Social stress induces robust behavioral and physiological changes, some of which may alter the responsiveness to pharmacological agents, including diazepam (DZP). We used a resident–intruder paradigm to (1) develop a comprehensive ethogram of behavioral changes following social defeat (SD) in the socially reactive strain, DBA/2 male mice, (2) determine whether acute exposure of DBA/2 mice to low-dose DZP would induce flight or aggressive behavior, both of which have been observed in other rodent models and (3) to test whether prior social stress affects responses to DZP. Behavioral responses to a nonaggressive intruder (NAI) mouse 24 h post-SD were measured in resident subject mice exposed to DZP (0, 0.5, 2.0 mg/kg, ip) either prior to the resident–intruder test (Experiment 1) or immediately post-SD (Experiment 2); control mice were not defeated (NOSD). In general, SD mice displayed increased passive and active avoidance, defense, immobility, and risk assessment relative to NOSD mice. In Experiment 1, mice treated acutely with 0.5 mg/kg DZP had more approach and flight behavior, while those treated with 2.0 mg/kg DZP had more avoidance than vehicle-treated mice, independent of SD. In Experiment 2, acute DZP (2 mg/kg) induced effects 24 h later, possibly secondary to withdrawal. In a nonsocial context (Experiment 3), DZP increased exploratory activity.

Acute pain tests using mechanical stimuli typically do not involve objects important in the evolutionary history of the subjects, and may fail to evaluate the contribution of biobehavioral defensive reactions to the total pain response. Spines are common structural defenses that project plants and animals against predation. The present studies examined the reaction to contact with such natural, mechanical pain stimuli in the laboratory rat, utilizing a floor board with protruding pins located in the middle of a novel alley (the "fakir" test). Behavioral responses were characterized in 10-min tests (Experiment 1). Subjects showed voluntary contact with the pins followed by patterns of avoidance and risk assessment (Stretch attend and stretch approach). Few subjects crossed the array of pins. The amygdala has been implicated in the perception of pain, particularly in stressful or fearful contexts. In Experiment 2, the fakir test was used to examine, concurrently, the effects of amygdala lesions on analgesiometric (frequency and duration of pins crossings) and anxiometric (risk assessment) measures. Large, bilateral, lesions of the amygdala significantly increased both the number of pin crossings and time spent on the pins without affecting the risk assessment measures. These findings suggest a possible dissociation between anxiety and pain perception with an important (nonaffective) role for the amygdala in the latter. (C) 1999 Elsevier Science Inc.

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.

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 intravenous cocaine administration upon defensive responses of rats to a threatening conspecific in a test situation, an oval runaway, permitting the display of the full range of the rat defensive repertoire. A battery of tests was employed to evaluate avoidance/escape, flight, freezing, defensive upright and defensive attack behaviors. In the first experiment male Long–Evans rats implanted with a chronic indwelling jugular catheter were placed in the runway and tested immediately after administration of either 0, 1, or 4 mg/kg of cocaine hydrochloride. The 4-mg/kg dose produced a dramatic flight response, the direction of which depended upon the direction of the approaching threat source. The same dose produced increased defensive upright postures during forced contact with the stimulus animal. Experiment 2 examined the time course for cocaine-induced hyperdefensiveness. Rats were administered either saline or 4 mg/kg cocaine intravenously and were tested following a delay of either 0, 5, 15, or 30 min following infusion. Cocaine-treated rats again displayed high levels of flight, which declined with increased time between infusion and testing. However, increased defensiveness persisted even at the 30 min delay for several defensive measures including avoidance, freezing, and defensive upright posture. Thus, following an initial period of rapid flight with intravenous cocaine administration, there was a lasting hyperdefensiveness in cocaine-treated rats. The present results suggest that cocaine may exert its panic-producing effects by acting upon neurobehavioral systems subserving defensive behavior, and that understanding of these systems is critical for understanding the neurobiology of panic disorder.

