Mitigation of adverse behavioral impact from predator exposure by the nociceptin/orphanin FQ peptide antagonist J-113397 in rats

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The nociceptin/orphanin FQ peptide (NOP) receptor is believed to have an integral modulatory function in the stress response system. We evaluated the highly selective NOP antagonist J-113397 (7.5 and 20.0 mg/kg), using a predator exposure in which rats were exposed to predator cats as a stressor. A single dose of J-113397 or vehicle was administered (intraperitoneally) shortly before exposure to the predators or a sham exposure. Behavioral impact was measured using elevated plus maze (EPM), open field activity (OFA), and an olfactory discrimination (OD). The predator exposure produced a relatively long-lasting deficit (decreased time in open arms, decreased basic activity) on the EPM while having little effect on performance on the OFA or OD. J-113397 mitigated the performance deficits on the EPM in a dose-dependent manner while having little effect on performance on the OFA or OD. The largest dose of J-113397, administered with a sham exposure, was essentially devoid of effects on the EPM, OFA, and OD. These results demonstrate that J-113397 can significantly and selectively mitigate the effects of a stressor typically used in a preclinical model of post-traumatic stress disorder. Furthermore, these results are consistent with and extend previous results showing that the NOP receptor has an important role in the response to stress and that NOP antagonism may, potentially, have therapeutic benefit in stress disorders.

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