Rationale <p>There is a connection between respiratory pathologies and panic disorder, since episodes of hypercapnia can trigger anxiety-related behaviors. The locus coeruleus (LC) is a CO₂/pH chemosensitive region capable of generating emotional and physical responses during stress episodes. The acid-sensitive ion channel type 1a (ASIC1a) participates in the panicogenic response induced by CO₂.</p> Objectives <p>Our study investigated the role of ASIC1a channels in the LC in detecting hypercapnic acidosis and their participation in the respiratory and behavioral responses induced by CO₂.</p> Methods <p>We tested the effects of injection of an ASIC1a antagonist [Psalmotoxin-1 (Pstx-1—50&#xa0;ng/0.1uL)] into the LC of C57BL/6 male and female mice on respiratory, metabolic, and behavioral responses to 20% CO₂. To assess the role of ASIC1a channels in basal activity and CO₂ chemosensitivity of LC neurons, whole-cell patch-clamp recordings were performed on brainstem slices from male mice using Pstx-1 (0.050&#xa0;µg/mL).</p> Results <p>Pstx-1 intra-LC did not change ventilation and metabolism under normocapnic and hypercapnic conditions in both male and female mice. As to CO₂-behavioral responses, Pstx-1 injection decreased the number of jumps in males, but there was no significant difference in females. In vitro, Pstx-1 reduced the activity of LC chemoreceptors under hypercapnia in males, but no change was observed under control conditions.</p> Conclusions <p>ASIC1a channels in the LC do not participate in respiratory control under normocapnia and hypercapnia, but are involved in CO₂-induced panic behavior, demonstrating a sex-dependent response. Furthermore, ASIC1a channels contribute to the CO₂ chemosensitivity of LC neurons in males.</p>