Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Δ9-tetrahydrocannabinol

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<ul><li><p>ORIGINAL INVESTIGATION</p><p>Discriminative stimulus effects of the cannabinoid CB1antagonist SR 141716A in rhesus monkeys pretreatedwith 9-tetrahydrocannabinol</p><p>Lance R. McMahon</p><p>Received: 22 February 2006 /Accepted: 29 June 2006 / Published online: 5 September 2006# Springer-Verlag 2006</p><p>AbstractRationale Drug discrimination can be used to examinetolerance and dependence in agonist-treated animals byestablishing an appropriate antagonist as a discriminativestimulus.Objective Establish intravenous SR 141716A as a discrim-inative stimulus in four rhesus monkeys pretreated with arelatively small dose of9-tetrahydrocannabinol (9-THC).Methods Rhesus monkeys received i.v. 9-THC(0.32 mg/kg) and discriminated i.v. SR 141716A (1 mg/kg) from vehicle while responding under a fixed ratio (FR) 5schedule of stimulus-shock termination.Results The discriminative stimulus effects of SR 141716Awere dose-dependent (ED50=0.33 mg/kg) and were mim-icked by the CB1 antagonist AM 251 (ED50=0.98 mg/kg),but not by a benzodiazepine (midazolam) or an N-methyl-D-aspartate antagonist (ketamine). An additional dose(0.32 mg/kg in addition to 0.32 mg/kg administered beforethe session) of 9-THC shifted the SR 141716A doseeffect curve 3-fold rightward. Omitting 9-THC before testsessions resulted in responding on the SR 141716A leverthat was attenuated by subsequent administration of 9-THC (ED50=0.13 mg/kg), CP 55940 (ED50=0.013 mg/kg),and WIN 55212-2 (ED50=0.35 mg/kg); midazolam andketamine did not attenuate responding on the SR 141716Alever. SR 141716A (1 mg/kg) shifted the 9-THC and CP55940 doseeffect curves 3.4-fold rightward; the WIN55212-2 doseeffect curve was not significantly modifiedby a dose of 1 mg/kg of SR 141716A.</p><p>Conclusions SR 141716A can be established as a discrim-inative stimulus in animals pretreated with 9-THC, andthis assay is selective for cannabinoid activity. Differentialantagonism of cannabinoids by SR 141716A might indicatethat the mechanism of action of WIN 55212-2 is notidentical to other cannabinoids. This study demonstratesthat, under the appropriate conditions, drug discriminationhas utility for examining cannabinoid dependence andwithdrawal.</p><p>Keywords Antagonist . Cannabinoid . Cannabis .</p><p>9-tetrahydrocannabinol . Drug discrimination .</p><p>Rhesus monkey . Rimonabant . SR 141716A</p><p>Introduction</p><p>The CB1 antagonist SR 141716A (rimonabant) is a usefulpharmacologic probe for examining CB1 receptors thatmediate the effects of naturally occurring cannabinoids[9-tetrahydrocannabinol (9-THC) and other cannabi-noids in Cannabis sativa] and synthetic cannabinoidagonists (e.g., CP 55940 and WIN 55212-2). Cannabinoidagonists have a variety of effects in animals, e.g., theydecrease body temperature, induce catalepsy, increase heartrate, and disrupt short-term memory, and these effects areattenuated by SR 141716A (Compton et al. 1996; Huestiset al. 2001; Lichtman and Martin 1996). Moreover,cannabinoid agonists have discriminative stimulus effectsthat provide a pharmacologically selective measure ofcannabinoid activity in vivo inasmuch as cannabinoidagonists share discriminative stimulus effects with eachother and not with noncannabinoids (Balster and Prescott1992), and these effects are attenuated by SR 141716A</p><p>Psychopharmacology (2006) 188:306314DOI 10.1007/s00213-006-0500-6</p><p>L. R. McMahon (*)Department of Pharmacology,The University of Texas Health Science Center at San Antonio,7703 Floyd Curl Drive,San Antonio, TX 78229-3900, USAe-mail: mcmahonl@uthscsa.edu</p></li><li><p>(Jrbe et al. 2001; McMahon et al. 2005; Wiley et al.1995b). That SR 141716A attenuates the discriminativestimulus effects of cannabinoid agonists is consistent withclinical studies reporting that SR 141716A attenuates thesubjective effects of smoked marijuana (Huestis et al.2001). Collectively, most studies with SR 141716A showit to be an appropriate antagonist of the behavioral effectsof 9-THC and provide ample pharmacologic evidence tosupport the hypothesis that CB1 receptors mediate thebehavioral effects of cannabinoid agonists.