The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic

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Abstract

The Mouse Defense Test Battery was developed from tests of defensive behaviors in rats, reflecting earlier studies of both acute and chronic responses of laboratory and wild rodents to threatening stimuli and situations. It measures flight, freezing, defensive threat and attack, and risk assessment in response to an unconditioned predator stimulus, as well as pretest activity and postthreat (conditioned) defensiveness to the test context. Factor analyses of these indicate four factors relating to cognitive and emotional aspects of defense, flight, and defensiveness to the test context. In the Mouse Defense Test Battery, GABAA–benzodiazepine anxiolytics produce consistent reductions in defensive threat/attack and risk assessment, while panicolytic and panicogenic drugs selectively reduce and enhance, respectively, flight. Effects of GABAA–benzodiazepine, serotonin, and neuropeptide ligands in the Mouse Defense Test Battery are reviewed. This review suggests that the Mouse Defense Test Battery is a sensitive and appropriate tool for preclinical evaluation of drugs potentially effective against defense-related disorders such as anxiety and panic.

Section snippets

Phenomenological status

The unconditioned defensive behaviors of rodents appear to consist of at least the following: flight, hiding, freezing, defensive threat, defensive attack, and risk assessment. Undoubtedly, more such defensive behaviors remain to be discovered or analyzed. These are species-typical (i.e. typically expressed by individuals of those species under appropriate circumstances) but not species-specific: they occur in much the same form across a variety of mammalian species (Blanchard et al., 2001).

The Fear/Defense Test Battery

The same research that described defensive behaviors in laboratory rodents also yielded the first test situations for analysis of drug effects on these same responses. In particular, a long (6 m), oval runway apparatus utilizing a human experimenter as the threat stimulus was developed in order to permit the adequate expression of flight behaviors in wild rats (Rattus norvegicus). These animals, both wild-trapped or first-generation laboratory-bred, show a very high probability of rapid flight

The Mouse Defense Test Battery: an experimental model of different emotional states: evidence from factor analysis

Factor analyses are commonly used to describe the relationship between different variables and, consequently, to identify specific indices or factors such as anxiety and locomotor activity. Thus, the question whether the different defensive responses elicited in the Mouse Defense Test Battery provide different measures of the same state or measure distinct states of defensiveness, fear, or anxiety has been approached by performing a factor analysis of the various behavioral defense reactions

GABAA–benzodiazepine receptor ligands

Introduced over 40 years ago, benzodiazepines quickly became the most widely used of all psychotropic drugs. Their marked anxiolytic, hypnotic, anticonvulsant, and muscle relaxant properties and their relative safety rapidly elevated benzodiazepines to the treatment of choice for common and recurrent conditions such as generalized anxiety disorder, muscle tension, and insomnia. However, these compounds have come under critical review because of the problems of drug dependence, tolerance,

Selective and nonselective 5-HT-interacting drugs

Although benzodiazepines remain the mainstay of the treatment of anxiety disorders, preclinical research in this area has mainly focused on compounds modulating 5-HT (5-hydroxytryptamine) neurotransmission during the last two decades Griebel, 1995, Griebel, 1997. However, it is somewhat surprising to note that after all this research effort, only a few direct 5-HT-acting compounds have been launched for the treatment of generalized anxiety disorder (i.e. buspirone and tandospirone) Barradell

Neuropeptides and neuropeptide receptor ligands

The treatment of anxiety disorders remains an active area of research, and anxiolytic drug discovery focuses more and more on the involvement of neuroactive peptides in the modulation of anxiety behaviors. Among these, corticotropin-releasing factor (CRF), cholecystokinin (CCK), and tachykinins (substance P and neurokinin A and B) have been the most extensively studied, but the involvement of other neuroactive peptides such as neuropeptide Y, arginine vasopressin, nociceptin/orphanin FQ, and

Summary

The Mouse Defense Test Battery was specifically developed on the basis of previous rat defense test batteries. These, the Fear/Defense Test Battery and Anxiety/Defense Test Battery, had also provided information on specific defense effects of a number of anxiolytic or potentially anxiolytic drugs, effects that could be, and overwhelmingly have been, confirmed by results of Mouse Defense Test Battery drug studies. Analyses of the behaviors measured in the Mouse Defense Test Battery suggest four

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