Defensive Behaviors In Mice Research Articles

Role of glutamate NMDA receptors and nitric oxide located within the periaqueductal gray on defensive behaviors in mice confronted by predator

The midbrain periaqueductal gray (PAG) is part of the brain system involved in active defense reactions to threatening stimuli. Glutamate N-methyl-D: -aspartate (NMDA) receptor activation within the dorsal column of the PAG (dPAG) leads to autonomic and behavioral responses characterized as the fear reaction. Nitric oxide (NO) has been proposed to be a mediator of the aversive action of glutamate, since the activation of NMDA receptors in the brain increases NO synthesis. We investigated the effects of intra-dPAG infusions of NMDA on defensive behaviors in mice pretreated with a neuronal nitric oxide synthase (nNOS) inhibitor [Nomega-propyl-L: -arginine (NPLA)], in the same midbrain site, during a confrontation with a predator in the rat exposure test (RET). Male Swiss mice received intra-dPAG injections of NPLA (0.1 or 0.4 nmol/0.1 microl), and 10 min later, they were infused with NMDA (0.04 nmol/0.1 microl) into the dPAG. After 10 min, each mouse was placed in the RET. NMDA treatment enhanced avoidance behavior from the predator and markedly increased freezing behavior. These proaversive effects of NMDA were prevented by prior injection of NPLA. Furthermore, defensive behaviors (e.g., avoidance, risk assessment, freezing) were consistently reduced by the highest dose of NPLA alone, suggesting an intrinsic effect of nitric oxide on defensive behavior in mice exposed to the RET. These findings suggest a potential role of glutamate NMDA receptors and NO in the dPAG in the regulation of defensive behaviors in mice during a confrontation with a predator in the RET.

Effects of intra-PAG infusion of ovine CRF on defensive behaviors in Swiss-Webster mice

The midbrain dorsal periaqueductal gray (DPAG) is part of the brain defensive system involved in active defense reactions to threatening stimuli. Corticotrophin releasing factor (CRF) is a peptidergic neurotransmitter that has been strongly implicated in the control of both behavioral and endocrine responses to threat and stress. We investigated the effect of the nonspecific CRF receptor agonist, ovine CRF (oCRF), injected into the DPAG of mice, in two predator–stress situations, the mouse defense test battery (MDTB), and the rat exposure test (RET). In the MDTB, oCRF weakly modified defensive behaviors in mice confronted by the predator (rat); e.g. it increased avoidance distance when the rat was approached and escape attempts (jump escapes) in forced contact. In the RET, drug infusion enhanced duration in the chamber while reduced tunnel and surface time, and reduced contact with the screen which divides the subject and the predator. oCRF also reduced both frequency and duration of risk assessment (stretch attend posture: SAP) in the tunnel and tended to increase freezing. These findings suggest that patterns of defensiveness in response to low intensity threat (RET) are more sensitive to intra-DPAG oCRF than those triggered by high intensity threats (MDTB). Our data indicate that CRF systems may be functionally involved in unconditioned defenses to a predator, consonant with a role for DPAG CRF systems in the regulation of emotionality.

The rat exposure test: a model of mouse defensive behaviors

In order to facilitate behavioral, and potentially pharmacological, analyses of risk assessment behaviors in mice, a rat exposure test (RET) was devised and evaluated. This test provides a home chamber connected via a tunnel to a rat (predator) exposure area. Familiar substrate is provided to permit burying, and mouse subjects are habituated to the apparatus prior to exposure to an amphetamine-activated rat. In comparison to toy-rat-exposed controls, rat-exposed BALB/c mice showed significantly more risk assessment [stretch attend posture (SAP) and stretch approach], freezing, and avoidance (time in the home chamber), and less time in contact with the wire mesh screen between itself and the threat stimulus. When BALB/c, C57BL/6, CD-1, and Swiss–Webster mice were compared in this test, the two inbred strains (BALB/c and C57BL/6) tended to show more extreme values of particular defensive behaviors, compared to the two outbred strains (Swiss–Webster and CD-1). C57BL/6 mice showed more avoidance and higher levels of SAP, freezing, and burying than BALB/c and more than one or both outbred strains as well. BALB/c mice showed little defensive burying, both in comparison to toy-exposed controls (Experiment 1), and in comparison to the three other strains in Experiment 2. These findings are somewhat at variance with characterizations of anxiety in C57BL/6 and BALB/c mice, based on tests utilizing novel areas and noxious stimuli, suggesting strain differences in defensiveness to such stimuli, compared to antipredator defense levels. Nonetheless, with the exception of burying in BALB/c mice, all strains showed all defensive behaviors measured to the rat stimulus. In particular, SAP levels were substantial in all strains tested, suggesting the usefulness of this test in assessment of the role of risk assessment in defense.

