European Journal of Pharmacology, 105 (1984) 137-142 137 Elsevier NARCOTIC DISCRIMINATION IN PIGEONS: ANTAGONISM BY NALTREXONE SEYMORE HERLING *, RITA J. VALENTINO **, ROBERT E. SOLOMON *** and JAMES H. WOODS Departments of Pharmacology and Psychology, University of Michigan, Ann Arbor, Michigan 48109, U.S.A. and Clinical Institute, Addiction Research Foundation, Toronto, Ontario, Canada Received 27 June 1984, accepted 9 July 1984 S. HERLING, R.J. VALENTINO, R.E. SOLOMON and J.H. WOODS, Narcotic discrimination in pigeons." Antagonism by naltrexone, European J. Pharmacol. 105 (1984) 137-142. In pigeons trained to discriminate between morphine (10 mg/kg) and saline, both morphine and ethylketazocine produced dose-related morphine-appropriate responding. The maximum effect produced by meperidine, however, was only 60% of that produced by morphine or ethylketazocine. Naltrexone (0.1-1.0 mg/kg) produced dose-related shifts to the right in the dose-response curves for the discriminative stimulus and rate-decreasing effects of morphine and ethylketazocine without affecting the response produced by meperidine. Thus, in contrast to the effects observed in other species, morphine and ethylketazocine produce similar discriminative effects in the pigeon. In addition, the morphine-like discriminative effects and the rate-decreasing effects of meperidine in the pigeon are not mediated by the naltrexone-sensitive mechanisms which mediate these effects of morphine or ethylketazocine. Morphine Ethylketazocine Meperidine Drug discrimination Antagonism Pigeons 1. Introduction man, 1980; Schaefer and Holtzman, 1981). In the pigeon, however, morphine, ethylketazocine, and Several lines of evidence suggest that many of ketazocine appear to share discriminative stimulus the effects of ethylketazocine and other x-receptor effects, since each of these drugs produces dose-re- agonists in several species are mediated by a recep- lated drug-appropriate responding in pigeons tor that differs from that mediating the effects of trained to discriminate between either morphine or morphine (a /x-receptor agonist) (Woods et al., ethylketazocine and saline (Herling and Woods, 1978; Iwamoto and Martin, 1981; Wood, 1982). 1981). Results of drug discrimination studies are con- Additional evidence that the behavioral effects sistent with this concept (Herling and Woods, of morphine and ethylketazocine in certain species 1981). For example, in rats or squirrel monkeys are mediated by different mechanisms is derived trained to discriminate between morphine and from studies on the antagonism of these effects by saline, neither ketazocine nor ethylketazocine sub- naloxone or naltrexone. In rats, for example, the stitutes for morphine as a discriminative stimulus effects of ketazocine and ethylketazocine on sched- (Shannon and Holtzman, 1977; Teal and Holtz- ule-controlled responding are more difficult to antagonize by naltrexone than are similar effects * To whom all correspondence should be addressed: Addic- of morphine (Harris, 1980). More recently, Leander tion Research Foundation, 33 Russell Street, Toronto, (1982) has shown that the effects of phenazocine Ontario, Canada M5S 2S1. (a proposed /~ agonist) on schedule-controlled re- ** Present address: Department of Pharmacology, George sponding in the pigeon were also reversed by Washington University Medical Center, 2300 Eye Street considerably smaller doses of naloxone (0.01-1.0 NW, Washington, D.C. 20037, U.S.A. *** Present address: University of Iowa College of Medicine, mg/kg) than were comparable effects of either Iowa City, IA 52242, U.S.A. ethylketazocine or ketazocine. Thus, in contrast to 0014-2999/84/$03.00 © 1984 Elsevier Science Publishers B.V. 138 the discriminative effects of ethylketazocine and required to emit 20 consecutive responses on one ketazocine in the pigeon, which on the basis of of two keys to produce 4-s access to food. The key cross-generalization results were suggested to be on which responses produced food was determined mediated similarly to the discriminative effects of by the i.m. presession injection of either 10 mg/kg /~ agonists (Herling and Woods, 1981), the re- morphine (left key) or saline (right key). Re- sponse rate-decreasing effects of ethylketazocine sponses on the inappropriate key reset the re- and ketazocine in the pigeon appear to be media- sponse requirement on the appropriate key. Ses- ted differently than the rate-decreasing effects of/~ sions ended after 32 food deliveries or 1 h, agonists (Leander, 1982). whichever occurred first. Training sessions were The purpose of the present experiment was to conducted 6 days per week with morphine and compare the ability of the narcotic antagonist saline injections alternating from one session to naltrexone to antagonize the discriminative stimu- the next. lus and rate-decreasing effects of morphine and Once the training criteria were met (refer to ethylketazocine in the pigeon to determine if dif- Herling et al., 1980 for details), test sessions were ferent behavioral effects of these drugs are media- conducted with