Co-occurrence of anxiety and depressive-like behaviors following adolescent social isolation in male mice; possible role of nitrergic system

• Social isolation stress induced affective responses in adolescent Swiss male mice.
• Nitrergic system is involved in the behavioral deficits caused by social isolation.
• Social isolation induced nitric oxide overproduction in the cortex and hippocampus.
• Aminoguanidine and L-NAME, but not 7NI, reversed the behavioral difficulties.
• Decrease in nitric oxide production by nNOS did not change the affective responses.

Approximately more than 50% of patients with depression have the co-occurrence of anxiety, which complicates the treatment of disease. Recently, social isolation stress (SIS) paradigm has been suggested as an animal model to investigate the underlying mechanism involved in depression–anxiety co-occurrence. In this study, applying six weeks of SIS to adolescent mice, we tested whether nitrergic system plays a role in co-occurrence of depression and anxiety. In this study, comparisons between socially and isolated conditioned (SC and IC) animals showed that SIS induces behaviors relevant to depression and anxiety in IC mice and in addition, nitrergic system is involved in mediating the negative outcomes of SIS. Administration of subeffective doses of aminoguanidine (a specific inducible nitric oxide synthase inhibitor or iNOS, 50 mg/kg) and L-NAME (non-specific inhibitor of NOS, 10 mg/kg) significantly reversed the negative effects of SIS on behavioral profile as well as nitrite levels in the cortex of IC mice, Although administration of subeffective dose of 7-nitroindazole (a specific neuronal NOS inhibitor, 25 mg/kg) decreased the nitrite levels in the hippocampus, but had no effect on depressant and anxiogenic effects of SIS. Results of this study confirmed that SIS is an appropriate animal model to investigate the potential mechanisms in depression–anxiety co-occurrence. We also showed that nitrergic system has contributed to co-occurrence of depression and anxiety in IC mice as an underlying mechanism.