Behavioral pharmacology of local anesthetics: Reinforcing and discriminative stimulus effects

PharmacologyBtochemtstrv&Behavtor, Vol 16, pp 491-500, 1982 Pnnted m the U S A

Behavioral Pharmacology of Local Anesthetics: Reinforcing and Discriminative Stimulus Effects I WILLIAM

L

WOOLVERTON

~ AND

ROBERT

L

BALSTER

Department o f Pharmacology, M e d w a l College o f Virgtnla Vtrglma Commonwealth Untvers~ty, R w h m o n d , VA 23298 Received

6 August

1981

WOOLVERTON, W L AND R L BALSTER Behavu~ralpharmacology of local anesthett~s Remforcmg and dlscrtmtnatt~e sttmulu~ effects PHARMAC BIOCHEM BEHAV 16(3)491-500, 1982--The reinforcing properties of several short-acting esteratlc local anesthetics were determined m rhesus monkeys experienced m the IV selfadministration of cocaine In addition, the discnmmattve stimulus properties of these and several other local anesthetics of both the ester and am~de class were determined m rats trained to discriminate procaine from saline m a 2-1ever operant task IV dehvery of chloroprocame, dlmethylprocalne or dtmethocame maintained responding above vehicle levels in most monkeys while propoxycalne, piperocame and dlmethylammoethanol (Deanol) faded to maintain self-administration behavior Thus some, but not all, short-acting esteratlc local anesthetics are positive reinforcers m rhesus monkeys In add~tton, ~t ~s unhkely that the reinforcing effects of dlmethylprocame are mediated by its metabohte dlmethylaminoethanol In rats, all local anesthetics tested except p~perocalne and procamam~de resulted in responding on the procaine-appropriate lever indicating procalne-hke dlscnmmatwe stimulus effects for these compounds In addition, InjecUons of d-amphetamine resulted m pnnclpally procaine lever responding All local anesthetics that were self-administered by rhesus monkeys had discriminative stimulus effects m rats that were slmdar to those of procaine However, not all local anesthetics that were procame-hke m rats were self-admtmstered by rhesus monkeys These data may represent a separation of these two stimulus properties for local anesthetics although other variables such as spectes differences may play a role Local anesthetics Drug d~scnmmat~on Self-admm~stratlon Rhesus monkey Rat Procaine Lldocame Tetracame Procamamide Propoxycalne Piperocalne Chloroprocame Dlmethylprocalne Dimethocame Cocaine Deanol T H E s u r p r i s i n g finding t h a t I V p r o c a i n e c a n f u n c t i o n as a p o s i t i v e r e i n f o r c e r in r h e s u s m o n k e y s [6,7] h a s led to s p e c u lation t h a t o t h e r local a n e s t h e t i c s m i g h t also h a v e r e i n f o r c i n g effects w h i c h could c o n t r i b u t e to t h e i r a b u s e O n e m e m b e r of this g r o u p , c o c a i n e , is clearly s e l f - a d m i n i s t e r e d b y b o t h labo r a t o r y a n i m a l s a n d h u m a n s In a d d i t i o n , V a n D y k e et al [18], u s i n g h u m a n v o l u n t e e r s , f o u n d t h a t m t r a n a s a l h d o c a m e was indistinguishable from cocaine administered by the same r o u t e F u r t h e r r e s e a r c h with a m m a l s h a s r e v e a l e d t h a t o t h e r local a n e s t h e t i c s h a v e r e i n f o r c i n g effects in r h e s u s m o n k e y s [9,20], t h o u g h this is not a p r o p e r t y o f all m e m b e r s o f this class, a n d h a s a l l o w e d t h e t e n t a t i v e c o n c l u s i o n t h a t s h o r t acting e s t e r a t i c local a n e s t h e t i c s are m o s t likely to h a v e this effect T h e first p u r p o s e o f t h e p r e s e n t r e s e a r c h w a s to f u r t h e r e v a l u a t e t h e h y p o t h e s i s t h a t s h o r t - a c t i n g , e s t e r a t l c local a n e s t h e t i c s are m o r e likely to b e s e l f - a d m i n i s t e r e d t h a n o t h e r t y p e s o f local a n e s t h e t i c s , a n d w h e t h e r this w a s a p r o p e r t y of e s t e r a t i c local a n e s t h e t i c s m g e n e r a l It w a s also o f i n t e r e s t to e v a l u a t e the r e i n f o r c i n g effects o f d l m e t h y l a m i n o e t h a n o l

