but only PCP caused a concurrent increase m rate of arm entry Sagmficant effects of PCP on rate and effioency lasted for greater than 6 hours and less than 40 minutes, respectwely Verapamd (20 mg/kg, IP, 30 minutes) was found to selectavely potentiate the effect of PCP on effaclency This finding does not support the suggestaon that verapamd may be useful an the treatment of PCP mtox~cataon It Js concluded that the radml maze may provade an mterestang method for the study of PCP and other psychoactwe drugs Radml maze

Phencychdme

N-allyl-N-normetazoclne (SKF-10,047)

T H E radial m a z e w a s d e s c r i b e d less t h a n a d e c a d e ago by Olton a n d S a m u e l s o n [34,38] Spatial m e m o r y w a s t h e t e r m t h e y used to d e s c r i b e the m e a n s b y w h i c h rats solve the m a z e T h e initial studies o f the radial m a z e as well as m a n y s u b s e q u e n t i n v e s t i g a t i o n s h a v e g e n e r a l l y s u p p o r t e d t w o prev a d l n g ideas r e g a r d i n g spatial m e m o r y T h e s e are t h a t (a) e n w r o n m e n t a l stimuli e x t e r n a l to t h e m a z e are e s s e n t i a l [35,37] a n d (b) the h l p p o c a m p u s is the crucial a n a t o m i c region [38,39] B e c a u s e a c e t y l c h o h n e ( A C h ) is g e n e r a l l y b e l i e v e d to be o f p r i m a r y i m p o r t a n c e m t h e p r o c e s s e s of m e m o r y , the effects of s c o p o l a m i n e a n d a t r o p i n e m t h e radial m a z e h a v e b e e n well d o c u m e n t e d In g e n e r a l , it h a s b e e n f o u n d t h a t A C h - a n t a g o n l s t s b l o c k b o t h the acqmslt~on [49,55] a n d perf o r m a n c e [9, 16, 22, 33, 45, 55, 56] o f the m e m o r y t a s k O t h e l drugs w h i c h h a v e b e e n s t u d i e d m the radial m a z e are d - a m p h e t a m i n e [5, 8, 9, 16, 25], a p o m o r p h l n e [9], chloral h y d r a t e [7], c h l o r d i a z e p o x l d e [22], c h l o r p r o m a z m e [22], 3,4-diamlnopyndme [12], d i p r e n o r p h m e [20], e t h a n o l [14,15], h a l o p e n d o l [6], l e u p e p t m [48], m e t h o h e x l t a l [7], m e t h y s e r g l d e [6], m o r p h i n e [4], n a l o x o n e [20], p e n t o b a r b i t a l [16], p e n t o x i f y l h n e [13], p h e n c y c h d l n e [26], p h e n o b a r b t t a l [40], p h e n t o l a m l n e [6,22], p h y s o s t l g m l n e [9], p i r a c e t a m [9], propranolol [6,22], serotonm [6], and delta-9t e t r a h y d r o c a n n a b m o l [50,51]

Verapamd

In the only p r e v i o u s s t u d y o f p h e n c y c h d m e (PCP), K e s n e r et al [26] f o u n d that e f f i o e n c y o f r e s p o n d m g b y rats was r e d u c e d b y the drug T h e p u r p o s e o f the p r e s e n t mvestigat~on was to e x a m i n e m g r e a t e r detail the effects o f P C P u p o n p e r f o r m a n c e m the radial m a z e In a d d i t i o n , P C P w a s c o m p a r e d with N - a l l y l - N - n o r m e t a z o c m e (SKF-10,047), a p r e s u m e d a g o m s t at opiate r e c e p t o r s of the s i g m a t y p e [30] w h i c h h a s stimulus p r o p e r t i e s similar to t h o s e o f P C P [46] Finally, the i n t e r a c t i o n of v e r a p a m d , a c a l c i u m a n t a g o n i s t p r e v i o u s l y r e p o r t e d to a n t a g o n i z e c e r t a i n o f the effects o f P C P [1] was e x a m i n e d METHOD

Antmals All s u b j e c t s were male F i s c h e r 344 rats o b t a i n e d f r o m Charles River Breeding Laboratories, Inc, Wilmington, M A T h e y w e r e h o u s e d m pairs u n d e r a n a t u r a l h g h t - d a r k cycle a n d h a d free a c c e s s to w a t e r m the h o m e cage Subj e c t s were m a i n t a i n e d at 7 5 - 8 0 % o f t h e i r e x p e c t e d freefeeding w e i g h t b y h m t t m g a c c e s s to d r y food to 2 h o u r s p e r day

