Locus coeruleus noradrenergic neurons mediate panic-like escape response elicited by CO2

The CO exposure has been used to investigate the panicogenic response in patients with panic and other anxiety disorders since these patients are more sensitive to this stimulus, and therefore, more likely to experience the "suffocation false alarm" which, in turn, triggers the panic attack. It is well described that imbalances in the modulation of Locus coeruleus noradrenaline (LC-NE) neurotransmission are responsible for several psychiatric disorders, including panic disorder and these neurons are sensitive to changes in CO /pH. Therefore, we investigated the participation of LC-NE neurons in the CO -induced panic like scape response by using C56BL/6 mice with a conditional knockout allele of Dbh (Dbh ) crossed with En1 (En1 Dbh - LC-NE mutants). In addition, an intermediate genotype animal of the same genetic background was used (WT Dbh ) as well as control animals (WT/WT) of both sexes (10-12 weeks; 20-25 g). Mice were placed in chamber where behavioral responses such as escape (jumping/running) and time spent immobile (freezing) were recorded under 20% CO during 7 min. CO -enriched air evoked an active escape response (jumping behavior) interpreted as escape attempts. En1 Dbh mutants had a blunted jumping response (P=0.001) and spent more time in freezing compared to the other groups (P<0.0001). Furthermore, En1 Dbh animals had fewer racing episodes (P=0.028) compared to WT/WT animals, but not different from WT DbhcKO group, that also presented a long freezing time, little movement, and a small number of jumps. No sex difference was observed among groups. These findings suggest that noradrenaline originating from the LC has an important role in the panic-like escape response elicited in mice by exposure to CO in a sex independent way.