( D M A E , D e a n o l ) since th~s drug is a m e t a b o h t e o f s e v e r a l local a n e s t h e t i c s t h a t are r e i n f o r c e r s , a n d as well h a s p s y c h o t r o p i c effects m its o w n r i g h t [2,12] A s e c o n d p u r p o s e o f this r e s e a r c h w a s to d e t e r m i n e w h e t h e r p r o c a i n e c o u l d f u n c t i o n as a d i s c r i m i n a t i v e s t i m u l u s a n d w h e t h e r o t h e r local a n e s thetics had stimulus properties m common with procaine [15] T h e results p r e s e n t e d d e m o n s t r a t e r e i n f o r c i n g effects m m o n k e y s for s e v e r a l a d d i t i o n a l local a n e s t h e t i c s a l t h o u g h n o t all e s t e r s w e r e r e i n f o r c e r s In a d d i t i o n , m o s t o f t h e local a n e s t h e t i c s t e s t e d h a d d i s c r i m i n a t i v e s t i m u l u s effects t h a t w e r e s l m d a r to t h o s e o f p r o c a i n e in rats

EXPERIMENT

1 SELF-ADMINISTRATION

STUDIES

METHOD T h e g e n e r a l m e t h o d s for this s t u d y w e r e s i m d a r to t h o s e used p r e v i o u s l y to s t u d y t h e s e l f - a d m i n i s t r a t i o n o f p r o c a i n e a n d o t h e r local a n e s t h e t i c s [6,20]

~Research supported by N I D A Grant DA-00490 Mml repnnt requests to Robert L Balster, Box 613, Medical College of Virginia, Richmond, VA 23298 2Postdoctoral Fellow Supported by N I D A Fellowship DA-05164 Present address Umverslty of Chicago, Department of Pharmacological and Physiological Soences, Chicago, IL 60637

Copyright

© 1982 A N K H O

International

Inc--0091-3057/82/030491-10503

00/0

492 Anlmala and Appatatus The ammals were six adult male rhesus monkeys (Mac a¢ a mulatta) that weighed between 7 9 and 11 7 kg at the beginmg of the experiment All ammals had experience m the self-administration of various psychoactive drugs including local anesthetics and phencychdme Each was fitted with a stainless steel restraint harness [4] and spring arm which attached to the rear of the experimental cubicle The ammal hved m the experimental cubicle (0 8 × 0 8 × 1 0 m) for the duration of the experiment Water was continuously available and each monkey received approximately 150 g of Purina Monkey Chow and a chewable mulnple wtamin tablet each day. after the expenmental session On the mside front of each experimental cubicle two response levers were mounted on the transparent Plexlglas door 30 cm above the floor and a food dish was mounted between them Three jewelled stimulus hghts were mounted directly above each lever Drug infusions were dehvered vm peristaltic infusion pumps (Cole-Parmer Co , Chicago IL) All programming and recording was accomplished by sohd state eqmpment located m an adjacent room

Pro( edut c Surgery Following adaptation to the cubicle and restraint system, each animal was removed from the cubicle and rejected with a combination of phencyclldlne hydrochlonde (1 mg/kg. IM) and atropine sulfate (0 04 mg/kg. IM) followed in 20-30 mln by sodium pentobarbltal (10-20 mg/kg IV) When anesthesia was adequate, a silicone catheter C0 08 cm ID. Ronsi1 Rubber Products, Bell Mead. NJ) was surgically implanted into a major vein Internal and external jugular and femoral veins could be catheterized The catheter was threaded through the spnng arm to the back of the cubicle and connected to the Infusion pump which delivered drug solutions at a rate of 1 ml/10 sec I f a catheter became nonfuncnonal during the experiment, a new catheter was ~mplanted as before following a I-2 week period to allow any mfechon to clear Following surgery, the animal was returned to the cubicle Tpamlng Initially, each animal was trained in the presence of the two white hghts above the left lever to press the left lever for a 10-sec injection of 0 1 mg/kg cocaine hydrochlonde During an injection the white lever hghts were extinguished and the center red lever light was illuminated Responses occurmg on the left lever during the mjecnon as well as those occurring on the right lever had no programmed consequence Following acquisition of the lever press response, the number of responses required for drug dehvery was increased to l0 over the period of one 2-hr session (fixed ratio 10 FR 10) After responding during daily 2-hr sessions stabilized (2-3 days), a dose of 0 I p.mole/kg/mj cocaine hydrochloride (34/~g/kg/inj) was used to maintain responding m all animals Substttutton procedure Daily sessions were signaled by the illumination of the white lights over the left lever During baseline sessions, the animals received IV mjecnons of 0 l p.mole/kg/mj cocaine contingent upon left lever responding on an FR10 schedule The number of injections delivered was recorded every 30 min and the total left lever responses were recorded for the session Following the establishment of stable rates of responding under baseline conditions (less than 10°~ varmtlon m total numbers of injections per session for 3 consecutive sessions), 0 9% sahne or a dose of one of

