Phencyclidine and behavior: II. Active avoidance learning and radial arm maze performance1

Pharma~oh~g~ Btothemlstr~ & Beha~tor, Vol 18, pp 351-356 1983 ' Copyright Ankho International lnc Printed m the U S A

Phencyclidine and Behavior: II. Active Avoidance Learning and Radial Arm Maze Performance RAYMOND

P

KESNER.

JOHN

D

HARDY

AND JEANNE

M

NOVAK

D e p a r t m e n t o f P s y c h o l o g y . Untverstty o f U t a h . Salt Lal, e Cttv. U T 84112 Received

14 A p r d 1982

KESNER, R P J D HARDY AND J M NOVAK Phen~vchdme and beha*tor H A~tzve a*otdan~e learmng and radtal arm maze perJorman~e PHARMACOL BIOCHEM BEHAV 18(3) 351-356, 1983 ---,~ats with rejections of 4 or 8 mg/kg of phencychdlne (PCP) are lmpmred m the acqulsmon of active avoidance learning and radml arm maze performance This impairment was not due to a change m detectablhty of averslve st~muh or the mabdlty to perform the correct response The primary defiot appears to be the mabdlty of PCP rejected ammals to encode the approprmte attributes (e g , environmental context, response selection, and emotion) assocmted w~th each task Phencychdlne

Active avoidance

Radml arm maze

S I N C E its discovery, phencychdlne 1-(l-phencyclohexyl) piperldlne (PCP) has been used as an anesthetic, mainly because o f its central n e r v o u s system depressant properties H o w e v e r , clinical investigations of its anesthetic properties in humans were discontinued because the drug caused major side effects such as long duration confusional and stuperous states Recently the drug has appeared on the llhcit market and has b e c o m e known as " a n g e l d u s t " or " P C P " A c c o r d i n g to Burns and L e r n e r [4] one tablet containing 2-6 mg of PCP will result in a " h i g h " which is reached wlthm 15-30 mln and will last for 4-6 hr H o w e v e r , a completely normal state is not reached until 24-48 hr later A c c o r d i n g to Burns and L e r n e r 14] an o v e r d o s e o f PCP in the range of 1/2 to 1 g leads to severe acute intoxication This state has been either characterlzed as a confuslonal and dehrious state or as stupor and c o m a It is often the case that drugs o f abuse have marked effects on cognitive functlontng well below the dose n e c e s s a r y for severe acute Intoxication T h e s e effects may be more subtle and are detectable only with more sophisticated behavioral analyses, including learning and m e m o r y tasks F o r example, there have been anecdotal reports suggestlng that specific episodes e x p e r i e n c e d while under the influence of PCP are not r e m e m b e r e d when the subject r e c o v e r s from P C P effects [4,8] In the animal hterature there have been a n u m b e r of studies assessing the impact of PCP on well-learned responses For example, A d e y and Dunlop [1] showed that 1-3 mg/kg injections of PCP in cats disrupted for many hours p e r f o r m a n c e of a learned approach response in a T m a z e L o w e r doses (0 3-1 0 mg/kg) p r o d u c e d a similar but short-acting (seconds) impairment o f performance B r o w n and Bass [3] showed that in m o n k e y s an injection o f 0 5

mg/kg PCP resulted in c o m p l e t e disruption o f a previously learned a v o i d a n c e response At lower doses (0 05-0 25 mg/kg) there was a d o s e - d e p e n d e n t Increase in latency to respond Similar results were found in rats. in that 1 . 2 . 4 . or 8 mg/kg PCP injected subcutaneously resulted in a dosed e p e n d e n t impairment of a previously learned avoidance response [7] H o w e v e r . it is important to note that these inJections also blocked escape responding and resulted in gross disorganization Pryor et al [16] also found a disruption of a learned conditioned avoidance response with PCP. but not until a dose of 5 mg/kg was given L o w e r doses (1 25 or 2 5 mg/kg) had no effect Changes in performance on food-reinforced operant behavior have also been reported following injections of PCP Wenger [17] and W e n g e r and D e w s [18] used a multiple fixed-ratio (FR). fixed interval (FI) schedule of food remf o r c e m e n t in the mouse and pigeon They report Increased response rates at low doses and d e c r e a s e d response rates at high dose levels of PCP during the FI c o m p o n e n t , but only a dose-related d e c r e a s e in response rate was o b s e r v e d d u n n g the FR c o m p o n e n t Balster and Chalt [2] found that P C P injected in rhesus m o n k e y s p r o d u c e d only decreased response rates in a food reinforced chain FI. FR schedule In rats trained to respond on a variable interval 60 sec schedule of water reinforcement. PCP in doses of 0 2 5 . 0 5. 1 0 mg/kg increased, while doses of 2 and 4 mg/kg decreased response rates [13] Similar results were reported for rats using an FI schedule of reinforcement, namely low doses ( 1 . 2 . 4 . mg/kg) increased overall response rates, high doses (8 mg/kg) decreased overall response rates [19] Also in squirrel m o n k e y s low doses of PCP produce a small increase in VI responding. while higher doses produce decreases in rates of responding [5] Unfortunately. it is difficult to evaluate all of the a b o v e

