Nitric Oxide in the Dorsal Periaqueductal Gray Mediates the Panic-Like Escape Response Evoked by Exposure to Hypoxia

Exposure of rats to an environment with low O2 levels evokes a panic-like escape behavior and recruits the dorsal periaqueductal gray (dPAG), which is considered to be a key region in the pathophysiology of panic disorder. The neurochemical basis of this response is, however, currently unknown. We here investigated the role played by nitric oxide (NO) within the dPAG in mediation of the escape reaction induced by hypoxia exposure. The results showed that exposure of male Wistar rats to 7% O2 increased nitrite levels, a NO metabolite, in the dPAG but not in the amygdala or hypothalamus. Nitrite levels in the dPAG were correlated with the number of escape attempts during the hypoxia challenge. Injections of the NO synthesis inhibitor NPA, the NO-scavenger c- PTIO, or the NMDA receptor antagonist AP-7 into the dorsolateral column of the periaqueductal gray (dlPAG) inhibited escape expression during hypoxia, without affecting the rats' locomotion. Intra-dlPAG administration of c-PTIO had no effect on the escape response evoked by the elevated-T maze, a defensive behavior that has also been associated with panic attacks. Altogether, our results suggest that NO plays a critical role in mediation of the panic-like defensive response evoked by exposure to low O2 concentrations.