Differential behavioral sensitivity to carbon dioxide (CO) inhalation in rats.

Inhalation of carbon dioxide (CO) is frequently employed as a biological challenge to evoke intense fear and anxiety. In individuals with panic disorder, CO reliably evokes panic attacks. Sensitivity to CO is highly heterogeneous among individuals, and although a genetic component is implicated, underlying mechanisms are not clear. Preclinical models that can simulate differential responsivity to CO are therefore relevant. In the current study we investigated CO-evoked behavioral responses in four different rat strains: Sprague-Dawley (SD), Wistar (W), Long Evans (LE) and Wistar-Kyoto, (WK) rats. We also assessed tryptophan hydroxylase 2 (TPH-2)-positive serotonergic neurons in anxiety/panic regulatory subdivisions of the dorsal raphe nucleus (DR), as well as dopamine β hydroxylase (DβH)-positive noradrenergic neurons in the locus coeruleus, implicated in central CO-chemosensitivity. Behavioral responsivity to CO inhalation varied between strains. CO-evoked immobility was significantly higher in LE and WK rats as compared with W and SD cohorts. Differences were also observed in CO-evoked rearing and grooming behaviors. Exposure to CO did not produce conditioned behavioral responses upon re-exposure to CO context in any strain. Reduced TPH-2-positive cell counts were observed specifically in the panic-regulatory dorsal raphe ventrolateral (DRVL)-ventrolateral periaqueductal gray (VLPAG) subdivision in CO-sensitive strains. Conversely, DβH-positive cell counts within the LC were significantly higher in CO-sensitive strains. Collectively, our data provide evidence for strain dependent, differential CO-sensitivity and potential differences in monoaminergic systems regulating panic and anxiety. Comparative studies between CO-vulnerable and resistant strains may facilitate the mechanistic understanding of differential CO-sensitivity in the development of panic and anxiety disorders.