GABA-A receptors and the response to CO(2) inhalation - a translational trans-species model of anxiety?

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2008-07, Vol.90 (1), p.51-57
• Main Authors: Bailey, Jayne E, Nutt, David J
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Animals; Anti-Anxiety Agents - pharmacology; Anxiety - chemically induced; Anxiety - psychology; Benzodiazepines - pharmacology; Carbon Dioxide - administration & dosage; Carbon Dioxide - pharmacology; gamma-Aminobutyric Acid - pharmacology; gamma-Aminobutyric Acid - physiology; Humans; Models, Psychological; Receptors, GABA-A - physiology; Receptors, Serotonin - drug effects; Receptors, Serotonin - physiology; Species Specificity
• ISSN: 0091-3057
• DOI: 10.1016/j.pbb.2008.04.002

The mechanisms by which the inhalation of carbon dioxide (CO(2)) produces anxiety and panic are not fully understood, although more recently there is evidence to suggest the involvement of a neural 'fear circuit'. We have suggested that this neural fear circuit is partly mediated by the brain noradrenaline network [Bailey, J.E., Argyropoulos, S.V., Lightman, S.L. and Nutt, D.J., (2003) Does the brain noradrenaline network mediate the effects of the CO(2) challenge? J Psychopharmacol 17(3): 252-259.]. However, we now review evidence that GABA-A may also play an important role in the modulation of CO(2)-induced anxiety. The review of this evidence starts with a key publication showing that 1 min of 35% CO(2)/65% air produced anxiogenic effects in a rat model of anxiety, to a similar extent to the anxiogenic betacarboline derivative FG7142, a benzodiazepine receptor inverse agonist. The effects of both anxiogenic stimuli were abolished with pre-treatment with alprazolam (0.5 mg/kg), but only those of FG7142, not CO(2), was blocked by a benzodiazepine antagonist [Cuccheddu, T., Floris, S., Serra, M., Porceddu, L., Sanna, E., Biggio, G., (1995) Proconflict effect of carbon dioxide inhalation in rats. Life Sci 56: PL 321-324.]. Although the evidence from this study did not conclusively prove that CO(2) had an action to reduce GABA function, it was an experiment designed to be translational to compare what was known about CO(2)-induced anxiety in patients, and to also to explore if GABA mechanisms are involved. Additional evidence from the literature is found in the association between GABA and chemoreceptors, both in laboratory and human studies and GABA and anxiety disorders. Evidence of this association is found across species from stress-induced change in GABA levels in plants and insects to humans, where there is now much evidence of abnormalities in GABA/benzodiazepine receptors in anxiety and other psychiatric disorders. This paper reviews some of the evidence and attempts to relate and compare these findings across species from the human to the Drosophila.