WOOLVERTON AND BALSTER the test compounds, was subsntuted for 6 consecuhve sessions after whzch the ammal was returned to basehne conditions Several local anesthetics were subsntuted for cocame m a counterbalanced order using th~s procedure At least three doses of each drug were tested in an unsystematic order m each ammal, and all doses of one drug were completed before testing another drug Doses were m~tmlly selected m a range comparable to known reinforcing doses of procaine (1 0-3 0 tzmoles/kghnj) and were tested over a 30 to 100-fold range untd doses hlgh enough to suppress lever pressing m the first session of a subsntunon period were achieved In add~non, sahne was subsntuted for s~x sessions at the beginning of the dose series for each drug DMAE was also tested m one of the subjects (No 4173) used for the testing local anesthehcs as well as two add~nonal subjects Dru ~ The hydrochlonde ~alts of the following local anesthencs were used chloroprocalne (Penwalt Corporanon, Rochester, NY), dlmethylprocame (Abbott Laboratones N Chicago, IL). dzmethocaine (Hoffrnan-LaRoche, Nutley N J), piperocalne (Ell Ldly and Co , Indlanapohs. IN), and propoxycalne (Sterhng-Wmthrop Research Insntute. Rensselaer, NY) In addition, llqmd dlmethylammoethanol (DMAE) was used (Pfaitz and Bauer, Stanford, CN) Each compound was dissolved in 0 9% sahne for rejection with concentranons adjusted so that mjecnons were administered in a volume of 1 0 ml over a 10-see period Doses were expressed as tzmoles/kg/lnject~on For purposes of comparison. 1 0/xmole of each compound is eqmvalent to the followmg cocaine HC1-340 /zg. chloroprocame HCI-307 t~g, d~methylprocame HC1-244 /xg, dlmethocame HC1-315 /zg. plperocaine HC1-298/xg, dimethylprocame HC1-244 p.g, dlmethocalne HC1-315 p.g, plperocalne HCI-298 p.g, propoxycalne HCI-331 p.g. and DMAE-89 /xg The chemical structure of each local anesthenc IS shown m Fig 1 Data Anal~ ~ta The number and d~stnbutlon of Injections over the last three sessions of a test drug substitution period were used m data analysis For each drug these values were compared to the same values for the last three sessions of the correspondlng saline substitution period A drug was considered to be a positive reinforcer in a particular subject if the mean number of lnjecnons for the last three sessions of a test period exceeded the mean value for the corresponding saline subsntunon, and the ranges d~d not overlap RESULTS Under the baseline conditions, cocaine maintained stable responding that was above the range of sahne values for each subject (values above C and S In Fig 2) There was. however. considerable variability between subjects m cocaine intake per session, with mean values ranging between 35 (No M263) and 118 (No 7623) lnj/sesslon When saline was substituted for cocaine, low rates of responding (<10 mj/ session) were usually observed by the sixth session When chloroprocaine, dimethocalne or dimethylprocaine were substituted for cocaine, self-administration was maretamed above saline levels at least at one dose in all animals tested, and was often in excess of 100 lnj/sesston (Figs 2 and 3) Although rates of responding were often not as high for

493

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chloroprocame and dlmethylprocalne as for dlmethocame, dose-response relaUonshlps for all three of these compounds were generally of the inverted " U " shape frequently described for drugs that are positive remforcers [19] Of these three, dlmethocaine was the most potent with responding consistently maintained in the range of 0 1 to 1 0 ~moles/ kg/lnj as compared to the 1 0-3 0 ~moles/kg/lnj doses of chloroprocalne and dimethylprocalne that were usually required to mmntam self-administration In addition, the range of doses of dlmethocalne that supported self-administration behavior was relatively wide In contrast, when plperocalne or propoxycaine were substituted for cocaine, responding at or below saline levels was consistently observed (Figs 2 and 3) Furthermore, there was no systematic dose-response relationship for these compounds until doses high enough to suppress responding were achieved In this regard, propoxycame and plperocalne were approximately equlpotent, with 3 /xmoles/kg/inj usually suppressing responding to below saline levels D MA E. which was tested m two additional ammals not shown m Fig 2 (No 3018, M-269), also fatled to maintain response rates above vehicle control values (Table 1) Comparisons are made between drugs in terms of pattern of responding over the experimental session in Figs 3 and 4 and Table 1 Consistent with the findings of others [1, 5, 20], responding for cocaine was relatively evenly distributed over the session, with slightly more than 25% of the toal number of Injections taken in the first 1/4 of the session In contrast, when sahne was substituted for cocaine, a typical extinction pattern of responding was observed with approximately 75% of the total number of lnjectmns taken in the first 1/4 of the session Responding for chloroprocalne and dlmethylprocaine was evenly spaced over the session in ammals that reliably self-administered these drugs at high rates (Fig 3) However, low rates of responding m later segments of the session by M263 and 7623 account for the irregular pattern seen in the group data in Fig 4 At doses that were selfadmlmstered, dImethocalne maintained a pattern of evenly spaced responding that was similar to that seen with cocaine (Figs 3 and 4) Responding for plperocalne, propoxycame and D M A E occurred with a saline-like pattern m all cases at all doses tested (Figs 3, 4 and Table l)

