The discriminative stimulus properties of cocaine and d-Amphetamine: The effects of three routes of administration

Pharmacologr Blo(heml~tr~ & Behavior Vol 24, pp 765-768, 1986 ~ Ankho International lnc Pnnted m the U S A

0091-3057/86 $3 00 + 00

BRIEF COMMUNICATION

The Discriminative Stimulus Properties of Cocaine and d-Amphetamine: The Effects of Three Routes of Administration I R E N I ~ DE LA G A R Z A 2 A N D

CHRIS

E

JOHANSON

3

The University o f Chwago, D e p a r t m e n t o f Psychiatry, Drug A b u s e R e s e a r c h Center 5841 S M a r y l a n d Avenue, Chicago, IL 60637 Received

5 August

1985

The dtv~rtrnmattve ~tlmulu~ properties ofcotame and d-amphetamine The effe~t~ oJ three Joute~ oJ administration PHARMACOL B1OCHEM BEHAV 24(3)765-768, 1986--Fave rhesus GARZA, R DE LA AND C E JOHANSON

monkeys were trained to d~scnmmate intramuscular cocaine (0 25 mg/kg, 10 mln presesslon) from sahne In subsequent tests, intramuscular cocaine (0 03-0 5 mg/kg, 10 man presessaon) and intravenous cocaine (0 03-0 25 mg/kg, 10 mln presess~on) controlled cocame-approprmte responding in a dose-dependent manner and all monkeys tested reached training criterion (greater than 90% cocame-approprmte responses) levels after the higher doses were tested d-Amphetamine (0 03-0 5 mg/kg) dehvered intramuscularly (10 mln presesslon) or mtragastrlcally (60 mln presesslon) also controlled cocame-approprmte responding m a dose-dependent manner and, at the h~gher doses, all monkeys tested reached criterion Regardless of route, cocaine and d-amphetamme were slmdar m potency lntragastnc cocaine (0 5-16 0 mg/kg, 60 rain presessaon) also controlled cocaine-appropriate responding at some dose m each monkey tested, but the drug was less potent More amportantly, the effects of IG cocaine were less systematac possibly due to uncontrolled pharmacoklnet~c factors Cocaine

d-Amphetamine

Drug dNscnmmataon

Routes of admm~straUon

IN d r u g d i s c r i m i n a t i o n p r o c e d u r e s , r e i n f o r c e m e n t ts m a d e c o n t i n g e n t u p o n o n e type o f o p e r a n t r e s p o n s e m the prese n c e o f a drug and a n o t h e r type of r e s p o n s e in t h e p r e s e n c e o f its vehicle U n d e r test c o n d i t i o n s , d o s e s l o w e r t h a n t h e t r a i n i n g d o s e typically result m p r o p o r t i o n a l d e c r e a s e s in d r u g - a p p r o p r i a t e r e s p o n d i n g , i e , a d o s e - e f f e c t f u n c t i o n is o b t a m e d F u r t h e r m o r e , w h e n d r u g s o t h e r t h a n the t r a m m g drug are tested, they p r o d u c e d r u g - a p p r o p r i a t e r e s p o n d i n g to the e x t e n t t h a t they r e s e m b l e the training drug, ~ e , t h e r e ts d r u g class specificity Drug d i s c r i m i n a t i o n p r o c e d u r e s c a n also be u s e d to c o m p a r e the effects o f the s a m e drug o r related d r u g s a d m i n i s t e r e d b y different r o u t e s S u c h c o m p a r i s o n s m a y be useful for e v a l u a t i n g a drug s u c h as c o c a i n e w h i c h p r e s u m a b l y has relatively m i n o r effects w h e n g i v e n

