Naloxone as a stimulus in drug-discrimination learning: Generalization to other opiate antagonists

Non-opiate-dependent animals were trained to discriminate the opiate antagonist naloxone (1 mg/kg) from distilled water within the conditioned-taste-aversion baseline of drug-discrimination learning. Specifically, rats injected with naloxone prior to a saccharin-LiCl pairing and with its vehicle prior to saccharin alone rapidly acquired the drug discrimination, avoiding saccharin following the administration of naloxone and consuming saccharin following its vehicle after only three conditioning trials. Once the discrimination was acquired, generalization tests revealed that the opiate antagonists diprenorphine and naltrexone and the mixed opiate agonist/antagonist nalorphine completely generalized to the naloxone cue at doses of 1.8, 5.6, and 18.0 mg/kg, respectively. That discriminative control was established with a low dose of naloxone (i.e., 1 mg/kg) and other compounds with opiate antagonist activity generalized to the naloxone cue suggests that the stimulus effects of naloxone were likely mediated through the opiate receptor. Because each of these compounds is reported to bind to the mu receptor (with varying affinities and varying degrees of selectivity), the stimulus properties of naloxone are likely mediated at this specific receptor subtype.