Systemic administration of ZLc-002 exerts anxiolytic-like effects by dissociation of nNOS from CAPON in adult mice

Anxiety is recognized as primary clinical phenotype of psychiatric disorders. However, many patients with anxiety have not yet received effective treatment. Our previous study demonstrated that hippocampal nNOS-CAPON interaction is implicated in anxiety-related behaviors, and blocking nNOS-CAPON interaction in the hippocampus produces anxiolytic-like effects. Here, ZLc-002, a small molecule inhibitor of nNOS-CAPON coupling, was evaluated for anxiolytic-like properties after systemic administered using anxiety behavioral tests, including open-field (OF), elevated plus maze (EPM), novelty-suppressed feeding (NSF) and light-dark (LD) tests. We reported that ZLc-002 when administered intraperitoneally at the dose of 40 or 80 mg/kg/d for 14 days produces anxiolytic-like effects. Furthermore, the similar effects of ZLc-002 were observed when administered intravenously at the dose of 10, 20 or 40 mg/kg/d for 7 days. More importantly, the mice dosing with 80 mg/kg/d ZLc-002 intraperitoneally or 40 mg/kg/d ZLc-002 intravenously for 3 days exerted significant behavioral effects. However, intragastric administration with ZLc-002 was devoid of effect on anxiety behaviors, even at high doses. Furthermore, intraperitoneal or intravenous treatment of ZLc-002 significantly disrupted the interaction between nNOS and CAPON in the hippocampus of adult mice, and there was a significant anxiolytic-like effect of ZLc-002 at day 3 after intrahippocampal microinjection. Our results verified that systemic administration of putative small molecule inhibitor of nNOS-CAPON can be used for the treatment of anxiety disorders.