Apparatu~ T h e radml maze c o n s i s t e d of a central hub, 34 c m m diame-

'Requests for repnnts should be addressed to J C Winter

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McCANN AND WINTER

ter, with eight 86 cm by 9 cm arms radmtlng from it The sides of each arm were 10 cm high at the center of the maze and sloped to a height of 6 cm at the end o f the arms The m a z e was c o n s t r u c t e d entirely of a l u m i n u m with the e x c e p t i o n of the food wells which w e r e plastic cups 1 5 cm deep with a d i a m e t e r of 2 cm The entire d e v i c e was elevated 46 cm from the floor

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Druga P h e n c y c l l d m e HCI and N - a l l y l - N - n o r m e t a z o c l n e HCI (SKF-10,047) w e r e provided by the National Institute on Drug A b u s e , Rockvllle, M D V e r a p a m d HCI was obtained from Searle R e s e a r c h and D e v e l o p m e n t Division o f G D Searle and C o , Skokle, I L All drugs w e r e dissolved in saline and InJected IP in a constant v o l u m e of 1 ml/kg of body weight Statt~tl~ Values for efficiency and rate of responding were compared with control data by m e a n s o f individual applications o f W i l c o x o n ' s signed ranks test for paired data Differences w e r e c o n s i d e r e d to be significant if they would be e x p e c t e d to arise by r a n d o m sampling alone with a probability less than 0 05 RESULTS

All rats b e c a m e highly efficient in obtaining the eight food pellets available d u n n g e a c h session Stable p e r f o r m a n c e was a s s u m e d to be present w h e n a criterion o f 89% efficiency in five c o n s e c u t i v e sessions was reached The mean n u m b e r

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a Training At the start of a session, a 45 mg N o y e s food pellet was placed m a well at the end of each arm and, on the first day only, a pellet was placed a short distance from the starting point to e n c o u r a g e exploration of the m a z e A session lasted until all eight food pellets were obtained or 10 minutes had elapsed An entry into an arm was scored w h e n e v e r a rat had all four paws m an arm P e r f o r m a n c e d u n n g e a c h session was scored by visual o b s e r v a t i o n in terms of (a) efficiency of responding (8/number of arm entries before all eight arms w e r e entered, e x p r e s s e d as a percentage) and (b) rate of responding (arm entries per minute until all eight arms w e r e entered) T w o groups o f subJects were trained G r o u p I (N =8) was trained first and used to determine the d o s e - r e s p o n s e functions for P C P and SKF-10,047 and the time course for PCP The interactions b e t w e e n verapamll and PCP were e x a m i n e d m Group II ( N = 8 ) b Drug te~ts (1) Rats p e r f o r m e d m the m a z e M o n d a y through Friday The effects of vehicle or drug inJection w e r e d e t e r m i n e d on W e d n e s d a y s and Fridays All test sessions were 10 minutes m length e v e n if all 8 food pellets were obtained earher m the session Thus, Figs 1-3 give response rates for an entire 10-minute session Tests w e r e c o n d u c t e d only if efficiency on the immediately preceding day was at least 89% PCP and SKF-10,047 w e r e administered 15 rain and 30 mln, respectively, before testing (2) The time course o f the effects of PCP was determined by interposing delays b e t w e e n injection and testing which ranged from 15 mln to 24 hours (3) The interaction b e t w e e n verapami1 and PCP was e x a m i n e d by injecting verapamll 30 mln before testing, l e , 15 mm before the injection of PCP or saline

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FIG I A and B Dose-response relationship for PCP (ctrcle~) and SKF-10,047 (squares) m an 8-arm radml maze Each point represents the mean of 1 determination m each of 8 subjects Abs
of sessions to achieve that criterion (STC) was 15 for Group lI Indwldual values were 11 for 4 rats. 14, 18, 20, and 21 Mean and Individual values for STC were not calculated for Group I because of lmtml varmtlons m the training conditions of the group G r o u p I I ' s m e a n rate of responding in obtaining the food pellets in the five sessions immediately preceding criterion p e r f o r m a n c e was 4 7 arms per minute Thin rate is considerably higher than the control values shown m Figs 1-3 The apparent discrepancy is explained by the fact that training sessions were terminated after all 8 food pellets had been obtained, a procedure which greatly reduced time req u i r e m e n t s for observation U n t r e a t e d rats usually decrease their rate o f exploration after each arm has been entered o n c e This fact ~s reflected in the lower control rates for the 10-minute sessions presented in the figures Figure 1, panel A shows the dose-related d e c r e a s e m efficiency caused by PCP (circles) and S K F - 10,047 (squares) in G r o u p I Efficiencles following doses of 6 mg/kg of PCP and 30 mg/kg o f SKF-10,047 were significantly different from their respective control values The decreased efficiency following the 6 mg/kg dose of PCP was accompanied by a significantly increased rate of responding (panel B) In contrast, the m a x i m u m increase in rate following SKF-10,047 was not correlated with the m a x i m u m effect on efficiency and it was of m u c h smaller m a g m t u d e than that at 6 mg/kg of PCP Figure 2 illustrates the time course m Group I of the 6 mg/kg dose of P C P As e x p e c t e d , the effects on both efficiency and rate of responding diminish with t~me H o w e v e r , a significant effect on rate persists for a much longer p e n o d In Fig 3 are seen the results of experiments m G r o u p II

