Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats

Abstract

Endogenous opioid systems regulate neurobiological responses to threatening stimuli. Stimulation of -opioid receptors (KORs) produces analgesia, but induces prodepressive-like effects in a variety of animal models. In contrast, KOR antagonists have antidepressant-like effects. KORs and their endogenous ligand dynorphin are expressed throughout brain areas involved in fear and anxiety, including the extended amygdala. Here we examined if KOR antagonists would affect unlearned fear (anxiety) in the elevated plus maze (EPM) and open field (OF) paradigms, and learned fear in the fear-potentiated startle (FPS) paradigm. These studies were designed to accommodate the slow onset (~24 hr) and extended time course (>3 weeks) of the prototypical KOR antagonists nor-binaltorphimine (norBNI) and JDTic. Rats received an intraperitoneal (IP) injection of norBNI (3.0-30 mg/kg) or JDTic (1.0-10 mg/kg) 48 hr before EPM testing. One day later they were tested in the OF, and five and seven days later they were trained and tested in the FPS paradigm. Both KOR antagonists dose-dependently increased open arm exploration in the EPM without affecting OF behavior. They also decreased conditioned fear in the FPS paradigm. The anxiolytic-like effects of KOR antagonists were qualitatively similar to those of the benzodiazepine chlordiazepoxide in the EPM. The selective serotonin reuptake inhibitor (SSRI) fluoxetine had no effect in the EPM and anxiogenic-like effects in the OF. Our results indicate that KOR antagonists produce a unique combination of antidepressant- and anxiolytic-like effects, and suggest that this class of drugs may be particularly effective for the treatment of co-morbid depressive and anxiety disorders.