~Support for this research was provided by Biomedical Research Support Grant, NIH RR07092-12

351

352

KESNER, HARDY AND NOVAK

mentioned changes in performance, because PCP can produce changes in activity level, motor ataxla, changes in motivational state, and possibly analgesia for painful input All of these changes could alter performance without affectlng memory or learning functions Even though there have been a large number of studies dealing with the effects of PCP upon performance of a welllearned response, there are relatively few studies that have dealt with the effects of PCP on acquisition, while only one study on the effects of PCP on long-term retention could be found in the literature With respect to acquisition Moerschbaecher and Thompson [11,12] showed that with an increasing dose of PCP injected in monkeys there was an Increase in number of errors in the acquisition of a set of response sequences or conditional discriminations Also Domino, Caldwell, and Henke [7] demonstrated that low doses of PCP (600 k~g/kg) In rats retard learning of a pole jump avoidance With respect to retention, Ghck and Zimmerberg [9] injected PCP in mice 12 mln before or immediately after passive avoidance trmnlng with a retention test 24 hr later They showed that at 5 mg/kg doses there was a significant impairment in retention, but only when reJections were given prior but not after training Neither of the two above mentioned studies has dealt with the mechanism of action for the impaired acquisition/retention of passive and active avoidance learning Thus, the purpose of the present study was first to demonstrate that PCP affects acquisition of active avoidance learning using dose levels (4 or 8 mg/kg) that In a previous study were shown to have httle effect on sensory-motor function [10], and second to subsequently analyze possible mechanisms of action

EXPERIMENT 1 METHOD

Subjc~ Is Forty-five male Long-Evans rats, initially weighing 325340 g were used as subjects All animals were maintained ad lib throughout the experiment Apparatus The apparatus consisted of a rectangular (40× 24× 54 cm) red, Plexlglas box A black ledge was mounted 10 cm above a brass rod grid floor Scrambled AC shock could be delivered to the grid floor A photocell located above the ledge was used to detect escape or avoidance responses The ledge could be retracted or extended into the box automatically with the use of a motor No handling of the animals was required during learning Relay circuitry was used to program and record events during the experiment

TABLE 1 EFFECTS O F PCP UPON ACQUISITION OF ACTIVE A V O I D A N C E

Group

N

Mean number of than to criterion

Standard Error

Saline 4 mg/kg PCP 8 mg/kg PCP

25 13 7

39 4 56 8 95 6

36 62 32

curred A jump response whether escape or avoidance resulted m a 15 sec intertrlal-lnterval followed by retraction of the ledge untd the animal fell off Immediately thereafter the ledge was again extended starting a new trial Each ammal was trained until it reached an avoidance learning criterion of 10 consecutive avoidance responses or had been given 100 trials The latter criterion was necessitated by the observation that animals injected with 8 mg/kg of PCP could not learn this task The number of trials to criterion was used as the learning measure R E S U L T S AND DISCUSSION