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FIG 2 A and B Time course for the effects ofa 6 mg/kg dose ofPCP m an 8-arm radml maze Each point represents the mean of 1 determination in each of 8 subjects A b s c :*sa Time m hours after admmtstratlon of PCP expressed on a log scale Dotted lines indicate mean control values O r d m a t e ~ A--effmmncy, B--rate of responding *p
whmh were designed to test the interaction b e t w e e n PCP and verapamll The dose-response relationship for PCP on effio e n c y (panel A, open circles) is shifted to the left in the p r e s e n c e of v e r a p a m d (panel A, closed circles) When combined w,th v e r a p a m d , the 3 mg/kg dose was stgmficantly potentmted A c o m p a r a b l e stat~stmal statement cannot be made at doses of 4 2 and 6 mg/kg because too few of the rats c o m p l e t e d the m a z e Failure to c o m p l e t e the m a z e was not due to decreased response rate On the contrary, the comb~nation of v e r a p a m d and PCP p r o d u c e d ataxm to the point that the subjects repeatedly fell from the m a z e H o w e v e r , the data o f Fig 3 leave little doubt o f potentiation at those doses as well Data for the c o m b m a n o n of 8 5 mg/kg of PCP and verapamll are not shown because only 1 of 8 subjects was able to complete the maze m the allotted 10 minutes In contrast with the potentiation by verapamll of P C P ' s effects on efficiency, there were no significant effects on rate of responding (panel B) By itself, v e r a p a m d caused a d e c r e a s e m rate T o a v m d possible fatahties in trained ammals, the effects of greater doses of v e r a p a m d on p e r f o r m a n c e in the maze w e r e not e x t e n m v e l y e v a l u a t e d H o w e v e r , m five trials subjects r e c e i v e d v e r a p a m d at a dose of 30 mg/kg (IP, 30 minutes before testing) N o subjects c o m p l e t e d the m a z e d u n n g a 10-mmute sesmon The number of arm entries ranged from I to 7 with no reentries DISCUSSION

The present results confirm the o b s e r v a t i o n by K e s n e r e t a/ [26] that PCP d e c r e a s e s the efficiency of rats m solving a

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FIG 3 A and B Dose response relationship for PCP alone ( 15 mm before testing, open circles) and m combination with verapamd HC1 (20 mg/kg, 30 mm before testing, closed circles) m an 8-arm radial maze Each point represents the mean of 1 determination m each of at least 4 subjects Aba~ l ~ a Dose of PCP expressed on a log scale O r d i n a t e s A--efficiency, B--rate of responding *p<0 05 'Five of e~ght rats did not complete the maze t'Four of eight rats did not complete the maze

radial maze The observed increases in rate of responding are c o n s o n a n t with many p r e w o u s reports of P C P - m d u c e d increases m spontaneous motor activity (e g , [32]) H o w e v e r , effects on efficiency and on r e s p o n s e rate appear to be dinsociable m that (a) SKF-10,047 p r o d u c e s effects on efficiency without a rate increase and (b) P C P ' s effects on efficiency and rate appear to follow a s o m e w h a t different time course