FIG 1 Chemical structures of local anesthetics

TABLE 1 SELF-ADMINISTRATIONOF DIMETHYLAMINOETHANOL(DMAE) BY RHESUS MONKEYS*

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Dose (/.~moles/kg/ InJections/Session rejection) Mean Range 0 1 -l0 30 10 30

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47-96 3-12 3-5 2-5 3-8 3-8

Percent of'Iotal per 30 Minutes First Second Third Fourth 31 67 78 77 83 78

25 20 9 7 3 8

22 8 13 0 8 14

22 5 0 16 6 0

*Injecuon data are means for three rhesus monkeys (Nos 4173, 3018 and M269) Ranges include all three monkeys

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FIG 2 Self-administration of esteratlc local anestheUcs by rhesus monkeys Each point represents the mean number of mjecnons of each compound for each animal during the last three sessions of a substitution period, and vertical bars represent the range Occasmnally the range is smaller than the point The points above S represent responding over the corresponding period of saline substltutmn during each dose-response determination The points above C represent the average number of rejections of cocaine (0 1 /zmoles/kghnj) taken during the last three sessions preceding each dose of that test drug, usually a total of 12 cocaine sessions

EXPERIMENT 2 DRUG DISCRIMINATION STUDIES METHOD

Animals and Apparatu6 The animals were l0 drug-naive male albino SpragueDawley derived DU B rats (Flow Laboratories, Dublin, VA) that weighed between 180 and 260 g at the beginning of the experiment During the course of the experiment, several animals died either from an overdose of a local anesthetic or

from an unspecified illness Because of the extended duration of the experiments, body weights were allowed to increase gradually and the animals weighed between 260 and 325 grams at the end of the experiment They were individually housed m ceiling suspended steel cages (18 × 19 × 25 cm) m a room with a 12 hour light-dark cycle Experimental sessions were conducted during the hght cycle Water was available at all tunes except during experimental sessions, and food avallabthty was restricted to that dehvered in the experimental sessions in the form of 45 mg food pellets (Formula

LOCAL ANESTHETICS

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FIG 3 Cumulative response records of local anesthetic self-admlmstraUon by a single animal (Monkey 4173) Records were selected from one of the last three sessions of a six-session substitution period Each diagonal mark of the response pen represents an rejection, and vertical marks of the event pen denote 30 mm segments of the session In addmon, the response pen reset each 1/2 hour For remforcmg drugs, the dose that maintained the highest response rates was selected For non-reinforcing drugs, the highest dose that did not suppress responding was selected Drug doses (/xmoles/kghnj) are m parentheses

A, P J Noyes Co , Lancaster, NH) and adjusted supplemental feedings of 10-15 g of laboratory rat chow (Rodent Lab Chow, Ralston Purina Co , St Louis, MO) given after each session Experimental sessions were conducted In two identical two-lever modular operant chambers (Model El0-10, Coulbourn Instruments, LeHigh Valley, PA) Both levers were mounted on one wall 60 cm above the floor, and a food trough was centered between them A white light dlummated the chamber dunng experimental sessions The chamber was enclosed in a sound attenuating cubicle equipped with an exhaust fan Solid state programming equipment located In an adjacent room controlled the contingencies and recorded behavior Procedure Trammg sessions

Animals were trained in a two-lever

food-reinforced drug discrimination paradigm The rats were divided into 2 groups of 5 rats each, food deprived to 75-80% of their free-feeding weights, and assigned to one of the two experimental chambers For the group of animals in one experimental chamber, the right lever was designated the drug lever and the left lever was designated the saline or non-drug lever This condition was reversed for the second group of animals Initial training was carried out in the non-drug condltlon, with each animal in each group trained to press the non-drug lever on a FR-I schedule for the delivery of a single pellet After responding occurred reliably on the non-drug lever, animals were injected (1 0 ml/kg, IP) 10 mln before some experimental sessions with 200 /xmoles/kg procaine HCI (54 6 mg/kg), and only responding on the drug lever was reinforced during the experimental session On non-drug days, each animal received a saline injection (1 ml/kg, IP) 10 mln before the experimental session Procaine (P) or saline

496

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(S) pretreatments were given on a double alternation schedule in which two c o n s e c u t i v e sessions with drug pretreatment followed two c o n s e c u t w e sessions with saline pretreatment O v e r about 10 sessions the response r e q u i r e m e n t on both levers was gradually Increased to 32 r e s p o n s e s per food pellet (FR-32) Sessions w e r e c o n d u c t e d Sundays through Fridays and lasted 30 mm Te~t ~esstons W h e n responding was stable (less than 1(1% vartatlon in overall r e s p o n s e rate from day to day) and under good stimulus control (90% correct) test sessions w e r e begun Test sessions w e r e c o n d u c t e d on T u e s d a y s and Fridays An IP injection of sahne or a test drug was given 10 mln before the test session, during which food was avadable for responding on either l e v e r on a FR 32 schedule Generally, a