The mean number of trials to criterion as a functmn of PCP or sahne inJections is shown m Table 1 q he data clearly indicate that animals under the influence of 8 mg/kg of PCP cannot learn the one-way active avoidance task, while some retardation in acquisition can be seen in the 4 mg/kg group A one-way analysis of variance resulted in a significant drug effect, F(2,42)=27 3, p < 0 001 Subsequent NewmanKeuls tests revealed that the 4 mg/kg of PCP group required a significantly higher number of trials to reach criterion than the saline group p < 0 05, but significantly fewer trials than the 8 mg/kg o f P C P g r o u p p < 0 01 The 8 mg/kg of PCP group required significantly higher number of trials to reach criterion than the saline group p < 0 01 The data are consistent with previous observations by Domino et al [7], that PCP impairs the acquisition of active avoidance It is also apparent that animals under the influence of 8 mg/kg PCP cannot learn the task Even though 8 mg/kg PCP does not produce marked changes in responsiveness to olfactory, somato-sensory, and visual stlmuh [10] the possibility exists that the inability to learn the active avoidance response is due to a decreased sensitivity to pain Thus, the purpose of the next experiment was to test for the effects of 4 or 8 mg/kg PCP on behavioral sensitivity to painful shocks EXPERIMENT 2

Pro~ edure The animals were randomly assigned to a 4 mg/kg phencychdlne hydrochloride (Sernylan, Bioceutic Co ) (n= 13), 8 mg/kg PCP (n=7), or saline (n=25) group Each animal received the appropriate injection IP 30 mm prior to onset of acquisition training Each rat was placed in the apparatus and 30 sec later given the first acquisition trial At the commencement of each trial the ledge (CS) was slowly extended Ten seconds later a 1 mA shock (UCS) was delivered and continued until the animal jumped onto the ledge If the animal jumped before the end of the 10 sec CS-UCS interval, an avoidance response was registered and no shock oc-

METHOD

Aublet t~ Ten male Long-Evans rats (300-450 g) were used Animals were maintained ad lib throughout the expenment Appat atu The testing apparatus consisted of a clear Plex~glas box 30x21 x20 cm and a grid floor composed of ~/s In metal rods spaced 1 cm apart through which electric shock could be delivered

PHENCYCLIDINE

AND BEHAVIOR

353 TABLE 2

E F F E C T S O F PCP U P O N M E A N S H O C K T H R E S H O L D

Flinch (mA)

Saline 4 mg/kg PCP 8 mg/kg PCP

Vocahzatlon (mA)

Avoidance (mA)

3 × Jump and Squeal (mA)

Mean

Standard Error

Mean

Standard Error

Mean

Standard Error

Mean

Standard Error

12 17

(0 16) (0 22)

32 35

(0 24) (0 28)

32 37

(0 43) (0 29)

43 45

(0 35) (0 34)

16

(0 12)

37

(0 30)

39

(0 37)

49

(0 31)

Te~ttng Procedure All a n i m a l s w e r e i n j e c t e d I P with 4 or 8 mg/kg P C P or saline 30 mln p r i o r to testing E a c h a n i m a l r e c e i v e d e a c h drug d o s e or saline with the o r d e r o f the drug Injection c o u n terbalanced among animals Injections were given once a d a y w~th 2 d a y s b e t w e e n Injections T h e e x p e r i m e n t e r was n a i v e as to t h e drug d o s e a d m i n i s t e r e d as well as the type o f drug a d m i n i s t e r e d (l e , P C P or s a h n e ) T h i r t y m i n u t e s after Injection e a c h a n i m a l was g i v e n a s h o c k t h r e s h o l d test to d e t e r m i n e its s e n s i t i v i t y to s h o c k E a c h a n i m a l was i n t r o d u c e d a n d a d a p t e d for 1 mln to t h e small b o x A f t e r the a d a p t a t i o n period, f o o t s h o c k s (starting with 0 5 m A i n t e n s i t y ) w e r e d e h v e r e d In a s c e n d i n g o r d e r o f s h o c k i n t e n s i t y until j u m p a n d s q u e a l r e s p o n s e s w e r e obs e r v e d on t h r e e c o n s e c u t i v e f o o t s h o c k s o r until 8 0 m A Intensity was r e a c h e d S h o c k s w e r e d e l i v e r e d b y a s c r a m b l e d A C s h o c k g e n e r a t o r using a t r a m d u r a t i o n o f 0 5 sec Succ e s s i v e s h o c k s were i n c r e a s e d b y 0 5 m A steps T h e inters h o c k interval was a p p r o x i m a t e l y 4 sec, b u t s h o c k s w e r e d e h v e r e d only w h e n the a n i m a l was m a k i n g c o n t a c t with t h e grid floor with all four p a w s T h e s h o c k i n t e n s i t i e s r e q u i r e d to mltlate a flinch, a v o c a l i z a t i o n , a n a v o i d a n c e r e s p o n s e , a n d r e a c h the c r i t e r i o n o f t h r e e c o n s e c u t i v e j u m p a n d s q u e a l r e s p o n s e s were used as d e p e n d e n t m e a s u r e s A flinch was defined as a r e s p o n s e to s h o c k c h a r a c t e r i z e d b y c r o u c h i n g or a rapid c h a n g e m p o s t u r e or limb m o v e m e n t w i t h o u t b o d y position m o v e m e n t in relatxon to the grid floor A v o c a h z a tlon was c h a r a c t e r i z e d b y o n e or m o r e audible v o c a l i z a t i o n s An a v o i d a n c e was c h a r a c t e r i z e d by rapid b o d y m o v e m e n t a c r o s s the grid, c r o s s i n g m o r e t h a n half t h e floor w i d t h A j u m p a n d squeal was c h a r a c t e r i z e d b y the c o m b i n a t i o n o f j u m p i n g a n d o n e or m o r e d e t e c t a b l e v o c a h z a t l o n s A res p o n s e was rated as a j u m p w h e n all four o f the a n i m a l ' s p a w s w e r e off the grid at o n e time

