The prevalence of anxiety disorders is higher in women than in men. Yet preclinical studies on anxiety are mostly performed in male subjects. This may have limited our understanding of mechanisms contributing to anxiety disorders. Since fear conditioning is considered an important factor in the etiology of anxiety disorders, the present study aimed to investigate the effect of sex and estrous cycle on conditioned fear and the anxiolytic effect of benzodiazepines in rats. We measured the fear-potentiated startle response in male and female rats during different estrous cycle stages and performed a replication study in a separate cohort. In addition, we assessed the response to diazepam (0-3.0 mg/kg IP) and chlordiazepoxide (0-10 mg/kg IP) in male and female rats in proestrous/estrous and diestrous stage. Our results showed that there were no sex differences in the expression of fear-potentiated startle. The estrous cycle also did not affect the fear-potentiated startle response. In addition, male and female rats did not differ in their fear-potentiated startle response following treatment with either diazepam or chlordiazepoxide. In conclusion, the current study shows that male and female rats do not differ in their conditioned fear response and the responsiveness to benzodiazepines. The results further indicate that conditioned fear-related processes are not affected by gonadal hormone fluctuations in this paradigm. These findings may suggest that the higher prevalence of anxiety disorders in women more likely results from differences in responding to previous experiences or differences in other predisposing factors, rather than differences in conditioned fear per se.

Rationale Fear conditioning is an important factor in the etiology of anxiety disorders. Previous studies have demonstrated a role for serotonin (5-HT) 1A receptors in fear conditioning. However, the relative contribution of somatodendritic 5-HT 1A autoreceptors and post-synaptic 5-HT 1A heteroreceptors in fear conditioning is still unclear. Objective To determine the role of pre- and post-synaptic 5-HT 1A receptors in the acquisition and expression of cued and contextual conditioned fear. Methods We studied the acute effects of four 5-HT 1A receptor ligands in the fear-potentiated startle test. Male Wistar rats were injected with the 5-HT 1A receptors biased agonists F13714 (0–0.16 mg/kg, IP), which preferentially activates somatodendritic 5-HT 1A autoreceptors, or F15599 (0–0.16 mg/kg, IP), which preferentially activates cortical post-synaptic 5-HT 1A heteroreceptors, with the prototypical 5-HT 1A receptor agonist R(+)8-OH-DPAT (0–0.3 mg/kg, SC) or the 5-HT 1A receptor antagonist WAY100,635 (0–1.0 mg/kg, SC). Results F13714 (0.16 mg/kg) and R(+)-8-OH-DPAT (0.03 mg/kg) injected before training reduced cued fear acquisition. Pre-treatment with F15599 or WAY100,635 had no effect on fear learning. In the fear-potentiated startle test, F13714 (0.04–0.16 mg/kg) and R(+)-8-OH-DPAT (0.1–0.3 mg/kg) reduced the expression of cued and contextual fear, whereas F15599 had no effect. WAY100,635 (0.03–1.0 mg/kg) reduced the overall startle response. Conclusions The current findings indicate that activation of somatodendritic 5-HT 1A autoreceptors reduces cued fear learning, whereas 5-HT 1A receptors seem not involved in contextual fear learning. Moreover, activation of somatodendritic 5-HT 1A autoreceptors may reduce cued and contextual fear expression, whereas we found no evidence for the involvement of cortical 5-HT 1A heteroreceptors in the expression of conditioned fear.

Chronically elevated levels of corticotropin-releasing hormone (CRH) are implicated in human stress-related and affective disorders, including generalized anxiety disorder and major depression. To gain more insight into the relationship between hyperactivity of the CRH system and associated neuroendocrine, autonomic, physiological, and behavioral changes, we have developed a transgenic mouse model of CRH overproduction (CRH-OE). In this study, we explored the behavioral consequences of chronic CRH overproduction in mice of the two available transgenic lines (CRH-OE2122 and CRH-OE2123) in paradigms measuring behavioral aspects of stress, anxiety, and depression. These paradigms include tasks based on free exploration of novel environments (unfamiliar homecage and unfamiliar open field), stress-induced hyperthermia, tests associated with anxiety-related behavior (elevated plus maze and light-dark box), and paradigms in which (anti-)depressant-like behaviors can be detected (tail suspension test and forced swim test). The only relatively consistent finding, although not always significant, was reduced locomotor activity in CRH-OE 2122 mice, corresponding well with the known effects of CRH on locomotion. Contrary to our predictions, CRH-OE mice did not show an altered response to stress, and a phenotype indicative of increased anxiety and/or depression was not evident in CRH-OE mice.Corticotropin-releasing hormone (CRH) plays a pivotal role in the response of an organism to various stressors, coordinating neuroendocrine, autonomic, behavioral and immunological responses to stress (

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