test session lasted 100 sec If the subjects did not c o m p l e t e a fixed ratio during the 100 sec, the test session was e x t e n d e d up to 10 mm until the first reinforcer was d e h v e r e d The same dose of a test c o m p o u n d was administered before both test sessions m a w e e k so that each dose was tested with each training condition in effect on the preceding day to correct for any t e n d e n c y to respond on the lever that had been reinforced on the preceding day Doses that ranged from one that had no effect on responding to a dose that suppressed rates of responding to less than 50% of control levels were tested in a non-systemaUc o r d e r The effects of all doses of one drug were determined before testing another drug, and sahne was tested as part o f the d o s e - r e s p o n s e function of each drug The order of drug testing was procaine, hdocalne, tetracame, p r o c a m a m l d e , p~perocame, & m e t h o c a l n e , c h l o r o p r o c a m e , & m e t h y l p r o c a m e , cocaine, propoxycalne Thus under terminal c o n d m o n s ammals r e s p o n d e d on a F R 32 schedule food d e h v e r y with the weekly sequence of sessions for all animals being P,S, Test, S,P, Test Animals were fed but experimental sessions were not c o n d u c t e d on Saturdays Dtu~,~

In addlUon to the local anestheUcs used m the selfadministration e x p e r i m e n t / c o c a m e , chloroprocalne, &methocalne, dimethylprocatne, p r o p o x y c a m e and p~perocame), procaine, procaInamide, hdocalne and tetrac a m e (Pfaltz and Bauer) were tested In a d d m o n , the effects of selected doses of d - a m p h e t a m i n e (City Chemical Corp , NY) were determined m these rats All drugs were dissolved m 0 9% saline to an mjecUon volume of 1 0 ml/kg Doses are expressed m ~ m o l e s / k g F o r purposes of comparison, 1 0 ~ m o l e of each c o m p o u n d ~s equivalent to procaine HCI-273 ~g, procalnamlde HC1-272 ~g, hdocalne HC1-271 t~g, t e t r a c a m e HCI-300 p.g and d - a m p h e t a m i n e S O : 1 1 6 5 ~g (233 p~g/2 p~mole) D a t a A n a A ws

Data from test sessions were analysed m terms of drug effects on overall response rate (responses/sec) and the percent o f total responses that occurred on the drug lever Data were calculated for in&vldual ammals and the mean and standard error of the mean were calculated for the group A test drug was considered to have p r o c a m e - h k e & s c n m m a tlve effects f i a t some dose an average of 75% of the respondmg m a session occurred on the drug lever F o r potency c o m p a r i s o n s , response rate data were c o n v e r t e d to percent o f control response rates using the rates during the sahne test sessions from that dose-response determinaUon as control rates, again indwldually calculated D o s e - r e s p o n s e hnes were calculated for response rate and percent drug lever responding by the method o f least squares linear regression using the sensibly linear portion of each d o s e - r e s p o n s e function ED~o values were calculated from these lines F o r overall response rate, the data for all animals tested w e r e included m the analysis F o r percent drug lever responding, the constraint was added that at least 50% of the ammals tested c o m p l e t e at least 32 total responses for those data to be included m the analysis RESULTS

The procaine-sahne discrimination was acquired o v e r a

LOCAL ANESTHETICS

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DOSE ()JMOLES/KG ) FIG 5 The dlscnmmatwe stimulus properties of local anesthetics m rats There are two dependent measures for each local anesthetic--percent drug lever responding and effects on overall response rate Each point is the mean of two determmauons in 6-10 subjects Standard errors are represented for sahne test values (S) For other points the standard errors ranged between _ 10% of the mean Two of three ammals tested died following injections of 400 /xmoles/kg chloroprocame so others were not tested The open circle at 200 /zmoles/kg hdocalne represents a retest of this dose Values for % drug-lever responding are not presented when response rates were low, i e , most animals d~d not respond (see text)

period of about 40 training sessions By the 20th doublealternation, rates of responding under the FR 32 schedule were stable and 90-100% of the total responses occurred on the appropriate lever The effects of each local anesthetic on overall response rate and percent of drug lever responding m a test session are presented m Fig 5 Under control conditions (saline pretreatment), average response rates ranged between 0 9 and 1 6 responses/second Each of the test compounds decreased response rates in a dose-related manner In addition, with the exceptions of piperocame and procamamide, each of the compounds produced at least 75% procaine lever responding at some dose In contrast to what was found with procaine, it was often necessary to use doses that decreased overall response rates to achieve this effect Only chloroprocame and tetracame produced procaine lever responding at a level that was comparable to that produced by the training dose of procaine The remaining compounds resulted m 7_5--90% procaine lever responding or less than 50% procaine-lever responding (procamamide and piperocame) The data in Table 2 compare the ED50's of the various