EXPERIMENT

3

H o w e v e r , it is p o s s i b l e that a n i m a l s c a n learn t h e task b u t u n d e r the i n f l u e n c e o f 8 mg/kg P C P c a n n o t p e r f o r m t h e app r o p r i a t e e s c a p e or a v o i d a n c e r e s p o n s e ( j u m p i n g o n a platform) In o r d e r to test this possibility, a n i m a l s w e r e Initially t r a i n e d to c r i t e r i o n o n the a c t i v e a v o i d a n c e t a s k a n d t h e n t e s t e d for r e t e n t i o n o f the a v o i d a n c e r e s p o n s e If the a n i m a l s c a n n o t p e r f o r m t h e a v o i d a n c e r e s p o n s e u n d e r the i n f l u e n c e o f PCP, t h e n t h e a n i m a l s s h o u l d s h o w no r e t e n t i o n a n d s h o u l d take o n t h e a v e r a g e 95 trials (see E x p e r i m e n t 1) to r e a c q u l r e the a v o i d a n c e r e s p o n s e If t h e a n i m a l s r e l e a r n or retain the a v o i d a n c e r e s p o n s e in significantly f e w e r t h a n 95 trials, t h e n it c o u l d be a r g u e d t h a t P C P has a n effect o n learning METHOD

Subje~ ts T w e n t y - f o u r male L o n g - E v a n s rats (300-450 g) w e r e used A n i m a l s w e r e m m n t a i n e d ad h b t h r o u g h o u t the e x p e r iment

Apparatus The a p p a r a t u s was the same as described in E x p e r i m e n t 1

Prot edure T h e a n i m a l s w e r e r a n d o m l y a s s i g n e d e i t h e r to a 4 mg/kg ( n = 9 ) , 8 mg/kg ( n = 8 ) PCP, or s a h n e ( n = 7 ) g r o u p O n Day 1 the p r o c e d u r e w a s identical to t h a t d e s c r i b e d in E x p e r i m e n t 1, e x c e p t t h a t n o d r u g s w e r e injected o n this d a y O n Day 2 (24 hrs later) a n i m a l s r e c e i v e d a p p r o p r i a t e rejections (IP) 30 m m prior to the r e t e n t i o n test w h i c h consisted o f training trials until the a n i m a l r e a c h e d a n a v o i d a n c e criterion o f 10 cons e c u t l v e a v o i d a n c e r e s p o n s e s o r h a d b e e n g i v e n 100 trials

R E S U L T S A N D DISCUSSION

T h e m e a n s h o c k t h r e s h o l d for flinch, v o c a l i z a t i o n , a v o i d a n c e , a n d 3 × j u m p a n d squeal u n d e r the influence o f 4. 8 mg/kg P C P or saline are s h o w n in T a b l e 2 T h e r e a p p e a r to be n o d i f f e r e n c e s o n a n y o f the m e a s u r e s O n e - w a y A N O V A s o n e a c h m e a s u r e r e v e a l e d t h a t t h e r e w e r e n o significant d i f f e r e n c e s a m o n g t h e t h r e e g r o u p s Since P C P h a d n o effect o n d e t e c t i o n o f s h o c k , a c h a n g e In r e s p o n s l v l t y to a v e r s l v e stimuli c a n n o t a c c o u n t for the p o o r a c t i v e a v o i d a n c e a c q u i s i t i o n o f P C P InJected a n i m a l s