</p><p>In addition to providing a highly quantitative andpharmacologically selective measure of acute drug actionin vivo, drug discrimination can be used to examine theconsequences of daily drug administration (e.g., toleranceand dependence). For example, in animals that discriminatean agonist from vehicle, the discriminative stimulus effectsof drugs can be compared before and after a period inwhich discrimination training is suspended and the trainingdrug, or a pharmacologic equivalent, is administeredchronically. This approach has been used to examinetolerance to opioids (Sannerud and Young 1987), benzo-diazepines (Pugh et al. 1992), and cannabinoids (Wiley etal. 1993). Alternatively, animals can be treated chronicallywith an agonist and trained to discriminate an antagonist;the consequences of agonist treatment are assessed bycomparing the effects of drugs in agonist-treated animals(that discriminate an antagonist) to the effects of drugs inuntreated animals that discriminate the same agonist or apharmacologic equivalent. For example, the discriminativestimulus effects of a benzodiazepine antagonist in benzo-diazepine-treated animals have been used to show thatbenzodiazepine treatment produces differential cross-toler-ance among drugs with benzodiazepine-like discriminativestimulus effects (McMahon et al. 2001). Moreover, underthe appropriate conditions, the discriminative stimuluseffects of an antagonist in agonist-treated animals can bepredictive of dependence and withdrawal.</p><p>In a previous study, SR 141716A (1 mg/kg) wasestablished as a discriminative stimulus in rhesus monkeysthat were treated daily with 9-THC, and the discrimina-tion appeared to be related to antagonism of 9-THC(McMahon and France 2003). However, there were markedindividual differences in the effects of cannabinoids,perhaps due to individual differences in the absorptionand metabolism of cannabinoids administered intramuscu-larly or subcutaneously, and limited information wascollected regarding the pharmacologic profile of the SR141716A discriminative stimulus in that study. Relative tothe intramuscular route, the time required for i.v. 9-THCto be absorbed and metabolized is more consistent acrossindividual rhesus monkeys (Perlin et al. 1985). To increasehomogeneity in the behavioral effects of cannabinoidsacross individuals, monkeys in this study received i.v. 9-</p><p>THC (0.32 mg/kg) immediately before sessions in whichthey discriminated i.v. SR 141716A (1 mg/kg) fromvehicle. A relatively small dose of 9-THC was chosenfor study so that the effects of 9-THC would beminimized on days when 9-THC was not administeredbefore test sessions. Relative to the previous study(McMahon and France 2003), discriminative stimuluseffects were more consistent among monkeys in the presentstudy, and a more comprehensive pharmacologic profilewas established by studying the CB1-selective antagonistAM 251 and the cannabinoid agonists CP 55940 and WIN55212-2, alone and in combination with SR 141716A.</p><p>Materials and methods</p><p>Subjects Four adult (two female and two male) rhesusmonkeys (Macaca mulatta) were housed individually on a14-h light/10-h dark schedule; were maintained at 95% free-feeding weight (range 5.59.4 kg) with a diet consisting ofprimate chow (High Protein Monkey Diet; Harlan Teklad,Madison, WI), fresh fruit, and peanuts; and were providedwater in the home cage. All monkeys had been previouslytrained to discriminate i.m. SR 141716A (1 mg/kg) whilereceiving s.c. 9-THC (1.12 mg/kg/day; McMahon andFrance 2003). Monkeys were maintained in accordance withthe Institutional Animal Care and Use Committee, TheUniversity of Texas Health Science Center at San Antonio,and the Guide for the Care and Use of Laboratory Animals(National Research Council 1996).