local anesthetics for producing procaine lever responding and for decreasing overall response rate The compounds are arranged m the order of decreasing potency for d~scnmmative stimulus effects Cocaine was the most potent and dimethylprocame the least potent m producmg procaine lever responding P~perocame and procalnam~de never resulted in the 50% drug lever responding necessary for an ED50 determination Propoxycame, d~methocame and tetracame were 1/2 to 1/3 as potent as cocaine m producing procmne lever responding In contrast, hdocaine, chloroprocaine and procaine were approxtmately 1/9 as potent as cocaine m th~s regard Potency relationships were m roughly the same order for response rate-decreasing effects, except for procaine and chloroprocame potencies were reduced m this measure Procamam~de was the least potent local anesthetic m reducing response rates In the final column of Table 2, the ratios of the ED50 for response rate disruption to the ED50 for producing procaine-lever responding are presented for each compound The ratios are all higher than 1 0, indicating the sensmvity of the drug discrimination method m detecting a pharmacologi-

498

WOOLVERTON AND BALSTER TABLE 2 P O T E N C I E S O F L O C A L A N E S T H E T I C S FOR G E N E R A L I Z A T I O N TO P R O C A I N E A N D FOR DISRUPTION O F R E S P O N D I N G D U R I N G TEST SESSIONS IN RATS

Compound Cocaine Propoxycalne Dlmethocame Tetracame Lldocalne Chloroprocalne Procaine Dlmethylprocaane Plperocame Procalnamlde

c~ Procaine-Lever Responding (G) ED50 (k~moles/kg)

Ratio to Cocaine

Response Rate Disruption (R) ED50 (/xmoles/kg)

Ratio to Cocaine

R/G

8 18 25 26 71 73 74 138 ---

10 22 31 32 89 9 1 92 17 2 ---

15 43 36 43 105 224 309 282 148 538

10 29 24 29 70 15 21 19 10 36

19 24 14 17 15 31 42 20 ---

cal effect The highest ratios were for procame and chloroprocaine, indicating a good separation of stimulus effects from non-speofic behavioral effects The ratio was also relatively high for propoxycalne, largely because of a very steep dose-response relationship for dlscnmmabihty For the majority of the other compounds, the ED50 for ratedecreasing effects was about 1 5-2 times the ED50 for procalne-hke discriminative stimulus effects At the end of the experiment, selected doses of d-amphetamine were tested A dose of 5 0 /zmoles/kg resulted m 88 5% drug lever responding (l 1 of 12 animals responding) and l0 /zmoles/kg resulted m 99 8% drug lever responding (5 of 12 ammals responding) Average response rates for these doses were 1 2 (-+0 2 S E M ) and 0 5 (-+0 2 S E M ) response/second respectively Thus, d-amphetamine generalized to procaine at a dose (5 0 /xmoles/ kg) that d~d not decrease response rates Though exact potency relations were not estabhshed d-amphetamine was considerably more potent than any other compound tested DISCUSSION Based on the results of the present experiment as well as reports by other investigators [6, 7, 9, 20], cocaine, procaine, chloroprocame, dlmethocame and dlmethylprocame are all local anesthetics that can clearly function as positive reinforcers when dehvered IV to rhesus monkeys Other local anestheUcs such as tetracame [20] and proparacame [9] are occasionally self-admlmstered at low rates and might be termed " m a r g i n a l " remforcers Furthermore, procaine can function as a discnmmaUve stimulus in rats, and several local anestheUcs have discriminative stimulus effects that are simdar to those of procaine in this species On the other hand, under these conditions hdocalne and procamam~de (shown m a prewous study) [20], and plperocame and propoxycame (shown m this study) are not posltlve reinforcers in monkeys and plperocame and procamam~de do not have procalne-hke dxscnmmatlve sttmulus effects m rats To the extent that the procedures used m these experiments are predictive of these sUmulus properties m humans, the lmphcation is that some but not all local anesthetics would be

expected to have abuse potentml m humans In th~s regard, at was partacularly provocauve to find that cocaine and d-amphetamine, drugs with well known abuse potenual, produced procame-appropmte responding m rats The results are m contrast to the findings ofColpaert et al [3] that procaine and hdocame faded to produce drug lever responding m rats trained to discriminate 10 mg/kg cocaine from sahne However, these authors tested only a single dose (10 mg/kg) of each of these drugs The potency dafferences reported m the present experiment make it likely that these doses of procaine and hdocame were too low to produce cocaine lever responding Alternatively, generahzatlon between local anesthetics may depend upon the training drug used In addatlon, it should be noted that hdocame, a drug that was not self-administered by rhesus monkeys [20], had procame-hke dascnmmatwe effects m rats, and has been reported to be mdlstmgmshable from cocaine m expenenced human volunteers [18] In many respects, the method used by Van Dyke et al [18] as more hke a drug dascnmmatmn procedure than selfadmanlstratmn Clearly, the posslbdlty that local anesthetics have stimulus properties in common with drugs of the psychomotor stimulant class deserves further research It is ~mportant to note that reinforcing effects m the monkey and procame-hke dmcnmmatave effects m the rat were not perfectly correlated All of the compounds that were self-administered by rhesus monkeys had dascnmmatave effects m the rat that were slmdar to those of procaine However, not all drugs that had procame-hke dascnmmatwe effects m rats were self-administered by monkeys 0 e, hdocame and propoxycame) It should be emphasazed, therefore, that these two procedures may not be measunng the same pharmacological effects, ~ e , that discnmmat~ve stimulus properties that are similar to those of a reinforcing drug are not necessarily predictive of reinforcing properties Alternatively, differences such as s p e o e s or route of admmlstratmn may play a role in this divergence of stimulus properties Further research with rats using self-admm~stration or rhesus monkeys using drug d~scrimmation techmques would help clarify this issue The mechanism for the behavtoral effects of local anesthetics is unclear, although prewous research has ~mphcated