R E S U L T S A N D DISCUSSION

T h e m e a n n u m b e r o f trials to c r i t e r i o n o n the r e t e n t i o n t e s t (Day 2) as a f u n c t i o n o f P C P or s a h n e Injections is s h o w n m T a b l e 3 T h e d a t a indicate t h a t a n i m a l s u n d e r t h e influence o f 8 mg/kg P C P take s o m e w h a t m o r e trials to r e l e a r n the a c t i v e a v o i d a n c e r e s p o n s e m c o n t r a s t to t h e 4 mg/kg P C P a n d saline g r o u p s It s h o u l d b e n o t e d , h o w e v e r , t h a t the a n i m a l s u n d e r the influence o f 8 m g / k g P C P c a n p e r f o r m a n d retain the a c t i v e a v o i d a n c e r e s p o n s e in f e w e r trials t h a n

354

KESNER, HARDY AND NOVAK

TABLE 3 EFFECTS OF PCP UPON RETENTION OF ACTIVE AVOIDANCE

Group

N

Mean number of trmN to criterion

StandArd Error

Sahne 4 mg/kg PCP 8 mg/kg PCP

7 9 8

14 6 14 2 28 1

I5 24 10 6

TABLE 4 EFFECFS OF PRE- AND POST-TRAINING PCP INJECTIONS ON RETENTION OF ACTIVE AVOIDANCE

Injections

Before

After a n i m a l s t h a t were required to learn the active a v o i d a n c e response u n d e r the influence of 8 mg/kg P C P (see E x p e r i m e n t 1 ) A o n e - w a y analysis o f v a r i a n c e r e v e a l e d t h a t t h e r e were n o significant drug effects, F ( 2 , 2 1 ) = I 77, p < 0 25 T h u s it c a n be c o n c l u d e d t h a t animals t h a t h a v e learned the active a v o i d a n c e r e s p o n s e can p e r f o r m the r e s p o n s e u n d e r the influence o f 8 mg/kg PCP, ruling out that the lmtlal learning deficit s e e n m E x p e r i m e n t 1 is due to the a n i m a l s ' l n a b l h t y to p e r f o r m a j u m p i n g r e s p o n s e u n d e r the influence o f P C P

EXPERIMENT

4

T h e p o s s l b l h t y exists that a n i m a l s u n d e r the influence of P C P h a v e an e n c o d i n g deficit, that is they do not p e r c e i v e a n d register the r e i n f o r c e m e n t c o n t i n g e n c i e s a n d / o r are unable to select the a p p r o p r i a t e a v o i d a n c e r e s p o n s e (jumping o n t o the platform) H o w e v e r , it is also possible t h a t inform a t i o n is e n c o d e d properly, but that c o n s o l i d a t i o n o f inform a t i o n is i m p a i r e d T h u s , the p u r p o s e o f the next e x p e r i m e n t is to differentiate b e t w e e n the a b o v e m e n t i o n e d p o s s l b l l m e s b y injecting P C P before or a f t e r ten training trials and a s u b s e q u e n t retention test 24 hr later Support for a more direct effect o f P C P o n the e n c o d i n g p r o c e s s would c o m e from the o b s e r v a t i o n t h a t pre-tralnlng injections h a d d e l e t e r i o u s effect u p o n r e t e n t i o n , while post-training injections had no effect S u p p o r t for a m o r e direct effect o f P C P on the c o n s o l i d a t i o n p r o c e s s would c o m e from the o b s e r v a t i o n that post-training injections p r o d u c e d a n i m p a i r m e n t of r e t e n t i o n , w h d e pretraining injections h a d no effect METHOD 5uble¢ t~

Fifty male L o n g - E v a n s rats (300-450 gl were used A n i m a l s were m a i n t a i n e d ad lib t h r o u g h o u t the e x p e r i m e n t Apparatu3

The a p p a r a t u s was the same as described in E x p e r i m e n t 1 Prot ('dllt t"

