Discriminative Stimulus Effects of Cyclorphan: Selective Antagonism with Naltrexone
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Psychopharmacology (1992) 106:189-194 Psychopharmacology Springer-Verlag 1992 Discriminative stimulus effects of cyclorphan: selective antagonism with naltrexone Albert J. Berta|mio and James H. Woods Departments of Psychology and Pharmacology, University of Michigan, Ann Arbor, MI 48109-0626, USA Received June 4, 1990 / Final version September 13, 1990 Abstract. The opioid antagonist, naltrexone, was used to to discriminate ethylketazocine (EKC) yielded high levels identify some of the receptor mechanisms responsible for of EKC-appropriate responding. Nevertheless, the levels the discriminative stimulus effects of cyclorphan in the that were attained with/-cyclorphan were not as high as pigeon. Subjects were trained to discriminate 10 mg/kg those that were readily obtainable with EKC itself, i.e., IM injections of either morphine or dextrorphan from there was a "ceiling" effect. Thus, that study suggested saline injections in a two key drug discrimination that /-cyclorphan shares some properties with opioid procedure in which responding was maintained by food agonists, but it also suggested that/ocyclorphan differs presentation. The dextrorphan-trained birds generalized from drugs in the opioid agonist class in some way. In to/-cyclorphan at 10 mg/kg; naltrexone did not alter the another phase of the previous study pigeons were chron- /-cyclorphan dose-response curve for this effect. In the ically treated with morphine and trained to discriminate morphine-trained group, l-cyclorphan produced only injections of naltrexone. The morphine-treated nal- partial generalization, and naltrexone greatly increased trexone-trained pigeons generalized fully to /-cyclor- the dose of/-cyclorphan necessary to produce this effect. phan, indicating that /-cyclorphan also shares some These results are consistent with the conclusion that in properties with drugs in the opioid antagonist class. morphine-trained pigeons the partial generalization to Finally, cyclazocine-trained pigeons generalized com- /-cyclorphan is mediated by opioid receptors. Moreover, pletely to /-cyclorphan, which was taken to mean that limited intrinsic efficacy at mu opioid receptors may be /-cyclorphan also shares some properties with phency- the characteristic of /-cyclorphan that prevents full clidine(PCP)-like drugs in this species. generalization in morphine-trained pigeons, d-Cyclor- It was not clear what receptor mechanisms were re- phan produced partial generalization in both groups, but sponsible for the atypical pattern of discriminative stimu- the involvement of opioid receptor mechanisms could lus effects found with /-cyclorphan. In the pigeon, if a not be confirmed, as 1 mg/kg naltrexone did not an- drug produces high levels of EKC-appropriate respond- tagonize d-cyclorphan in either group. ing it is considered likely that it does so by acting at mu opioid receptors, rather than at kappa opioid receptors Key words: Cyclorphan - Naltrexone - Levorphanol - (e.g., Herling and Woods 1981). Nevertheless, the ceiling Dextrorphan - Opioid antagonism - Intrinsic efficacy - effect found with/-cyclorphan in EKC-trained pigeons Drug discrimination - Morphine cast some doubt on the involvement of any opioid recep- tor mechanism in the discriminative stimulus effects of /-cyclorphan. On the other hand, if mu opioid receptor mechanisms were actually involved in producing such In this study the opioid antagonist, naltrexone, was used EKC-appropriate responding as did occur, then it was to help identify some of the receptor mechanisms respon- not clear what factor was imposing a ceiling. It was sible for the discriminative stimulus effects of/-cyclor- hypothesized that effects of/-cyclorphan on the PCP phan in the pigeon. In a previous drug discrimination receptor system might produce a PCP- or cyclazocine- study /-cyclorphan exhibited a complex profile of like cue that limited the levels of EKC-appropriate re- pharmacological activity (Herling et al. 1982). In that sponding that could be obtained with/-cyclorphan (Hert- study administration of/-cyclorphan to pigeons trained ing et al. 1982). In some cases an opioid antagonist can be used as a Offprint requests to: A.J. Bertalmio, Department of Pharmacology, tool to determine whether or not a drug is producing a M6322 Medical Science Building I, University of Michigan Medical behavioral effect through an opioid receptor system, al- School, Ann Arbor, MI 48109~)626, USA though it cannot be safely assumed that this will univer- 190 sally be the case (e.g., Young and Woods 1981). In the Following the injection the subject was placed in the experimental present study the discriminative stimulus and rate-reduc- chamber for the TO, during which the chamber was unilluminated ing effects of l- and d-cyclorphan were determined in and responses had no programmed consequences. During the re- sponse period the houselight was illuminated, the center and right pigeons trained to discriminate either the mu opioid keys were transilluminated, and reinforcement contingencies were