title: Differential behavioral sensitivity to carbon dioxide (CO2) inhalation in rats.
abstract: Inhalation of carbon dioxide (CO2) is frequently employed as a biological challenge to evoke intense fear and anxiety. In individuals with panic disorder, CO2reliably evokes panic attacks. Sensitivity to CO2is highly heterogeneous among individuals, and although a genetic component is implicated, underlying mechanisms are not clear. Preclinical models that can simulate differential responsivity to CO2are therefore relevant. In the current study we investigated CO2-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 CO2-chemosensitivity. Behavioral responsivity to CO2inhalation varied between strains. CO2-evoked immobility was significantly higher in LE and WK rats as compared with W and SD cohorts. Differences were also observed in CO2-evoked rearing and grooming behaviors. Exposure to CO2did not produce conditioned behavioral responses upon re-exposure to CO2context 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 CO2-sensitive strains. Conversely, DβH-positive cell counts within the LC were significantly higher in CO2-sensitive strains. Collectively, our data provide evidence for strain dependent, differential CO2-sensitivity and potential differences in monoaminergic systems regulating panic and anxiety. Comparative studies between CO2-vulnerable and resistant strains may facilitate the mechanistic understanding of differential CO2-sensitivity in the development of panic and anxiety disorders.
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, College of Medicine, Cincinnati, OH 45219, United States; Neuroscience Graduate Program, University of Cincinnati, College of Medicine, Cincinnati, OH 45219, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Winter
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, College of Medicine, Cincinnati, OH 45219, United States.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ahlbrand
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, OH 45219, United States.
authors.forename: Devanshi
authors.initials: D
authors.lastname: Naik
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, College of Medicine, Cincinnati, OH 45219, United States; Neuroscience Graduate Program, University of Cincinnati, College of Medicine, Cincinnati, OH 45219, United States; VA Medical Center, Cincinnati, OH 45220, United States. Electronic address: sahr@uc.edu.
authors.forename: Renu
authors.initials: R
authors.lastname: Sah
mesh_terms: D059331:Adrenergic Neurons / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism*; D002245:Carbon Dioxide / Q000008:administration & dosage*; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D065847:Dorsal Raphe Nucleus / Q000378:metabolism; D006120:Grooming; D008125:Locus Coeruleus / Q000378:metabolism; D009043:Motor Activity; D016584:Panic Disorder / Q000503:physiopathology; D051381:Rats; D011921:Rats, Inbred WKY; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D059326:Serotonergic Neurons / Q000378:metabolism; D013045:Species Specificity; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D002245:Carbon Dioxide; D014365:Tryptophan Hydroxylase; C504569:tph2 protein, rat; D004299:Dopamine beta-Hydroxylase
keywords: CO(2) sensitivity; dorsal raphe; locus coeruleus; noradrenergic; panic; serotonergic