T h e a n i m a l s w e r e r a n d o m l y a s s i g n e d e i t h e r to a 4 mg/kg ( n = 8 ) , 8 mg/kg (n =8) P C P or saline ( n = 8 ) pre-tralning g r o u p or a 4 mg/kg ( n = 7 ) , 8 mg/kg ( n = 7 ) , 12 mg/kg ( n = 4 ) PCP, or saline ( n = 8 ) post-training g r o u p T h e p r o c e d u r e was identical to that d e s c r i b e d in E x p e r i m e n t ! with the only difference that a n i m a l s m the pre-tramnlng g r o u p s r e c e i v e d 10 trials u n d e r the influence o f 4 or 8 mg/kg P C P or saline injected 30 mln prior to training, while the a n i m a l s m the p o s t - t r a i n i n g g r o u p s r e c e i v e d the a p p r o p r i a t e injection i m m e d i a t e l y after

Groups Sahne 4 mg/kg 8 mg/kg Saline 4 mg/kg 8 mg/kg 12 mg/kg

PCP PCP PCP PCP PCP

N

Mean number of Trials to Cntenon

StandArd Error

8 8 8 8 7 7 4

14 8 16 5 ~0 4 15 2 19 I 25 6 17 8

30 2 1 58 29 ~0 64 27

ten training trials T w e n t y - f o u r h o u r s later they were tested for r e t e n t i o n a n d t r a i n e d to criterion RESULTS AND DISCUSSION T h e effects o f different d o s e s of P C P injected before or after training u p o n m e a n n u m b e r o f trials to criterion are s h o w n m T a b l e 4 ~Ihe d a t a indicate that a n i m a l s lmtlally t r a i n e d u n d e r the Influence of 8 mg/kg o f P C P h a v e impaired r e t e n t i o n 24 h r later as indicated by the larger n u m b e r ot trials r e q u i r e d to r e a c h criterion c o m p a r e d to saline or 4 mg/kg P C P injected a n i m a l s A similar but m u c h smaller ret e n t i o n deficit can be seen in a n i m a l s that r e c e i v e d 8 mg/kg of P C P after training A o n e - w a y analysis of v a r i a n c e r e v e a l e d that t h e r e was a significant t r e a t m e n t effect F ( 6 . 4 3 ) = 2 98 p < 0 05 F u r t h e r D u n c a n - R a n g e t e s t s r e v e a l e d that the g r o u p that r e c e i v e d 8 mg/kg P C P after training h a d significantly p o o r e r r e t e n t i o n than the saline a n d 4 mg/kg P C P injected g r o u p s ( p < 0 05) H o w e v e r t h e r e were no significant diff e r e n c e s b e t w e e n the two g r o u p s of a n i m a l s that r e c e i v e d 8 mg/kg P C P b e f o r e or after t r a i n i n g T h e p r e s e n t e x p e r i m e n t suggests that t h e r e ~s a dosed e p e n d e n t d i s r u p t i o n of reterttlon primarily w h e n P C P Is rej e c t e d b e f o r e training This suggests that the p n m a r y effect of P C P might be o n the initial e n c o d i n g p r o c e s s H o w e v e r t h e r e might also be a small effect on the c o n s o l i d a t i o n process G i v e n that PCP has a m a j o r effect u p o n the e n c o d i n g of c r m c a l i n f o r m a t i o n , it is still n e c e s s a r y to d e t e r m i n e the e x a c t n a t u r e of this e n c o d i n g deficit EXPERIMENT

5

It is possible that a n i m a l s u n d e r the influence of P C P c a n n o t e n c o d e 1he e n v i r o n m e n t a l c o n t e x t , especially spatial a s p e c t s , e m o t i o n a l c o n s e q u e n c e s o f painful s h o c k s or selection of a p p r o p r i a t e m o t o r r e s p o n s e In o r d e r to a c c e n t u a t e the i m p o r t a n c e o f spatial a s p e c t s of the e n v i r o n m e n t and m i n i m i z e painful e x p e r i e n c e s we selected to s t u d y the effects o f P C P o n radial a r m m a z e p e r f o r m a n c e It h a s b e e n s u g g e s t e d t h a t p e r f o r m a n c e on this task r e q u i r e s a p p r o p r i a t e e n c o d i n g o f e x t r a - m a z e (spatial) cues [ 14] METHOD .S uble~ t

F w e male L o n g - E v a n s rats (weight 325-400 g) s e r v e d as

PHENCYCLIDINE AND BEHAVIOR

355

subjects Animals were maintained at 80% of their ad hb body weight, but allowed continuous access to water