Rhesus monkeys

orally [4], or a m p h e t a m m e w h i c h is used t h e r a p e u t i c a l l y by the oral route, but is often a b u s e d p a r e n t e r a l l y C o c a i n e c a n f u n c t i o n as a d i s c r i m i n a t i v e stimulus in prim a t e s A l t h o u g h this effect has b e e n s h o w n to be p h a r m a c o l o g ically specific [1, 3, 6]. little or no information is available o n the d i s c r i m i n a t i v e stimulus effects o f c o c a i n e a d m l m s t e r e d by v a r i o u s r o u t e s D o w n s et al [2] r e p o r t e d t h a t in r h e s u s m o n k e y s orally a d m l m s t e r e d c o c a i n e was 16 t i m e s less potent t h a n i n t r a m u s c u l a r (IM) a n d i n t r a v e n o u s (IV) c o c a i n e o n schedule-controlled behavior d-Amphetamme given IM and orally, o n the o t h e r h a n d , did n o t differ in p o t e n c y u n d e r the s a m e c o n d i t i o n s [2] T h e p u r p o s e o f the p r e s e n t e x p e r i m e n t w a s to f u r t h e r c o m p a r e c o c a i n e and d - a m p h e t a m i n e , g i v e n l n t r a g a s t n c a l l y (IG) a n d p a r e n t e r a l l y , o n t h e basis o f t h e i r

"This research was supported by a research grant from the Nauonal Institute on Drug Abuse (DA 00250) awarded to Charles R Schuster, Principal Invesugator 2present address Umverslty of Colorado, Health Sciences Center, Department of Pharmacology, Box C236, 4200 E 9th Avenue, Denver, CO 80262 aRequests for reprints should be addressed to Chris E Johanson, Department of Psychmtry, Umverslty of Chicago, 5841 S Maryland Avenue, Chicago, 1L 60637

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Fig 1 The percent of trials completed on the cocame-approprmte lever as a function of dose and route of adminlstrat,on dunng test sessions The point above sahne (S) ,s the mean of all sahne test days obtained during the determination of all the dose response functions

During e x p e r ] m e n t a l s e s s i o n s , e a c h m o n k e y was seated m a p r i m a t e r e s t r a i n i n g c h a i r ( P l a s - L a b s , L a n s i n g , MI) w h i c h was h o u s e d within a w o o d e n cubicle ( 8 5 × 6 4 × 175 cm) A Plexlglas plate was a t t a c h e d to t h e c h a i r p e r p e n d i c u l a r to the b o d y o f the animal to p r e v e n t r e s p o n d i n g o c c u r n n g on b o t h levers s ] m u l t a n e o u s l y T h e cubicle was e q u i p p e d with two p r i m a t e l e v e r s (PRL-001, B R S / L V E ) m o u n t e d on metal b o x e s (15× 13× 10 cm) a n d located b e l o w four white Dmlco s t i m u l u s h g h t s T h e levers w e r e 24 c m apart a n d 99 c m a b o v e the floor o f the cubicle A n o t h e r m e t a l b o x ( 1 3 × 2 3 × 15 cm) was m o u n t e d on the ceiling o f the cubicle This box had a c l e a r Plexlglas c o v e r and c o n t a i n e d a white b u l b t h a t s e r v e d as h o u s e h g h t A fan m o u n t e d o n the ceiling p r o v i d e d vent]latlon a n d m a s k i n g noise T h e m o n k e y s ' feet w e r e p l a c e d into s h o e s m o u n t e d on the c h a i r B r a s s plates were p e r m a n e n t l y fitted inside the s h o e s to allow the d e h v e r y of electric s h o c k s S h o c k s were d e h v ered by a s h o c k g e n e r a t o r (SG-903, B R S / L V E ) located outside the cubicle C a b l e s c o n n e c t e d the cubicle to sohd state p r o g r a m m i n g and r e c o r d i n g e q u i p m e n t located m an adjacent room P I 0¢ (Jdlll e

d i s c r i m i n a t i v e stimulus (DS) effects R h e s u s m o n k e y s w e r e lmtmlly t r a i n e d to d l s c n m l n a t e IM c o c a i n e f r o m saline a n d s u b s e q u e n t l y c o c a i n e was t e s t e d a f t e r IM, IV, a n d IG a d m i n i s t r a t i o n In addition, s u b s t i t u t i o n p a t t e r n s for IM a n d IG d - a m p h e t a m i n e w e r e also o b t a i n e d

