Examining face and construct validity of a noninvasive model of panic disorder in Lister-hooded rats

Increasing evidence suggests that defensive escape behavior in Lister-hooded (LH) rats induced by ultrasound application may be an animal model of panic disorder. The objectives of this study were to further explore the face and construct validity of ultrasound-induced escape behavior by characterizing the autonomic and neuroendocrine response to ultrasound, and to examine the underlying neuronal structures by comparing the effects of the anxiolytic with panicolytic properties, diazepam, with a preclinical anxiolytic without panicolytic-like activity, the NOP agonist Ro 64-6198. LH rats were implanted with telemetry transmitters to monitor heart rate and core body temperature before, during, and after ultrasound application. Blood samples were taken after ultrasound application for corticosterone analysis. Ultrasound-induced c-Fos expression was measured in different periaqueductal gray (PAG) and amygdala subregions after treatment with diazepam or Ro 64-6198. Ultrasound application increased heart rate and body temperature, but did not alter plasma corticosterone levels. Ultrasound application increased c-Fos expression in the dorsal and dorsolateral PAG (dPAG, dlPAG) and amygdaloid subregions. Diazepam, but not Ro 64-6198, reduced c-Fos expression in the dPAG/dlPAG, while Ro 64-6198, but not diazepam, reduced c-Fos expression in the central amygdala. Similar to human panic attacks, ultrasound application to LH rats activated the autonomic, but not the neuroendocrine, stress system. Also, like in humans, the current data confirm and extend that the dPAG/dlPAG plays a key role in ultrasound-induced escape behavior. These observations suggest that ultrasound-induced escape behaviors in LH rats have face and construct validity for panic disorders.