T h e r e is both behavioral and biochemical e v i d e n c e to support the suggestion that PCP and SKF-10,047 may decrease efficiency by a similar m e c h a n i s m , the two drugs have similar stimulus properties [46], they produce cross-physical d e p e n d e n c e and cross-tolerance [47], and they both appear capable of binding to m u s c a n m c A C h [3, 18, 23, 28, 54] and sigma opiate [18, 41, 42, 58] receptors Because of the well d o c u m e n t e d ability of atropine and scopolamine to d e c r e a s e efffictency of p e r f o r m a n c e in a radial m a z e [9, 16, 22, 33, 45, 55, 56], the m v i t r o d e m o n s t r a t i o n s that PCP can act as a muscarlnlc antagomst [3, 28, 29] are of obvious interest On the other hand both phencychdlne and SKF-10,047 show antlchohnesterase activity ltl v z t r o [23, 28, 29] V a n d e r w o l f and L e u n g [531 found that PCP and atropine differentially affected neuronal actxv~ty in the rat h~ppocampus, a brain area shown to be crucial for efficient p e r f o r m a n c e in a radial m a z e [38,39] P C P (10 mg/kg, IP) eliminated atropineresistant rhythmical slow activity (RSA) while actually increasing atropine-sensitive R S A The posmble i n v o l v e m e n t of sigma opiate receptors is supported by their h~gh concentration in rat htppocampal tissue [42, 44, 58] In addition, binding of PCP and S K F - 10,047 to s e r o t o n m , [31 ] and opmte

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r e c e p t o r s o f the mu [27, 54, 57] and k a p p a [57] t y p e h a v e b e e n r e p o r t e d Clearly P C P ' s e f f e c t s on efficiency and rate o f r e s p o n d i n g may be m e d i a t e d by different r e c e p t o r m e c h anisms F r o m t h e s e d a t a alone no c o n c l u s i o n s can be m a d e with regard to w h a t p s y c h o l o g i c a l f u n c t i o n s are d i s r u p t e d by P C P and SKF-10,047 T h e d e c r e a s e d efficiency may h a v e resulted f r o m a direct effect o n the m e m o r y p r o c e s s or an e f f e c t on a n o n a s s o c l a t t v e f a c t o r such as p e r c e p t i o n [36] B e c a u s e o f e v i d e n c e that v e r a p a m d b o t h d i s p l a c e s P C P f r o m its r e c e p t o r sites [17, 18, 19, 43] a n d a n t a g o m z e s P C P ' s contractile effects on isolated cerebral arteries [1] we examlned v e r a p a m l l in the radial m a z e with the e x p e c t a t m n that it w o u l d a n t a g o n i z e the b e h a v i o r a l e f f e c t s o f P C P H o w e v e r , the data o f Fig 3 clearly s h o w p o t e n t i a t i o n by v e r a p a m l l o f P C P - l n d u c e d d e c r e a s e s in e f f i c i e n c y Falling f r o m the m a z e by rats t r e a t e d with verapamfl plus P C P h k e w l s e s u g g e s t s p o t e n t i a t i o n Thns effect was u n a n t i c i p a t e d In that It n e v e r o c c u r s m d r u g - f r e e rats and only rarely at the highest d o s e s o f P C P alone B e c a u s e "falling f r o m the m a z e " s e e m s a c r u d e and u n d e s t r a b l e e n d point, future e x p e r i m e n t s will e m p l o y a m a z e wnth higher side walls On the o t h e r h a n d ,

m o r e e x p h c l t lnvestLgatton o f the verapamll plus PCPi n d u c e d i n c r e a s e s In a t a x m might p r o v e frmtful The o b s e r v e d p o t e n t i a t i o n may h a v e r e s u l t e d from vera p a m d ' s c a l c i u m a n t a g o n i s t p r o p e r h e s or zts ability to bind to a l p h a : a d r e n e r g l c [24], s e r o t o n m , [52], m u s c a n n l c A C h [10, 11, 24], or " h i g h a f f i n i t y " [~H]PCP r e c e p t o r s [17, 18, 19, 43] P r e s u m a b l y the latter t y p e o f r e c e p t o r is identical to the sigma opiate r e c e p t o r [18, 41, 42, 58] The h k e h h o o d that the p o t e n t m t l o n ns a c o n s e q u e n c e o f c h a n g e s m the d l s p o s l t m n o f P C P is d i m i n i s h e d by the failure o f v e r a p a m l l to alter P C P ' s e f f e c t s on r e s p o n s e rate W h a t e v e r the m e c h a n i s m Involved, the o b s e r v e d p o t e n t i a t i o n d o e s not s u p p o r t the p r o p o s a l that verapamfl be used m the t r e a t m e n t o f P C P intoxication [l] The p r e s e n t data s u g g e s t that the radial m a z e may p r o v i d e an i n t e r e s t i n g alternative m e t h o d for the s t u d y o f P C P and o t h e r p s y c h o a c t i v e agents ACKNOWLEDGEMENTS We thank Mr Wdham Tanskl for the construcUon of the maze This investigation was supported m part by a Blomedncal Research Support Grant from the US Pubhc Health Service

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