METHOD

Subje~ ta Five r h e s u s m o n k e y s w e r e used In this s t u d y T h e subj e c t s w e i g h e d b e t w e e n 8 a n d 10 kg and w e r e h o u s e d m stareless steel cages T h e y were g i v e n ad h b food and w a t e r a f t e r e a c h e x p e r i m e n t a l session All s u b j e c t s h a d p r e v i o u s e x p e r i m e n t a l histories in s e l f - a d m i n i s t r a t i o n a n d o t h e r studies o f s c h e d u l e - c o n t r o l l e d p e r f o r m a n c e using a v a r i e t y of p s y c h o acnve drugs

A trial procedure was used to tram the monkeys to avoid or escape the delivery of electric shocks Initially only the right lever was presented Trials were initiated with the illumination o f the househght and the lights above the lever A s h o c k period b e g a n five s e c o n d s after the initiation o f the trml D u r i n g this period, s h o c k s w e r e delivered e v e r y 2 sec (250 msec in d u r a t i o n , 10 m A in intensity) until a r e s p o n s e o c c u r r e d (escape) I m m e d m t e l y after a r e s p o n s e o c c u r r e d , the h o u s e h g h t , l e v e r lights, a n d s h o c k s w e r e t e r m i n a t e d If a r e s p o n s e o c c u r r e d b e f o r e the 5 sec p e r i o d had e l a p s e d , the h o u s e h g h t a n d l e v e r h g h t s were t e r m i n a t e d and no s h o c k s w e r e d e l i v e r e d ( a v o i d a n c e ) In b o t h c a s e s a 55 sec inter-trial interval (ITI) followed b e f o r e a n e w trial was initiated During the ITI the cubicle r e m a i n e d d a r k T h e session lasted until 30 trials were c o m p l e t e d or until 40 rain had e l a p s e d , w h i c h e v e r c a m e first W h e n the a v o i d a n c e r e s p o n s e occ u r r e d on m o r e t h a n 90c~ o f the trials for 3 c o n s e c u t i v e sessions, the left l e v e r was m a d e o p e r a t i o n a l a n d the right lever was c o v e r e d T h e same c o n t i n g e n c i e s r e m a ] n e d m effect

COCAINE DISCRIMINATION until 90% of the trials w e r e avoidance for 3 c o n s e c u t i v e sessions Thereafter, the operational lever was changed daily and, concurrently, appropriate drug m lectlons were administered 10 m m prior to the session The right lever was operative after the administration of cocaine (0 25 mg/kg, IM) for three of the m o n k e y s (4026, 6084, 8002) and the left for the other two (5127, 7037) The o t h e r lever was operative after saline T h e s e conditions remained in effect until 5 consecutive sessions with more than 90% avoidance trials were obtained Initially, the front of the restraining chair was placed flush with the lever boxes H o w e v e r , the chair was slowly r e m o v e d from the lever boxes so that a m o n k e y had to extend its arm to depress the lever The distance b e t w e e n the chair and the lever boxes was increased to prevent simultaneous responding on both levers During the next phase of training, the m o n k e y s were presented with both levers for the first time The lever that terminated the trial was made conditional upon cocaine or saline admlmstratlon, but all other conditions remained as previously described If a correct avoidance or escape response o c c u r r e d , i e , a response on the l e v e r associated with the drug condition, the trial was terminated If the monkey r e s p o n d e d on the incorrect lever, a c h a n g e - o v e r delay (COD) period was started During this period, responding on the correct lever did not terminate the trial until 2 seconds had elapsed since the last incorrect response (COD 2 sec) F u r t h e r incorrect responses reset the C O D timer Correct responses during the C O D period was signalled by a brief flicker of the househght and lever lights A trial was counted as correct w h e n no incorrect responses were emitted An additional p r o c e d u r e was introduced to facilitate discrlmmatlon training The ITI was reduced to a few seconds at the start of the training session, but all o t h e r conditions remained the same After several responses on the correct lever, without incorrect responses, the ITI was increased during the session in small increments (approximately 5 to 10 sec at a time) provided the subject continued responding on the correct lever This p r o c e d u r e was continued until the m o n k e y ' s p e r f o r m a n c e remained a b o v e 90% correct o v e r several sessions with the ITI reaching 55 sec for at least a portion of the session Subsequently, the m o n k e y was reintroduced to the initial condition in which the ITI was 55 sec throughout the entire session Initially, cocaine and saline injections were alternated on a daily basis When five c o n s e c u t i v e sessions under the terminal contingencies o c c u r r e d with more than 90% correct trials, the drug conditions were presented in a s e q u e n c e that was random e x c e p t that no condition could o c c u r more than twice in a row All o t h e r conditions remained the same When six c o n s e c u t i v e sessions of more than 90% correct trials were obtained, the abdlty of other cocaine doses, administered by the IM, IV, or IG route, to control drugappropriate responding was determined during test sessions Similar dose-effect functions were obtained with 1M and IG d - a m p h e t a m i n e When these drugs were tested IG, the drug solutions were generally g w e n 60 mm prior to the session For the other routes, drug solutions were given 10 mm prior to the session During test conditions, responding on either lever terminated the trial but all other conditions remained the same Each dose of a drug was generally given twice by each route All doses of a c o m p o u n d were presented in a mixed order and tested before a new route or drug was tested Test sessions o c c u r r e d no more frequently than twice a w e e k and at least 2 training sessions intervened N o t all m o n k e y s were tested with all routes and drugs