The development of laboratory rodent models for elicitation and measurement of a range of defensive behaviors raises the question of the relationship between defense in these animals and those of their wild congeners. To evaluate this relationship for mice, defensive responses to an anesthetized rat were compared for fourth-generation laboratory-bred wild mice and Swiss CD-1 (Swiss-Webster derived) laboratory mice in a Mouse Defense Test Battery. Wild mice showed enhanced levels of both freezing and flight, fleeing from distant approach of the predator in several situations and fleeing more quickly than the Swiss mice. However, Swiss mice did flee upon contact with the rat and also showed levels of several other defensive behaviors (risk assessment, defensive threat, and attack) that were often reliably higher than those of the wild mice. However, when wild mice were prevented from fleeing, their levels of defensive threat and attack were as high as, or at very short prey-predator distances higher than, those of the Swiss mice. These findings suggest that flight and freezing are the major defensive behaviors reduced in Swiss mice and that these reductions allow the appearance of higher levels of additional defensive behaviors in the laboratory animals. However, although Swiss mice do show lower levels of flight and freezing, their patterns of defensive behavior are sufficiently similar to those of wild mice that they provide adequate subjects for research on the biologic bases of defensive behavior. A final experiment indicated that when wild mice are familiarized with a chamber providing a place of concealment, they flee directly to this chamber on presentation of a rat, indicating that flight is a targeted response and not simply an abrupt increase in forward locomotion. Over 10 rat presentation trials with a blocked chamber entrance, however, this response declines.

In the early stages of an agonistic encounter between mice, the loser of the conflict initially exhibits pronounced flight and escape attempts. When exposure to attack is prolonged, however, defeated mice display a decrease in these active defenses and become increasingly passive. The generality of such defeat-induced passivity was investigated in the present study by examining acutely defeated mice in the forced swim test, a nonsocial but threatening environment that normally engenders high levels of escape behavior. In the present experimental model, highly aggressive male C57BL/6 mice were used to defeat smaller male intruders of the DBA/2 strain in a series of brief (2-min) encounters spaced 2 min apart. In Experiment 1, DBA/2 mice were administered four defeat encounters and were then given a 10-min swim test following a postdefeat delay of 0, 30, or 60 min. Activity in the swim test was determined both by a novel, automated device that detected movement-induced perturbations in the water medium via infrared beam interruptions and by the standard observational measurement of percent time immobile. Both activity measures indicated a significant suppression effect of defeat on swim activity, the magnitude of which declined steadily as the delay between the defeat encounters and the swim test increased. In Experiment 2, DBA/2 mice experienced zero, one, two, three, or four defeat encounters spaced 2 min apart and were administered the swim test 30 min following the last defeat encounter. Activity in the swim test decreased as the number of defeat encounters increased. The present findings suggest that defeat-induced passivity in mice is of a global nature, persisting in other threatening environments in which high levels of escape activity would normally be observed. Similarities between the parameters of the present phenomenon and those of opioid-mediated defeat analgesia are discussed. Aggr. Behav. 24:257–269, 1998. © 1998 Wiley-Liss, Inc.

Male hamsters that have been repeatedly defeated by larger, aggressive males subsequently flee from, rather than attack, nonaggressive male intruders that are introduced into their home cages. We have referred to this generalization of flight in response to nonaggressive intruders as "conditioned defeat" (CD). In an attempt to reverse CD pharmacologically, diazepam (DZP) was administered to hamsters at two different time points relative to CD acquisition and subsequent response generalization tests, which involved the exposure of subjects to nonaggressive intruders (NAIs). In Experiment 1, subjects were given a single injection of one of 4 doses of DZP (0, 2, 6, or 20 mg/kg) immediately following CD acquisition. Twenty-four hours later, contrary to expectations, subjects that had received the 6 mg/kg dose displayed elevated flight responses in the presence of an NAI. Flight responding declined over days except in subjects that received the highest dose. In the second experiment, hamsters were administered a single injection of either 0, 2, or 6 mg/kg DZP just prior to a response generalization test occurring 24 h following CD training. Flight responses to the NAIs were again exaggerated in subjects that were given the 6 mg/kg dose, an effect that persisted several days without further drug administration. The present findings suggest the possibility that benzodiazepines can potentiate fear responses under certain stressful conditions.