LOCAL ANESTHETICS chohnerglc systems m the mediation of some of the effects of local anesthetics m other preparations A local anesthetic binding site has been associated with the chohnerglc receptor in Torpedo electric tissue [14] and several local anesthetics have been shown to act as cholinerglc agomsts [8] or antagonists [13] Moreover, it is interesting to note the structural simllarltes between esteratlc local anesthetics and acetylchohne, as well as the fact that both can be hydrolyzed by chohnesterase [ll,16] The results of this and earlier experiments that all local anesthetics that have been found to be reinforcers in monkeys are esters, and that all of the esterahc local anesthetics had procmne-hke discriminative stimulus effects in rats are consistent with this possibility However, several factors argue against a chollnerg~c mechanism of action Drugs that interact with chohnegIc systems as agonlsts or antagonists, e g , arecohne, nicotine and scopolamine, are not self-administered by rhesus monkeys under conditions similar to those used here [10] In addition. cocaine and d-amphetamine are positive reinforcers and have procaine-hke discriminative effects in rats, though these are drugs which are not usually thought of in terms of their effects on chollnerglc systems Indeed, the reinforcing and discriminative stimulus properties of these compounds are generally though to involve dopamlnerglc systems [3.21] In spite of general structural similarities in common with acetylchohne, there are clearly addmonal structural requirements among esteratlc local anesthetics for these behavioral effects For instance, although propoxycaine and piperocaine are both esteratlc local anesthetics, they were not self-administered by rhesus monkeys and piperocaine did not have procaine-liKe discriminative effects in rats It IS possible that sterlc factors Influence the ability of these compounds to interact with the receptor necessary to produce these behavioral effects In addition, the amlde class of local anesthetics has not been tested extensively using these procedures and it would be premature to conclude that this type of local anesthetic IS devoid of reinforcing properties Indeed, hdocaine is an amlde with some procalne-hke discriminative stimulus effects in rats Systematic structureactivity comparisons between behavioral tests and m vitro chohnerglc assays as well as interaction studies with other chollnerglc drugs could help clarify this issue It can be said that it is unlikely that a metabohte of local anesthetics plays a role in mediating their reinforcing effects since neither D M A E nor dlethylaminoethanol (DEAE) [20] maintained responding in any monkey tested With the exceptions of cocaine and plperocaine, all of the esteratlc local anesthetics that have been investigated to date would be expected to have one of these compounds as a metabohte as a result of hydrolysis by serum esterases [16] In addition, propoxycaine which would be expected to have D E A E as a

499 metabohte, was not self-administered It is possible, however, that systemic administration of D M A E and D E A E may not result In their reaching sites of action due to pharmocoklnetlc factors Local anesthetics, then, may be prodrugs carrying these metabohtes to sites of actions In light of these data, it may be considered somewhat surprising that there is httle or no apparent abuse of local anesthetics among humans In this regard, several points deserve comment First, there may be a relatively high level of local anesthetic aubse that is now documented as cocaine abuse Most local anesthetics could subsUtute for cocaine on the basis of peripheral effects and taste [18], making it possible that local anesthetics are being used as an inexpensive subsUtute or adulterant for the more desirable cocaine Furthermore, potency differences might be expected to mitigate against abuse of compounds such as procaine and chloroprocame Although direct dose-response comparisons were not made in this experiment, the dose range that maintains responding for IV cocaine that is above saline levels m rhesus monkeys using this procedure is 0 1 to l 0 /xmole/kg/mj (approximately 0 03 to 0 3 mg/kg/lnj) compared to a dose range of 1 0 to 10 tzmole/kg/mj (roughly 0 3-3 0 mg/kghnj) necessary to maintain responding for procaine or chloroprocame [9,20] In rats, cocaine was nine times more potent as a discriminative stimulus and 15-20 times more potent than these compounds m decreasing response rates Considering the 7 7 mm half-hfe of IV procame m humans [17], frequent mject~ons (or insufflatlon) of large amounts of procaine would be necessary m order to maintain intoxication The constant, high rate of self-administration of these compounds by monkeys (Fig 3) is consistent with this notion Thus, the total mg weight of procaine comparable to recreational doses of cocaine would make it impractical to use Implicit in this argument is the possibility that more potent local anesthetics that are positive reinforcers m monkeys (e g , dimethocame) could have more significant abuse potential m humans It is also possible that the stimulus properties of local anesthetics in monkeys and rats are not related to their abuse potential In humans The demonstration of reliable IV selfadministration of these drugs in rhesus monkeys using a procedure commonly used in precllmcal assessment of abuse potential may therefore represent a false positive finding ACKNOWLEDGEMENTS The authors acknowledge the expert technical assistance of Earl Dowdy Jr in the conduct of these experiments Bonny Hopkins prepared the manuscript for publication We thank HoffmanLaRoche, Penwalt Corporation and Sterling-Winthrop for their generous supply of local anesthetics used in this study