receptor agonist, morphine, or the PCP receptor ligand, in effect. dextrorphan, i.e., drugs which in this species share dis- Some subjects were trained with 10 mg/kg morphine; others criminative stimulus properties with EKC and cyclazo- were trained with 10 mg/kg dextrorphan. The single trial of a cine, respectively (Herling et al. 1980, 1983). Then nal- training session was initiated with an injection of either the training trexone was given in combination with l- and with d- drug or a saline solution, i.e., the vehicle for the training drug. During the response period of a training session, emission of 20 cyclorphan in an attempt to reveal the opioid receptor- consecutive responses (CR 20) on the key that had been designated specific component of the mechanism of action of cyclor- as correct for that session activated the feeder for a 4-s period. While phan in these preparations. For reference, results from the feeder was activated the subject had access to grain. these antagonism experiments were compared to results For sessions initiated with a training drug injection, the right key from antagonism experiments in which naltrexone was was designated as correct; the center key was designated as correct used in combination with dextrorphan and its optical for saline injection sessions. Incorrect responses reset the response requirement on the correct key to 20. Response periods were stereoisomer levorphanol. Levorphanol and dextrorphan scheduled to be 60 min in duration, but if the subject gained access are close congeners of l- and d-cyclorphan, respectively. to food 32 times prior to the expiration of 60 min, the remainder Also, levorphanol, like morphine, is believed to act pref- of the response period was spent under TO conditions. Performance erentially at the mu opioid receptor, but levorphanol, in the response period of a training session was considered to be unlike l-cyclorphan, substitutes fully in morphine-trained adequate if the subject met a series of criteria which included pigeons. making no more than 39 responses prior to the first food presenta- tion and making at least 90% of all responses on the key that had been designated as correct for that session. Successive training sessions were scheduled until the subject met the performance Materials and methods criteria for eight consecutive sessions; then testing was initiated. Test sessions differed from training sessions in that they consist- Subjects. Pigeons (Colurnba livia) of the White Carneaux variety ed of a number of discrete trials. In a test trial the response period were individually housed, with water and grit freely available. To was 5 min in duration; ifa subject obtained access to food 10 times maintain the weights of the birds at no less than 80 % of free feeding before the expiration of 5 min, the remainder of the response period levels, Purina Pigeon Checkers and/or a mix of grains was provided was spent under TO conditions. Also, during the response period daily in the home cage, subsequent to any participation in the of a test trial, completion of a CR 20 on either key led to food experiment scheduled for that day. All subjects had previously been presentation. A test session was scheduled only if the subject had used in other experiments. In general, the eight birds in the mor- performed adequately for two successive training sessions, i.e., a phine-trained group had been exposed to opioid agonists, convul- training drug injection session and a saline injection session. If a sants and anticonvulsants, PCP-like drugs, and a few other drugs. subject failed to satisfy the criteria for adequacy in one of these In the dextrorphan-trained group the six subjects had been exposed sessions, testing was postponed and additional training sessions to other PCP-like drugs, to opioid agonists and antagonists, and to were run until the subject again met the criteria. All sessions were some other drugs. run at approximately the same time of day. Apparatus. Experiments were performed in 25 cm • 28 cm x (height) Data analysis. Data are presented only for contingent responding, 30 cm test cages (model El0-10, Coulbouru Instruments Inc. (CI), i.e., responding occurring on the two transilluminated keys during Lehigh Valley, PA), which were enclosed in ventilated isolation the response period. Data for the discriminative stimulus effects of chambers (model E 10-20, CI). A horizontal array of three translu- drugs are presented as the percent training-drug-appropriate re- cent plastic bird-pecking response keys (modified model E21-17, sponding, i.e., the number of responses made on the right key CI) was centered in one end wall of each test cage, 22 cm above the divided by the sum of the responses made on both the center and floor. Each key was approximately 2.5 cm in diameter; the lateral right keys, with the resultant fraction being multiplied by 100. Also keys were separated from the central key by approximately 5.5 cm. included are data on the overall rate of responding expressed as Each key could be transilluminated with a red 7 W bulb that was responses per second, i.e., the total number of responses made on located directly behind it.