Estradiol’s Permissive Role in Social Stress Susceptibility in Female Rats

Social stress is a common risk factor for both depression and cardiovascular disease (CVD), and individuals suffering from depression are at increased risk of CVD‐related mortality. Additionally, women are more likely than men to suffer from depression and anxiety along with comorbid CVD, however this increased risk is confined to the range between the beginning of puberty and end of menopause. Therefore, while specific systems regulating heightened susceptibility in females are unclear, there is evidence to suggest it may be regulated in part by ovarian hormones. Using a social stress model in female rats whereby a female is forced to witness a social defeat encounter between two males (15 mins, 5 days), we have previously shown that intact females are highly susceptible to this form of stress as evidenced by anxiety‐and depressive‐like behaviors, brain cytokines, and diminished vagal tone. Importantly, ovariectomized (OVX) females are resistant. Here we conducted two separate sets of studies to determine the role that 17‐β estradiol (17‐βE, 10μg/rat, sc) plays in susceptibility to social stress in females. In study #1, following ovariectomy and surgical implantation of cardiovascular transmitters (HD‐S11, DSI), rats were treated with either 17‐βE or vehicle and subjected to control or witness stress during cardiovascular recording. In study #2 all females were implanted with an i.v. catheter and either left intact (sham, and treated with vehicle) or OVX (and treated with vehicle or 17‐βE), followed one hour later by witness stress or control handling. Blood samples were collected (0, 15 and 60 mins) and behavior was video recorded. OVX females exhibited a blunted tachycardic response to stress that was reversed by 17‐βE administration. Moreover, epinephrine release in response to witness stress was highly reactive in intact females above that of OVX females, despite similar corticosterone levels. Anxiety‐like responses were also shown to be regulated by 17‐βE; witness stress‐evoked burying that emerged in intact females was blunted by OVX and reinstated by 17‐βE. Taken together these studies identify that proestrous levels of estradiol are critical for acute behavioral and cardiovascular responses to social stress in females. Future studies are aimed at determining the neural systems that are regulated by estradiol and precipitate stress susceptibility. Support or Funding Information MH113892‐01A1, NARSAD Young Investigator Award 26809