REFERENCES l Balster. R L and C R Schuster A comparison of d-am4 Deneau, G , T Yanaglta and M H Seevers Self-administration phetamme, /-amphetamine and methamphetamlne selfof psychoactive substances by the monkey A measure of psyadministration m rhesus monkeys Pharmac Blochem Beha~ chological dependence Psychopharmacologta 16 30-48, 1969 1 67-71, 1973 5 Downs, D A and J H Woods Codeine- and cocaine2 Casey, D E Mood alterations during deanol therapy Psychoreinforced responding in rhesus monkeys Effects of dose on pharmacology 62 187-191, 1979 response rates under a fixed-ratio schedule J Pharma~ erp 3 Colpaert, F C , C J E Nlemegeers and P A J Janssen Ther 191 179-188, 1974 Discriminative stimulus properties of cocaine Neurophar6 Ford, R D and R L Balster Reinforcing properties of intramacologlcal characteristics as derived from stimulus genervenous procaine m rhesus monkeys Pharmac Btochem Bealization experiments Pharmac Blochem Beha~ 10 535-546, hay 6 289-296, 1977 1979

500 7 Hammerbeck, D M and C L Mitchell The reinforcing propertles of procaine and d-amphetamine compared m rhesus monkeys J Pharmac exp Ther 204 558-569, 1978 8 Israel, J M and J M Meunler Procaine as an acetylchohne agomst m snarl neuron J Pharma~ exp Ther 211 93-98, 1979 9 Johanson, C E The reinforcing properties of procaine, chloroprocalne, and proparacame m rhesus monkeys Psychopharmacology 67" 189-194, 1980 10 Johanson, C E and R L Balster A summary of the results of a drug self-administration study using substitution procedures in rhesus monkeys Bull Narcot 30" 43-55, 1978 I I Kalow, W Hydrolysis of local anesthetics by human serum chohnesterase J Pharmac exp Ther 104. 122-134, 1952 12 Llpman, R S , A DiMasclo, N Reatlg and T Klrson Psychotropic drugs and mentally retarded children In Psvchopharmacology A Generatton o f Progrevs. edited by M A L p t o n , A DiMasclo and K Kdlam New York Raven Press, 1978, pp 1437-1449 13 Mlele, E and R P Rubm Further evidence for the dual action of local anesthetics on the adrenal medulla J Pharmac exp Ther 161" 296-301, 1968 14 Neubtg, R R , E K Krodel, N D Boyd and J B Cohen Acetylchohne and local anesthetic binding to Torpedo mcotlmC postsynaptlc membranes after removal of non-receptor peptides Proc natn Acad Scz U,5 A 76 690-694 1979

WOOLVERTON AND BALSTER

15 Overton. D A D~scrlmmattve control of behavior by drug states In Sttmuluv Properttes o f Drugs, edited by T Thompson and R Plckens, Appleton-Century-Crofts, New York. 1971, pp 85-110 16 Rltchle, J M and N M Greene Local anesthetics In The Pharmacological Basts o f Therapeutt~ ~ edited by A G Gdman, L S Goodman and A Gdman New York MacMdlan Pubhshlng Co , lnc 1980, pp 300-320 17 Selfen, A B , A A Ferran. E E Selfen, D S Thompson and J Chapman Pharmacoklnetlcsoflntravenousprocamemfuslon m humans Ane~th Analg 58 382-386, 1979 18 Van Dyke, C , P Jatlow, J Ungerer P Barash and R Byck Cocame and hdocame have slmdar psychological effects after mtranasal apphcatlon Ltfe S~t 24 271-274, 1979 19 Wdson, M C , M Hltoml and C R Schuster Psychomotor stimulant self-administration as a function of dosage per mjectJon m the rhesus monkey P ~ h o p h a r m a ~ o l o g t a 22 271-281, 1971 20 Woolverton, W L and R L Balster Reinforcing properties of some local anesthetics m rhesus monkeys Pharma~ Blot hem Beha~ 11 669-672, 1979 21 Yokel, R A and R A Wise Amphetamme-typeremforcement by dopammerg~c agomsts m the rat P s ~ hopharma~ologv 58 289-296, 1978