</p><p>Surgery Using aseptic surgical procedures, monkeys re-ceived chronic indwelling catheters (heparin coated poly-urethane, OD=1.68 mm, ID=1.02 mm; Instech Solomon,Plymouth Meeting, PA). Upon anesthesia with ketamine(10 mg/kg i.m.) and isoflurane (1.53.0%, inhaled via facemask), a catheter was inserted into a subclavian or femoralvein and advanced 5 cm. Suture silk (coated vicryl, EthiconInc., Somerville, New Jersey) was used to anchor thecatheter to the vessel and to ligate the section of the vesselproximal to the catheter insertion. The other end of thecatheter, which passed subcutaneously and exited at themidscapular region of the back, was protected by a custom-made nylon-mesh jacket (Lomir Biomedical, Toronto, ON).</p><p>Apparatus During experimental sessions, monkeys wereseated in chairs (Model R001; Primate Products, Miami,FL) that provided restraint and were placed in ventilated,sound-attenuating chambers equipped with two responselevers and stimulus lights. Feet were placed in shoescontaining brass electrodes through which a brief electricstimulus (3 mA, 250 ms) could be delivered from an A/Cgenerator. The operant conditioning equipment was</p><p>Psychopharmacology (2006) 188:306314 307</p></li><li><p>connected via an interface (MedAssociates, St. Albans, VT)to a computer that controlled and recorded experimentalevents.</p><p>Drug discrimination procedure Monkeys received i.v. 9-THC (0.32 mg/kg) 30 min before sessions and discriminat-ed i.v. SR 141716A (1 mg/kg) from vehicle whileresponding under a multiple-cycle procedure. Each cyclebegan with a 15-min time-out, during which responses hadno programmed consequence, followed by a 5-minresponse period, during which illumination of two redlights (one positioned above each of the two levers)signaled a pending electric stimulus (every 40 s). Thecorrect lever was determined by an infusion of vehicle orSR 141716A; determination of correct levers (e.g., left,vehicle; right, SR 141716A) varied among monkeys andremained the same for an individual throughout the study.Five consecutive responses (FR5) on the correct leverextinguished the red lights and postponed the schedule for30 s. Responding on the incorrect lever reset the responserequirement on the correct lever. Response periods endedafter 5 min or after the delivery of four electric stimuli,whichever occurred first.</p><p>During training, vehicle or SR 141716A was adminis-tered 15 min prior to sessions, during which additionalvehicle infusions or sham (catheter accessed from withinthe jacket only) were administered nonsystematically at thebeginning of subsequent cycles. SR 141716A trainingconsisted of 24 cycles and vehicle training consisted of26 cycles. Completion of the FR on the correct lever wasrequired for a reinforcer during each training cycle. Thefirst test was conducted when, for 5 consecutive or for 6 of7 days, at least 80% of the total responses occurred on thecorrect lever and fewer than five responses (one FR)occurred on the incorrect lever prior to completion of theFR on the correct lever; criteria had to be satisfied in everycycle. During test sessions, five consecutive responses oneither lever postponed the shock schedule. Tests wereconducted at least 3 days apart and only when performancefor consecutive training sessions, including both vehicleand SR 141716A training sessions, satisfied the samecriteria described above. The type of training sessionpreceding test sessions varied nonsystematically. Oncetesting began, monkeys received 9-THC (0.32 mg/kg) atleast 5 days per week.