Apparatus

The apparatus consisted of an e~ght arm maze s~mllar to that described by Olton and Samuelson [14] The central platform was 27 cm in dmmeter Eight arms radmted from the center platform at equidistant points Each arm was 10 cm w~de and 86 cm long The entire apparatus was constructed of wood painted white and was elevated 47 cm above the floor The testing room was well hghted w~th fluorescent hghts and with many p~ctures on the surrounding walls P~ o¢ edure

Ammals were trained using the standard e~ght arm procedure w~th all arms reinforced [14] Reinforcement consisted of small p~eces of Froot Loops cereal Each trml (one per day) continued until the rat has v~s~ted and eaten the food on all 8 arms Reentry into an arm prevmusly ws~ted was scored as an error Entries into arms were recorded by a single observer Each trml lasted about 5 mm After reaching criterion of errorless performance which was usually reached within 20 trials, each ammal received increasing doses of PCP (2, 3, 4, 5, 6, 7, 8, 9 mg/kg) w~th two days of sahne mject~ons between each dose of PCP Th~s procedure was used because m a prewous study [10], no behavioral tolerance effects were observed w~th repeated PCP reJections Ammals were always tested 30 mm after mjecuon When an ammal reached a dose which resulted m errors on the radml arm maze, the ammal would be tested four hmes at the same dose level w~th two sahne mjectmns in between each test When an ammal made errors on at least three of four tests, no add~tmnal PCP mjectmns were administered

RESULTS AND DISCUSSION The average dose of PCP that resulted m errors m at least 3 of 4 trials was 6 6 mg/kg with a range from 5-9 mg/kg The mean total number of errors for the 4 trials was 15 4 with a range from i l - 2 2 errors Animals reJected with sahne or doses of PCP less than 5 mg/kg produced very few errors It ~s of interest that the dose level that resulted m a failure to perform correctly on the radml arm maze is slmdar to the dose levels used to disrupt acqmsltmn and retentmn of active avoidance learning To the extent that encoding of spatial aspects of the environment is crmcal for errorless performance on the radml arm maze, the results suggest that PCP might indeed play a cnhcal role in th~s encodmg process

GENERAL DISCUSSION The data indicate that there is a dose-dependent dtsruptlon of active avoidance learning with PCP (Experiment 1) Th~s result ~s consistent w~th the observatmns of Domino et al [7], who also demonstrated that PCP resulted m an acqmsmon deficit of a somewhat d~fferent type of active avoidance task It should be noted that Domino et al [7] were able to obtain th~s deficit with s~gmficantly lower doses of PCP Further analysis revealed that this acqmsltmn impairment is not due to possible PCP induced changes m response sensmwty to shock, since there ~s no change m shock threshold m ammals w~th PCP mjectmns (Experiment 2) Also ammals under the influence of PCP can perform the appropriate avoidance response tf the drug was injected after animals had prevmusly learned the response, ruhng out the posslblhty that the acqmsltlon deficit is due to the lnabdlty to jump onto the platform (Experiment 3) Posstble changes m activity level also cannot account for the actwe avoidance deficit because (a) even though both 4 and 8 mg/kg PCP resulted m active avoidance impairments 4 mg/kg PCP rejected animals show increases m act~wty level, whde 8 mg/kg PCP injected ammals show decreases [10], and (b) 8 mg/kg PCP lnjectmns before trammg m a passive avoidance learning s~tuatlon produces a retention deficit 24 hrs later (unpubhshed observatmns) If a decrease in actlwty were responsible for the active avoidance deficit, then one would have expected faclhtatlon of retentmn of passive avoidance learnlng The findings that animals with 8 mg/kg PCP lnjectmns before training failed to show retentmn 24 hrs later, whereas animals that received PCP injections after training d~splayed relatwely normal retention ~s consistent w~th the results of Ghck and ZImmerberg [9] and suggest that the primary ~mpact of PCP is on the encoding phase (1 e , inadequate coding of appropriate attributes) However, we must be cautious m stating that PCP affects only the encoding of critical mformatron, because (a) any effect on the encoding process could easily have secondary effects on consohdatmn or retrieval and (b) a certain level of long-term consohdatmn might be taking place during the training phase The exact nature of the encoding deficit still needs to be determined The observatmn that animals cannot perform m a radml arm maze (Experiment 5), cannot learn and retain an achve avoidance response (Experiments 1 and 4), and cannot retain a passive avoidance response (unpubhshed observatmns) and cannot learn condlttonal discriminations [ 11,12] ~mphes a difficulty m encoding of a variety of attributes, but especially the environmental context It Is important to note that with low doses of PCP m humans there is also an lmpmrment in encoding of spatial components of the environmental context [15] More work needs to be done to characterize the exact nature of the encoding deficit

