Anxiety‐related diseases are more than twice as common in women than in men, and in women, symptoms may be exacerbated during the late luteal phase of the menstrual cycle. Despite this, most research into the underlying mechanisms, which drives drug development, have been carried out using male animals. In an effort to redress this imbalance, we compared responses of male and female Wistar rats during exposure to two unconditioned threatening stimuli that evoke panic‐related defensive behaviours: confrontation with a predator (Bothrops alternatus) and acute exposure to hypoxia (7% O2). Threatened by venomous snake, male and female rats initially displayed defensive attention, risk assessment, and cautious interaction with the snake, progressing to defensive immobility to overt escape. Both males and females displayed higher levels of risk assessment but less interaction with the predator. They also spent more time in the burrow, displaying inhibitory avoidance, and more time engaged in defensive attention, and non‐oriented escape behaviour. In females, anxiety‐like behaviour was most pronounced in the oestrous and proestrus phases whereas panic‐like behaviour was more pronounced during the dioestrus phase, particularly during late dioestrus. Acute hypoxia evoked panic‐like behaviour (undirected jumping) in both sexes, but in females, responsiveness in late dioestrus was significantly greater than at other stages of the cycle. The results reveal that females respond in a qualitatively similar manner to males during exposure to naturally occurring threatening stimuli, but the responses of females is oestrous cycle dependent with a significant exacerbation of panic‐like behaviour in the late dioestrus phase.

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Often the manifestation of anxiety cannot be explained by known environmental or hereditary factors. With this perspective, it has been reported that prenatal stress may lead to emotional disturbances in the offspring. However, studies relating prenatal stress to anxiety are controversial and generally the stressors used do not mimicks the reality experienced by mothers. Thus, this investigation evaluated the effects of an unpredictable chronic stress scheme applied in one of the three gestational weeks of rats on the manifestation of generalized anxiety and panic disorder in the progeny (males), analyzing, respectively, the avoidances and escapes in the elevated T-maze, at the 1st, 3rd or 6th month of progeny life. Control offspring showed increased generalized anxiety disorder and reduced panic at 6 months. The effects of prenatal stress depended on the gestational week where it occurred and on the progeny age: during the 1st gestational week the generalized anxiety decreased in 6 month old rats. Animals in the 3rd month, prenatally stressed during the last gestational week, showed anxiogenesis and panicogenesis, but effects reverted at the 6th month, when they presented anxiolysis and no changes related to panic. Together the results show that not only the gestational period in which the aversive experience occurred was important, but the age of the evaluated progeny, since the type and the intensity of behaviors related to anxiety may vary with the developmental stage. For the model of stress used in the present study, the effects of prenatal stress were more prominent when the exposure occurred during the 3rd gestational week in rats.

Background: Acute hypoxia, which is panicogenic in humans, also evokes panic-like behavior in male rats. Panic disorder is more common in women and susceptibility increases during the premenstrual phase of the cycle. Aims: We here investigated for the first time the impact of hypoxia on the expression of panic-like escape behavior by female rats and its relationship with the estrous cycle. We also evaluated functional activation of the midbrain panic circuitry in response to this panicogenic stimulus and whether short-term, low-dose fluoxetine treatment inhibits the hyper-responsiveness of females in late diestrus. Methods: Male and female Sprague Dawley rats were exposed to 7% O2. Females in late diestrus were also tested after short-term treatment with fluoxetine (1.75 or 10 mg/kg, i.p.). Brains were harvested and processed for c-Fos and tryptophan hydroxylase immunoreactivity in the periaqueductal gray matter (PAG) and dorsal raphe nucleus (DR). Results: Acute hypoxia evoked escape in both sexes. Overall, females were more responsive than males and this is clearer in late diestrus phase. In both sexes, hypoxia induced functional activation (c-Fos expression) in non-serotonergic cells in the lateral wings of the DR and dorsomedial PAG, which was greater in late diestrus than proestrus (lowest behavioral response to hypoxia). Increased responding in late diestrus (behavioral and cellular levels) was prevented by 1.75, but not 10 mg/kg fluoxetine. Discussion: The response of female rats to acute hypoxia models panic behavior in women. Low-dose fluoxetine administered in the premenstrual phase deserves further attention for management of panic disorders in women.