</p><p>For tests conducted 30 min after i.v. 9-THC(0.32 mg/kg), vehicle was administered 15 min beforeor at the beginning ofthe first cycle, followed bycumulative doses of SR 141716A, AM 251, midazolam,or ketamine in subsequent cycles, with doses increasing by0.25 or 0.5 log unit per cycle. Midazolam and ketaminewere chosen as noncannabinoid controls because benzodia-zepines and noncompetitive N-methyl-D-aspartate (NMDA)</p><p>antagonists (1) have discriminative stimulus effects thattypically differ from those of cannabinoid agonists (Browneand Weissman 1981; Wiley et al. 1995a) and (2) can besafely studied in rhesus monkeys up to doses that disruptoperant responding (e.g., McMahon and France 2002). Anadditional test was conducted by administering i.v. 9-THC(0.32 mg/kg) in the first cycle, in addition to i.v. 9-THC(0.32 mg/kg) administered 30 min before the session,followed by cumulative doses of SR 141716A. For testsconducted in the absence of 9-THC before sessions (i.e.,30 min after i.v. vehicle), i.v. vehicle or SR 141716A(1 mg/kg) was administered 15 min before sessions, inwhich vehicle was administered in the first cycle followedby cumulative doses of 9-THC, CP 55940, or WIN55212-2 in subsequent cycles. Additional tests wereconducted by administering i.v. vehicle before sessionsfollowed by cumulative doses of midazolam or ketamine.Tests conducted after i.v. 9-THC ended when greater than80% of the total responses occurred on the SR 141716Alever, and tests conducted in the absence of 9-THC beforesessions (i.e., 30 min after i.v. vehicle) ended when lessthan 20% of the total responses occurred on the SR141716A lever. Tests with midazolam and ketamine endedwhen response rate decreased sufficiently to result in thedelivery of electric stimuli. The duration of action of 9-THC (0.32 mg/kg) administered intravenously or subcuta-neously was determined by administering 9-THC onseparate days at a fixed time prior to 6-cycle test sessionsthat were conducted in 2-h increments thereafter. Tomaintain catheter patency, up to 5 ml of heparinized saline(100 /ml, Baxter Healthcare Corp., Deerfield, IL) wasadministered after each i.v. drug infusion.</p><p>Drugs SR 141716A base and 9-THC (The ResearchTechnology Branch, National Institute on Drug Abuse,Rockville, MD); AM 251 and CP 55940 (Tocris, Ellisville,MO); and WIN 55212-2 (Sigma, St. Louis, MO) wereadministered in a volume of 0.033 ml/kg and weredissolved in a 1:1:18 mixture of absolute ethanol, Emul-phor-620 (Rhone-Poulenc Inc., Princeton, NJ) and sterilewater. Midazolam hydrochloride (Roche Pharma Inc.,Manati, Puerto Rico) and ketamine hydrochloride (FortDodge Laboratories, Fort Dodge, IA) were purchased ascommercially prepared solutions and were diluted withsterile saline. Doses (in milligrams per kilogram) wereexpressed as the forms listed above.</p><p>Data analyses Discrimination data were expressed as apercentage of the total responses on the SR 141716A leveraveraged among monkeys (SEM) and plotted as a functionof dose. Doses of a compound required to produce 50% ofresponses (ED50) on the SR 141716A lever and the 95%confidence limits (CL) were estimated with linear regres-</p><p>308 Psychopharmacology (2006) 188:306314</p></li><li><p>sion on doses producing 2080% of responses on the SR141716A lever, including not more than one dose produc-ing less than 20% of responses on the SR 141716A leverand not more than one dose producing more than 80% ofresponses on the SR 141716A lever. ED50s were deter-mined for individual animals, and the 95% CL wasdetermined from the t statistic. ED50s were considered tobe significantly different when the 95% CL of their potencyratio did not include 1 (Tallarida 2000).</p><p>Differences in absolute r...</p></li></ul>

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