Rodent doxapram model of panic: Behavioral effects and c-Fos immunoreactivity in the amygdala

Background: Panic attacks, the hallmark of panic disorder, are often characterized by hyperventilation. Existing animal models of anxiety have not addressed the effects of the hyperventilation on anxiety-related behaviors. Doxapram is a respiratory stimulant that reliably evokes panic attacks in patients with panic disorder. We examined doxapram in four rodent models of anxiety and sought to identify brain regions involved in its behavioral effects. Methods: The effects of doxapram were determined for cue and contextual fear conditioning, the open field test, and the social interaction test. The effect of doxapram on c-Fos-like immunoreactivity was examined in three brain regions. Results: Doxapram at 4 mg/kg increased anxiety-related behaviors in all four anxiety models. An inverted U-shaped dose-response curve was identified for fear conditioning to cue. Doxapram induced c-Fos-like immunoreactivity in the central nucleus of the amygdala but not the lateral nucleus or the nucleus tractus solitarius. Conclusions: Doxapram enhanced anxiety-related behaviors in four animal models of anxiety that involve conditioning or spontaneous avoidance. The effect of doxapram may result from activation of neurons in the amygdala. Doxapram, by inducing hyperventilation, may be a useful adjunct to existing animal anxiety models for improving validity for panic anxiety.