Mouse defensive behaviors: pharmacological and behavioral assays for anxiety and panic

The natural defensive behaviors of laboratory mice have been evaluated in both seminatural and highly structured situations; and characterized in terms of eliciting stimuli, response to pharmacological agents, behavior patterns, and outcome or effect on the social and physical environment. The defense patterns of laboratory mice and rats are generally similar, but mice show risk assessment on initial exposure to highly threatening stimuli while rats do not, while rats display alarm vocalizations, missing in mice. Quantitative differences in freezing and flight for laboratory mice and rats appear to largely reflect domestication effects, with wild mice and rats more similar to each other. This nexus of detailed within-species and comparative data on defense patterns makes it possible to reliably elicit specific defenses in mice or rats in an experimental context, providing well-validated assays of the natural defensive behaviors themselves, as opposed to `models’ of defense. The mouse–rat comparisons indicate considerable cross-species generality for these defense patterns, as does a scattered but considerable literature on other mammalian species, generally involving field studies and typically focusing on those aspects of defensive behavior that are visible at a distance, such as vigilance, or flight. Although potential homologies between normal mouse and human defense systems should ideally involve all four pattern components (stimulus, organismic factors, response characteristics, outcome), predictive validity in terms of response to drugs active against specific defensive psychopathology is the most extensively investigated of these. Flight, as measured in the Mouse Defense Test Battery shows a consistently appropriate response to panicolytic, panicogenic, and panic-neutral drugs, while some other predictive ‘panic models’ (dPAG-stimulation; DMH-inhibition; possibly conditioned suppression of drinking paradigms) also elicit and (indirectly) measure behaviors potentially related to flight. Models unrelated to flight (e.g. ultrasonic vocalization to conditioned stimuli); or for which flight elements may a relatively minor contributor to the behavior measured (Elevated T-maze) are less predictive of panicolytic or panicogenic action. These findings indicate that natural defensive behaviors provide a well-characterized pattern for analysis of effects of genetic or other physiological manipulations in the mouse, and may also serve as a model for analysis of defense-related human psychopathology.

Cocaine Produces Panic-Like Flight Responses in Mice in the Mouse Defense Test Battery

There is an emerging body of clinical evidence that cocaine use in humans can result in serious fear or panic-related emotional disturbances. The present study evaluated the effects of cocaine administration upon defensive responses of mice to a predator (rat) in a Mouse Defense Test Battery (MDTB) that permits the display of the full range of the mouse defensive behaviors: avoidance/escape, flight, freezing, defensive upright, and defensive threat and attack. Mice were tested 30 min following intraperitoneal (IP) injections of either 0, 10, 20, or 30 mg/kg cocaine hydrochloride suspended in physiological saline. Cocaine produced an increase in flight and escape responses throughout the subtests comprising the MDTB. The percentage of subjects exhibiting escape increased in cocaine-treated mice in the Predator Avoidance Test. Cocaine increased mean flight speed and maximum flight speed in the Flight/Chase Test; frequency of flight responses in the Straight Alley Test; and the number of flight attempts in the Forced Contact test. The predominance of flight responding throughout the tests masked any possible cocaine effects on other defenses. The present findings indicate that cocaine may exert its panic-producing effects by acting upon particular neurobehavioral systems subserving defensive behavior.

