Defensive Test Battery

This test battery is based on rodent unconditioned behaviors such as freezing, hiding, taking flight, defensive threat/ attack, and risk assessment56,57 with the flight component being thought to relate to panic. NCEs that are clinically effective in treating panic disorder as well as anxiety are effective in this model. The fear/defense test battery developed for rats uses a long (6 m) oval runway apparatus with a human experimenter representing the threat stimulus. When the runway is in the oval configuration, rats exhibit flight and escape behaviors; changing the runway to a straight alleyway elicits a freezing response. This test is primarily conducted using wild trapped Rattus norvegicus and R. rattus since laboratory bred rats have blunted escape, freezing, and defensive behaviors.58 BZs selectively reduce defensive threat vocalizations while 5HT1A agonists reduce both defensive threat vocalizations and defensive attack while having no effect on flight avoidance or freezing.58-60 The anxiety/defense test battery also uses a threatening stimulus, usually a cat or cat odor, but the stimulus does not approach the animal during the test.57 Thus, this task measures the inhibition of normal behaviors, freezing and avoidance of the area containing the threatening stimulus. It is also used to measure risk assessment: the orientation of the animal to openings/corners in a stretched posture followed by episodes of head poking to scan and sniff the area.60 Diazepam and chlordiazepoxide reduce avoidance of the threat stimulus as well as general behavioral inhibition and also reduce risk assessment when cat odor is present, while 5HT1A agonists like gepirone and 8-OH-DPATreduce the avoidance behavior and behavioral inhibition but have no effect on risk assessment or freezing behavior.57

The mouse defensive battery is a parallel test to the rat fear/defense and anxiety/defense test battery.57 Overall, the behaviors are similar to those of the rat with one exception being the observation of putative risk assessment behaviors in the fear/defense portion of the assessment. These behaviors include flight, flight speed, freezing, defensive vocalizations and attacks, risk assessment, and contextual defense that involve attempts to escape after the predator (anesthetized rat) is no longer near. In the mouse battery, both nonselective GABAa positive allosteric modulators and compounds with functional selectivity for a2 subunit-containing GABAA receptors (SL-651498), are active,61 as are 5HT1A receptor antagonists.62 Selective and mixed SNRI compounds as well as MAO inhibitors have clear effects on the flight response when administered chronically but not acutely.63,64 This is perhaps consistent with the use of fluoxetine (SSRI), imipramine (SNRI), and phenelzine (MAO inhibitor) for the treatment of panic disorder in the clinic. CRF antagonists (reduce effective components of defensive behaviors), NK2 receptor antagonists (decrease flight, risk assessment, and contextual anxiety), neurotensin antagonists (reduce risk assessment), and vasopressin antagonists (reduce defensive aggression) also have activity in this battery of tests suggesting that it can be used to evaluate anxiolytic activity of compounds with novel mechanisms of action.57

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