Blockade of NOP receptor modulates anxiety-related behaviors in mice exposed to inescapable stress.

RATIONALE: Depression and anxiety frequently co-occur, and this has important clinical implications. Previous studies showed that activation of the nociceptin/orphanin FQ receptor (NOP) elicits anxiolytic effects, while its blockade promotes consistent antidepressant actions. NOP antagonists are effective in reversing footshock-induced depressive-like behaviors, but their effects on stress-induced anxiety are still unclear. OBJECTIVE: This study aimed to investigate the effects of the NOP antagonist SB-612111 on footshock stress-induced anxiety behaviors. METHODS: Male Swiss mice were exposed to inescapable electric footshock stress, and behavioral phenotype was screened based on the ability to escape from footshock (i.e., helpless or non-helpless). Animals were then treated with diazepam (1 mg/kg) and SB-612111 (0.1-10 mg/kg), and their behavior was assessed in the elevated plus-maze (EPM) and open field test. RESULTS: When compared with non-stressed mice, helpless, but not non-helpless, animals displayed significant reductions in the time spent in and entries into open arms in the EPM. Diazepam significantly increased open arms exploration in helpless, non-helpless, and non-stressed mice. However, treatment with the NOP antagonist SB-612111 was inactive in naive mice, while it reversed anxiogenic-related behaviors in helpless mice and increased anxiety states in non-helpless mice. No effects on locomotion were observed. CONCLUSION: Helpless mice displayed increased anxiety compared to non-stressed and non-helpless animals, thus supporting use of this approach as an animal model to investigate anxiety/depression comorbidity. Additionally, SB-612111 modulated anxiety-like behaviors in male mice depending on individual stress susceptibility. Ultimately, NOP antagonists could be useful for treating anxiety in depressed patients.

Nociceptin/orphanin FQ receptor agonists increase aggressiveness in the mouse resident-intruder test.

Aggressive behaviors can be considered symptoms of bipolar disorder, schizophrenia, post-traumatic stress, intermittent explosive, and personality disorders. Nociceptin/orphanin FQ (N/OFQ) is a peptide acting as endogenous ligand of the NOP receptor. Preclinical and clinical findings suggest the NOP receptor as an innovative target for the treatment of psychopathologies, such as anxiety, depression, and drug abuse. This study investigated the effects of NOP ligands and the behavioral phenotype of mice lacking the NOP receptor in an animal model of aggressiveness, the resident-intruder test. Mood stabilizers, such as valproate, lithium, and carbamazepine reduced aggressive behaviors of resident mice, while diazepam was inactive. In contrast, para-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis, increased aggressiveness in mice. Similar to PCPA, the treatment with the NOP agonists Ro 65-6570 and AT-090 also increased aggressive behaviors. The systemic administration of the NOP antagonist SB-612111 did not modify the behavior of resident mice, but it prevented the aggressive behavior of Ro 65-6570. NOP receptor knockout mice did not display any behavioral difference compared to wild-type animals in the resident-intruder test. None of the treatments affected non-agonistic behaviors and spontaneous locomotion. In conclusion, NOP receptor agonists increased aggressiveness, while the pharmacological and genetic blockade of NOP receptor signaling did not modify agonistic behaviors. Ultimately, the aggressive profile of action of NOP agonists should be taken into account in the development of innovative psychiatric drugs targeting the NOP receptor.