Study of the modulatory activity of bz (ω) receptor ligands on defensive behaviors in mice: Evaluation of the importance of intrinsic efficacy and receptor subtype selectivity

1. 1. This study examined the hypothesis that the anxiolytic effects of benzodiazepine (BZ (ω)) receptor ligands may be associated with actions at a defined receptor subtype and/or their level of intrinsic activity using the mouse defense test battery. 2. 2. This test has been designed to assess defensive reactions of Swiss mice confronted with a natural threat (a rat) and situations associated with this threat. Primary measures taken before, during and after rat confrontation were escape attempts, flight, risk assessment and defensive threat and attack. 3. 3. The drugs used were the non-selective BZ (ω) receptor full agonist diazepam, the non-selective BZ (ω) receptor partial agonist bretazenil and the β-carboline abecarnil which acts as a full agonist on GABA A receptors containing the α1- and the α3-subunits and as a partial agonist at receptors containing the α2- and the α5-subunits. The drugs were given alone and diazepam was co-administered with either bretazenil or abecarnil. 4. 4. When administered alone, diazepam attenuated several defensive responses including risk assessment activities, defensive threat/attack reactions upon forced contact with the rat and escape attempts following the removal of the rat from the apparatus. Unlike diazepam, bretazenil was devoid of significant activity on defense and abecarnil displayed depressant activity. 5. 5. Bretazenil blocked all behavioral effects of diazepam on defense behaviors. The co-administration of diazepam and abecarnil produced a behavioral profile similar to that observed when diazepam was administered alone, indicating that abecarnil did not influence the effects of diazepam on defense. By contrast, diazepam completely antagonized the sedative effects of abecarnil. 6. 6. These findings indicate that only BZ (ω)) ligands with high intrinsic efficacy at all BZ (ω) receptor subtypes display clear and specific effects on defensive behaviors in mice, and suggest that GABA A receptors containing the α3 subunit might represent the primary target involved in the modulatory action of diazepam on defensive behaviors.

Differentiation of anxiolytic and panicolytic drugs by effects on rat and mouse defense test batteries

The use of ethoexperimental techniques to elicit and maximize the full range of defensive behaviors of rats and mice enables a very precise analysis of the effects of drugs on these behavior patterns. Two rat defense test batteries (the fear/defense test battery or F/DTB and the anxiety/defense test battery or A/DTB) have provided evidence that anxiolytic drugs, even from different classes, produce a common pattern of changes in specific behaviors. A recently developed mouse defense test battery (MDTB) has enabled description of mouse defensive behaviors to a predator, for comparison to those of rats, and a series of studies of drug effects on the behaviors measured in the MDTB provides evidence of cross-species generality of anxiolytic drug effects, or lack of effect, on specific defensive behaviors. In addition, tests with panicogenic and panicolytic drugs in the MDTB indicate that these enhance and reduce, respectively, flight reactions, which generally are not altered by anxiolytic compounds. Thus, results from the MDTB, taken in conjunction with those of the two rat test batteries and other defense analyses in rats and mice, provide evidence that many defensive behaviors are similar across rodent species, while the differences obtained provide a consistent pattern across situations. Moreover, the defense test batteries may be used to differentiate the effects of drugs effective against generalized anxiety as opposed to panic, through effects on specific defensive behaviors.

Effects of non-contact exposure to rodents on defensive behaviors in mice

These experiments explored the effects of non-contact exposure to two rodent species (rats and gerbils) on the defensive behaviors of male CD-1 mice. In Experiment 1 it was found that rats evoked substantial levels of defensiveness which were positively related to increases in rat activity. This effect was considerably attenuated, but still detectable, 30 min after rat exposure (Experiment 2). In Experiment 3 the effectiveness of rats and gerbils were compared. Gerbils were found to evoke a more modest increase in defensiveness than rats. These experiments indicate that non-contact exposure to rodents displaying varying levels of activity and, perhaps, propensity for predatory behavior provide a useful level of experimental control over the intensity of fear-like responses.

Ethopharmacological analysis of the effects of thyroliberin and melanostatin on a model of timid defensive behavior in mice

Ethopharmacological analysis of the effects of thyroliberin and melanostatin on a model of timid defensive behavior in mice