The Opioid Receptor Antagonist Naloxone Enhances First-Order Fear Conditioning, Second-Order Fear Conditioning and Sensory Preconditioning in Rats

The opioid receptor antagonist naloxone enhances Pavlovian fear conditioning when rats are exposed to pairings of an initially neutral stimulus, such as a tone, and a painful foot shock unconditioned stimulus (US; so-called first-order fear conditioning; Pavlov, 1927). The present series of experiments examined whether naloxone has the same effect when conditioning occurs in the absence of US exposure. In Experiments 1a and 1b, rats were exposed to tone-shock pairings in stage 1 (one trial per day for 4 days) and then to pairings of an initially neutral light with the already conditioned tone in stage 2 (one trial per day for 4 days). Experiment 1a confirmed that this training results in second-order fear of the light; and Experiment 1b showed that naloxone enhances this conditioning: rats injected with naloxone in stage 2 froze more than vehicle-injected controls when tested with the light alone (drug-free). In Experiments 2a and 2b, rats were exposed to light-tone pairings in stage 1 (one trial per day for 4 days) and then to tone-shock pairings in stage 2 (one trial per day for 2 days). Experiment 2a confirmed that this training results in sensory preconditioned fear of the light; and Experiment 2b showed that naloxone enhances sensory preconditioning when injected prior to each of the light-tone pairings: rats injected with naloxone in stage 1 froze more than vehicle-injected controls when tested with the light alone (drug-free). These results were taken to mean that naloxone enhances fear conditioning independently of its effect on US processing; and more generally, that opioids regulate the error-correction mechanisms that underlie associative formation.