j-113397 and Stress-Disorders--Post-Traumatic

Evaluation of pharmacotherapies for acute stress disorder (ASD) or post-traumatic stress disorder (PTSD) is challenging due to robust heterogeneity of trauma histories and limited efficacy of any single candidate to reduce all stress-induced effects. Pursuing novel mechanisms, such as the nociceptin/orphanin FQ (NOP) system, may be a viable path for therapeutic development and of interest as it is involved in regulation of relevant behaviors and recently implicated in PTSD and ASD.. First, we evaluated NOP receptor antagonism on general behavioral performance and again following a three-species predator exposure model (Experiment 1). Then, we evaluated effects of NOP antagonism on fear memory expression (Experiment 2).. Adult, male rats underwent daily administration of NOP antagonists (J-113397 or SB-612,111; 0-20 mg/kg, i.p.) and testing in acoustic startle, elevated plus maze, tail-flick, and open field tests. Effects of acute NOP antagonism on behavioral performance following predator exposure were then assessed. Separately, rats underwent fear conditioning and were later administered SB-612,111 (0-3 mg/kg, i.p.) prior to fear memory expression tests.. J-113397 and SB-612,111 did not significantly alter most general behavioral performance measures alone, suggesting minimal off-target behavioral effects of NOP antagonism. J-113397 and SB-612,111 restored performance in measures of exploratory behavior (basic movements on the elevated plus maze and total distance in the open field) following predator exposure. Additionally, SB-612,111 significantly reduced freezing behavior relative to control groups across repeated fear memory expression tests, suggesting NOP antagonism may be useful in dampening fear responses. Other measures of general behavioral performance were not significantly altered following predator exposure.. NOP antagonists may be useful as pharmacotherapeutics for dampening fear responses to trauma reminders, and the present results provide supporting evidence for the implication of the NOP system in the neuropathophysiology of dysregulations in fear learning and memory processes observed in trauma- and stress-related disorders.

Topics: Animals; Benzimidazoles; Cycloheptanes; Dose-Response Relationship, Drug; Exploratory Behavior; Fear; Male; Memory; Nociceptin; Nociceptin Receptor; Opioid Peptides; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Stress Disorders, Post-Traumatic

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.

Topics: Animals; Anxiety; Benzimidazoles; Cats; Male; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Peptide Fragments; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Stress Disorders, Post-Traumatic; Stress, Physiological; Stress, Psychological