REFERENCES 1 Adey, W R and L W Dunlop The action of certain cyclohexamme on hlppocampal system dunng approach performance m the cat J Pharmacol Erp Ther 130 418-426, 1960 2 Balster, R L and L D Chalt The behavioral pharmacology of phencychdme Chn Tortcol 9 513-528, 1976 3 Brown, H and W C Bass Effect of drugs on visually controlled avoidance behavior m rhesus monkeys A psychophyslcal analysis Pvwhopharmatologv (Berlm) 11 143-153, 1976

4 Burns, R S and S E Lerner Perspecuve Acute phencychdme intoxication Clttl Toxtcol 9 477-501, 1976 5 Chalt, L D and R L Balster Effects of phencychdme, atropine and physosugmme, alone and in combmatmn, on variable-interval performance m the sqmrrel monkey Pharmacol Btochern Behav 11" 37-42, 1979

356

6 Domino, E F Neuroblology of phencychdme (Sernyl), a drug with an unusual spectrum of pharmacological actlwty lnt Re~ Neurobtol 6 303-347 1964 7 Domino, E F D F Caldwell and R Henke Effects of psychoactive agents on acquisition of conditioned pole jumping m rats Psvchopharma~ologv (Berhn) 8 285-289. 1965 8 Domino, E F and E D Luby Abnormal mental states reduced by phencychdlne as a model of schlzophrenm In Ps,~hopathoh~gv and Psxthopharma~ologv, edited by J O Cole, A M Freeman and A J Frledhoff Baltimore Johns Hopkins Press, 1973, pp 37-50 9 Ghck S D and B Zimmerberg Comparative learning impairment and amnesm by scopolamine phencychdme and ketamme P~v~hon S~t 25 165-166, 1971 10 Kesner, R P , J D Hardy and L D Calder P h e n c y c h d m e a n d behawor I Sensory-motor function, activity level, taste averslon and water retake Pharmacol Btothem Beha~ 15 7-13 1981 11 Moerschbaecher J M and D M Thompson Effects of d-amphetamine, cocaine, and phencychdme on the acqmsltton of response sequences wtth and wtthout stimulus fading J Erp Anal Behav 33 369--381, 1980 12 Moerschbaecher J M and D M Thompson Effects o f p h e n cychdme, pentobarbltal, and d-amphetamine on the acqmsltlon and performance of condmonal discriminations m monkeys Pharma~ ol Bto~ hem Beha~ 13 887-894 1980

KESNER, HARDY AND NOVAK

13 Murray T F The effect of phencychdlne on operant behavior in the rat blphaslc effect and tolerance development Lt/e St l 22 195-202 1978 14 Olton, D S and R J Samuelson Remembrance of places passed SpaUal memory m rats J E~:p P~c hol (Atom Beha~ ) 2 97-116 1976 15 Pearlson, G D Psychiatric and medical syndromes asso~.lated with phencychdlne (PCP) abuse Johns Hopkm~ Med J 148 25-33 1981 16 Pryor G T , S Husam S Larsen, C E McKenzle J D Carr and M C Braude Interactions between c~-tetrahydrocannabmol and phencychdme hydrochlonde m rats Ptuoma~,,I Bu,chem Behat 6 123-136 1977 17 Wenger, G R The effect of phencychdme and ketamme on schedule-controlled behavior m the pigeon J Pharma~ol L~p Ther 196 172-179 1976 18 Wenger G R and P B Dews The effects of phencydJdme ketamme, d-amphetamine and pentobarbltal on schedulecontrolled behavior in the mouse J Pharma~ol Erp Ther 196 616-624 1976 19 Woolverton W L and R L Balster Tolerance to the behavioral effects ofphencychdlne The importance of behaworal and pharmacological variables P~hopharma~ol.~.~ (Berhn) 64 19-24 1979