767

Data Analysts The percent of total responses that o c c u r r e d on the cocaine lever during test sessions was used as a measure of drug substitution The cumulative latency from the onset o f the trial to its termination was used as a measure of nonspecific drug effects

Drugs d - A m p h e t a m i n e sulfate and cocaine hydrochlorlde were obtained from the National Institute on Drug Abuse Both drugs were dissolved in physiological saline and drug doses were calculated from the salt RESULTS

Figure I shows that cocaine administered IM to five monkeys (0 03-0 5 mg/kg) or IV to four m o n k e y s (0 03-0 25 mg/kg) controlled cocaine-appropriate responding in a d o s e - d e p e n d e n t m a n n e r Cocaine did not increase the latency to the first response relative to saline by either route (data not shown) d - A m p h e t a m i n e (Fig 1) delivered IM or IG to four m o n k e y s (0 03-0 5 mg/kg) controlled cocaineappropriate responding In a d o s e - d e p e n d e n t m a n n e r at doses that did not increase the latency to respond W h e n cocaine was administered IG 60 m m pre-session, it controlled criterion levels (90%) of cocaine-appropriate responding in all 3 monkeys tested at some dose (Table 1) In monkey 7037, tested with IG cocaine with a 10 mln pretreatment, the administration of the same range of doses led to sahne-appropnate responding H o w e v e r , as shown in Table 1, responding at the 60 mln pretreatment time was not dosed e p e n d e n t and there was considerable variability across redeterminations The variability did not appear related to the drug administered the day prior to testing or o r d e r (first vs second d e t e r m m a h o n ) T w o of the three m o n k e y s died after the admlmstration of 8 mg/kg (4026) or 16 mg/kg (6084) M o n k e y 6084 died of convulsions at least 8 hours after the infusion and 4026 died of kidney and liver complications 2 days after the infusion Although it is difficult to estimate the potency of IG coc a m e because of the v a n a b t h t y , relative to cocaine given IV or IM or d - a m p h e t a m i n e given IM or IG, it was less potent All the other d o s e - r e s p o n s e functions were slmdar regardless of drug or route of administration DISCUSSION

Cocaine and d - a m p h e t a m i n e regardless of route of admmlstratton controlled drug-appropriate responding in m o n k e y s trained to discriminate IM cocaine from sahne E x c e p t when cocaine was delivered IG cocaine and d - a m p h e t a m i n e were similar m potency Although the varlabdlty of the IG cocaine results was too great to accurately estimate p o t e n c y relative to the o t h e r functions, IG cocaine was at least 2 fold less potent in each of the m o n k e y s tested In rhesus monkeys, similar effects of cocaine and d - a m p h e t a m i n e have been reported in studies that c o m p a r e d the effects of these drugs given by different routes of administration on behavior maretamed under a variable-interval schedule of food delivery D o w n s et al [2] showed that cocaine, given orally, was 16 times less potent than IM or IV cocaine when administered 30 mm before the session d - A m p h e t a m i n e given by the IM, IV and IG routes also p r o d u c e d simdar d o s e - d e p e n d e n t decreases m response rates c o m p a r e d to IM and IV cocaine Likewise, in the present e x p e r i m e n t , IV cocaine, IM co-

