Role of the NOS-cGMP pathways in time-dependent sensitization of behavioral responses in zebrafish

Nitric oxide (NO) is a molecule involved in plasticity across levels and systems. The role of NOergic pathways in time-dependent sensitization, a behavioral model of translational relevance to trauma and stress-related disorders, was assessed in adult zebrafish. In this model, adult zebrafish acutely exposed to a fear-inducing conspecific alarm substance (CAS) and left undisturbed for an incubation period show increased anxiety-like behavior 24 h after exposure. CAS increased forebrain glutamate immediately after stress and 30 min after stress, an effect that was accompanied by increased nitrite levels immediately after stress, 30 min after stress, 90 min after stress, and 24 h after stress. CAS also increased nitrite levels in the head kidney, where cortisol is produced in zebrafish. CAS-elicited nitrite responses in the forebrain 90 min (but not 30 min) after stress were prevented by a NOS-2 blocker. Blocking NOS-1 30 min after stress prevents TDS; blocking NOS-2 90 min after stress also prevents TDS, as does blocking calcium-activated potassium channels in this latter time window. TDS is also prevented by blocking guanylate cyclase activation in both time windows, and cGMP-dependent channel activation in the second time window. These results suggest that different NO-related pathways converge at different time windows of the incubation period to induce TDS.