morphine, ethylketazocine, or ted differently. In addition, the ability of naltre- meperidine, alone or in combination with naltre- xone to antagonize the discriminative and rate-de- xone. During test sessions, 20 consecutive re- creasing effects of meperidine was determined. As sponses on either the morphine- or saline-ap- a discriminative stimulus, meperidine substitutes propriate key resulted in food delivery; in all other only partially for morphine in the pigeon (Herling respects, test sessions were identical to training et al., 1980), and whereas the response rate-in- sessions. creasing effects of lower doses of meperidine are Morphine sulfate (Mallinckrodt Chemical antagonized by naloxone, the response rate-de- Works, St. Louis, MO), meperidine hydrochloride creasing effects of higher doses of meperidine are (Sterling-Winthrop Research Institute, Rensselaer, not (Leander and McMillan, 1977). Thus, whether NY) and naltrexone hydrochloride (Endo Labora- the partial morphine-like discriminative effects of tories, Garden City, NY) were dissolved in 0.9% meperidine might be blocked by naltrexone was sterile saline. Ethylketazocine methane sulfonate assessed. (Sterling-Winthrop Research Institute) was dis- solved in sterile water to which a small amount of lactic acid was added; sodium hydroxide was used to adjust the pH above 3. All drugs were injected 2. Materials and methods i.m., usually in a volume of 1 ml/kg, 10 rain before the start of the session. When drug combi- The subjects were four White Carneaux pigeons nations were studied, naltrexone was injected into maintained at approximately 80% of free-feeding the breast muscle on one side of the animal, fol- weight. These pigeons had served as subjects in an lowed immediately by an injection of morphine, earlier morphine discrimination experiment (Her- ethylketazocine or meperidine into the breast ling et al., 1980). muscle on the opposite side. Experimental sessions were conducted in cham- The data for test sessions are presented as the bers that have been described in detail previously average number of responses throughout the ses- (Herling et al., 1980). Briefly, the inside front sion that were emitted on the morphine-ap- panel of each chamber contained two translucent propriate key, expressed as a percentage of the response keys that were transilluminated during total responses. The overall rate of responding on experimental sessions by red 7-W lights. Food the two keys was also recorded during each ses- (mixed grain) could be presented to the pigeon sion. The average rate of responding after drug through a rectangular opening located below the injection is expressed as a percentage of the previ- keys. During training sessions, each pigeon was ous saline control rates. 139 3. Results fect curves for the discriminative effects of morphine and ethylketazocine to the right (fig. 1, Morphine and ethylketazocine, when adminis- upper panels). The minimum doses of morphine tered alone, produced dose-related increases in the and ethylketazocine required to produce at least percentage of responses emitted on the morphine- 90% morphine-appropriate responding were shifted appropriate key (fig. 1, upper panels: closed to the right by 0.1 mg/kg of naltrexone approxi- circles). Morphine doses of 10 mg/kg and higher mately 6-fold and 19-fold, respectively. In the and ethylketazocine doses of 3 mg/kg and higher presence of 1.0 mg/kg of naltrexone, doses of resulted in greater than 90% morphine-appropriate morphine or ethylketazocine up to 100 mg/kg responding in each pigeon. Meperidine also pro- produced less than 55% morphine-appropriate re- duced dose-related morphine-appropriate respond- sponding. Naltrexone also shifted the dose-effect ing, but the average maximum effect, which oc- curves for the rate-decreasing effects of morphine curred at 5.6 mg/kg, was only 60% of the maxi- and ethylketazocine to the right (fig. 1, lower mum effect produced by morphine or ethyl- panels). The shifts in dose-effect curves for the ketazocine (fig. 2, upper panel: closed circles). All rate-decreasing effects of morphine and ethyl- three drugs produced dose-related decreases in the ketazocine were less pronounced than the shifts rate of responding (figs. 1 and 2, lower panels: for the discriminative effects of the drugs. Doses closed circles). The lowest doses of morphine, eth- of morphine and ethylketazocine required to pro- ylketazocine, and meperidine which produced duce a 50% decrease in response rate were shifted maximum morphine-appropriate responding, re- to the right by 0.1 mg/kg of naltrexone approxi- duced response rates by approximately 20, 30 and mately 1.5- and 4.0-fold, respectively. 50%, respectively. In contrast to the effects of morphine and eth- Naltrexone (0.1-1.0 mg/kg) shifted the dose-ef- ylketazocine, neither the discriminative stimulus , MORPHINE ETHYLKETAZOCINE bJ = ,0o 7 ~ 8016o om ~ 40 >- 2O ~-~ o I I I I I t I I I I I I I I ,,~ 120- 0 m ~ I00- "~n~ (,,) 80- ~,~ 60- ~z~ 40" 0 + 1.0 MG/KG NALTREXONE =~ 20- 'e O- I I I l I F ~) I L I ~',~ 32 ,~o o.I 0.3 i 3 i 32 ioo DOSE (mg/kg, i.m.) Fig.