768

GARZA AND JOH'~NS()N

c a m e , IM d - a m p h e t a m i n e and IG d - a m p h e t a m i n e were e q u l p o t e n t in their ablhty to control c o c a l n e - a p p r o p r m t e res p o n d i n g w h e r e a s IG c o c a i n e was less p o t e n t Until r e c e n t l y , it was generally a c c e p t e d that c o c a m e w h e n t a k e n orally was l n a c t w e [4] H o w e v e r van Dyke et al [51 s h o w e d that orally a d m i n i s t e r e d c o c a i n e p r o d u c e d detectable c o c a i n e p l a s m a levels and subjective effects 30 rain after its d e h v e r y Peak p l a s m a levels and subjectr~e effects o c c u r r e d , h o w e v e r , b e t w e e n 50 and 90 rain atte~ a d m l m s t r a tlon The results o f the p r e s e n t study also d e m o n s t r a t e that c o c a i n e d e l i v e r e d dwectly into the s t o m a c h ~s active In each o f the m o n k e y s t e s t e d . IG c o c a i n e c o n t r o l l e d 100cA druga p p r o p r i a t e r e s p o n d i n g at s o m e d o s e H o w e v e r , the results w e r e e x t r e m e l y variable m that the effects were not related clearly to d o s e and there w e r e failures to r e p h c a t e w h e n d o s e s w e r e t e s t e d a s e c o n d time T h e s e i n c o n s i s t e n t results may have been due to erratic ,~b~orptJon C o c a m e 1~ not well

a b s o r b e d in the highly acidic s t o m a c h and must pass to the small intestine w h e r e a b s o r p t i o n o f basic c o m p o u n d s ~s more efficient The fmlure ot c o c a i n e to p r o d u c e d r u g - a p p r o p r m t e r e s p o n d i n g after a 10 m m p r e t r e a t m e n t m the present stud} w a s p r e s u m a b l y b e c a u s e not enough drug had passed from the s t o m a c h to the small intestine dullng testing Likewise, the results with the longer p r e t r e a t m e n t t~me may indicate that o t h e r factors, such as ¢.ocalne's vasoconstrlctp~e properties, result m variable rates o f a b s o r p t i o n Clearly t u r t h e r r e s e a r c h Js n e e d e d to d e s c r i b e the role o f these o t h e r pharm a c o k l n e t l c f a c t o r s in the b e h a v m r a l effects o f IG cocaine N e v e r t h e l e s s . regardless of varmbdLty the p r e s e n t results f u r t h e r d e m o n s t r a t e that oral cocaine IS not inactive Furt h e r m o r e , the d e l a y e d d e a t h seen m two m o n k e y s indicates that oral c o c a i n e has significant toxlctty o f u n k n o w n mechanism

REFERENCES 1 Ando, K and T Yanaglta The discriminative stimulus properties of intravenously administered cocaine in rhesus monkeys In 5lmtulu~ Propettte~ of Dtug~ Ten Year~ oJ P i o g l e ~ edited by F C Colpaert and J A Rosecrans Amsterdam Elsevier Bmmedlcal Press, 1978, pp 125-136 2 Downs, D A , L W Miller, J N Wiley and D E Johnston Oral vs parenteral drug effects on schedule-controlled behavmr in rhesus monkeys LtJe S~t 26. 1163-1168, 1980 3 Garza, R de la and C E Johanson The discriminative stimulus properties of cocaine in the rhesus monkey Phat mat ol Bu~c hem Behm 19. 145-148, 1983

4 Rltchle, J M , P J Cohen and R D Drlpps Cocaine, procaine and other synthetic local anesthetics In The PhaJma~ ologt~ al Baw~ oJ Thetapeutlt ~ edited by L S Goodman and A Gilman New York MacMillan. 1970, pp 155-168 5 Van Dyke, C , P Jatlow, J Ungerer P G Bar,ash and R Byck Oral cocaine Plasma concentration and central effects ~,t tent e 200 211-213, 1978 6 Woolverton. W L `and R C Trost Cocaine as a dlscnmln,atwe stimulus for responding maintained by food in sqmrrel monkey, Pharmac o[ Bm~ hem Behm 8 627-630, 1978