R. E. Solomon

Narcotic discrimination in pigeons: Antagonism by naltrexone

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.

Opioid receptor subtype-specific cross-tolerance to the effects of morphine on schedule-controlled behavior in mice.

Key-press responding of mice was maintained under a fixed-ratio (FR) 30-response schedule of food presentation. Successive 3-min periods during which the experimental chamber was illuminated and the schedule was in effect were preceded by 10-min time-out (TO) periods during which all lights were out and responses had no scheduled consequences. Intraperitoneal (IP) injections of saline or of cumulative doses of drugs were given at the start of each TO period. Successive saline injections had little or no effect on response rates, whereas the μ-opioid agonists morphine (0.1–10.0 mg/kg) and levorphanol (0.1–3.0 mg/kg), the κ-opioid agonist ethylketazocine (0.03–3.0 mg/kg), the mixed μ-/δ-opioid agonist metkephamid (0.1–10.0 mg/kg), and the nonopioid dissociative anesthetic ketamine (1.0–100.0 mg/kg) generally produced dose-related decreases in response rates. Following chronic administration of morphine (100.0 mg/kg/6 h), tolerance developed to the effects of morphine on rates of responding. In addition, a comparable degree of cross-tolerance developed to the effects of levorphanol and metkephamid. On the other hand, there was no evidence of cross-tolerance to the effects of ethylketazocine or ketamine. These results are consistent with the evidence suggesting that different opioid agonists exert their behavioral effects through distinct classes of opioid receptors.

Discriminative stimulus effects of N-substituted analogs of phencyclidine in rhesus monkeys

In daily sessions of a two-lever, discrete-trial, food-reinforced procedure, rhesus monkeys were trained to discriminate between subcutaneous injections of ketamine (1.0 or 1.8 mg/kg) and control injections. In tests of stimulus generalization, cumulative doses of drugs were administered in single sessions and either control- or ketamine-appropriate responding produced food. Ketamine (1.8 and 3.2 mg/kg) and phencyclidine (0.32 mg/kg) produced an average of more than 90% ketamine-appropriate responding. In contrast, d-amphetamine, atropine, chlorpromazine, codeine, diazepam and quipazine, tested at doses up to and including those that markedly reduced response rates, produced exclusively control-appropriate responding. Dose-related ketamine-appropriate responding was produced by each of ten 1-phenylcyclohexylamines, the potencies of which varied with the length, electronegativity, and number of N-alkyl chains present. The most potent analog of phencyclidine, N-ethyl-1-phenylcyclohexylamine, was approximately equipotent with phencyclidine. These data are consistent with previous reports that the discriminative stimulus effects produced by phencyclidine are representative of a unique class of drugs, and that alkyl substitutions in the region of the piperidine ring alter the potency, but not the characteristic pharmacological activity, of the resulting analogs. The potencies of some of these analogs compared to phencyclidine in rhesus monkeys, however, differed from their relative potencies in rodents. Thus, there appear to be species differences in the role of the nitrogen pharmacophore of these compounds in producing phencyclidine-like behavioral effects.

DISCRIMINATIVE STIMULUS EFFECTS OF MONOHYDROXYLATED PHENCYCLIDINE METABOLITES IN RHESUS MONKEYS

Rhesus monkeys were trained to discriminate saline from an injection of ketamine. In tests of stimulus generalization, phencyclidine (PCP) produced dose-related ketamine-appropriate responding in each monkey. Two monohydroxylated PCP metabolites also produced ketamine-like discriminative effects, although only at considerably higher doses than did PCP. A third monohydroxylated PCP metabolite produced only sham-appropriate responding. The results suggest that these PCP metabolites contribute little to the behavioral actions of PCP in the monkey.

KETAMINE-LIKE DISCRIMINATIVE CHARACTERISTICS OF THE STEREOISOMERS OF METAZOCINE, CYCLAZOCINE, AND SKF 10,047 IN RHESUS MONKEYS

The optical isomers and racemic forms of the N-substituted benzomorphans, metazocine, cyclazocine, and SKF 10,047, were studied in rhesus monkeys trained to emit 100 consecutive responses on one of two levers following a sham injection and, within the same daily session, to emit 100 consecutive responses on the other lever following a s.c. injection of ketamine (1.0 or 1.8 mg/kg). In tests of stimulus generalization, ketamine-appropriate responding was produced by the d-isomers of metazocine, cyclazocine, and SKF 10,047, and by the racemic form of metazocine. The racemic forms and 1-ismers of cyclazocine and SKF 10,047 and the 1-isomer of metazocine did not produce ketamine-appropriate responding. Following pretreatment with naltrexone (1 mg/kg), however, racemic SKF 10,047 did produce ketamine-appropriate responding. These results suggest that the actions of the 1-isomers of cyclazocine and SKF 10,047 at narcotic receptors interfered with the ability of their racemic forms to produce ketamine-appropriate responding.