Differential effects of imipramine and CORT118335 (Glucocorticoid receptor modulator/mineralocorticoid receptor antagonist) on brain-endocrine stress responses and depression-like behavior in female rats.

Depression is commonly associated with hypothalamic-pituitary adrenal (HPA) axis dysfunction that primarily manifests as aberrant glucocorticoid secretion. Glucocorticoids act on Type I mineralocorticoid (MR) and Type II glucocorticoid receptors (GR) to modulate mood and endocrine responses. Successful antidepressant treatment normalizes HPA axis function, in part due to modulatory effects on MR and GR in cortico-limbic structures. Although women are twice as likely to suffer from depression, little is known about how antidepressants modulate brain, endocrine, and behavioral stress responses in females. Here, we assessed the impact of CORT118335 (GR modulator/MR antagonist) and imipramine (tricyclic antidepressant) on neuroendocrine and behavioral responses to restraint or forced swim stress (FST) in female rats (n=10-12/group). Increased immobility CORT118335 in the FST is purported to reflect passive coping or depression-like behavior. CORT118335 dampened adrenocorticotropic hormone (ACTH) and corticosterone responses to the FST, but did not affect immobility. Imipramine suppressed ACTH, but had minimal effects on corticosterone responses to FST. Despite these marginal effects, imipramine decreased immobility, suggesting antidepressant efficacy. In an effort to link brain-endocrine responses with behavior, c-Fos was assessed in HPA axis and mood modulatory regions in response to the FST. CORT118335 upregulated c-Fos expression in the paraventricular nucleus of the hypothalamus. Imipramine decreased c-Fos in the basolateral amygdala and hippocampus (CA1 and CA3), but increased c-Fos in the central amygdala. These data suggest the antidepressant-like (e.g., active coping) properties of imipramine may be due to widespread effects on cortico-limbic circuits that regulate emotional and cognitive processes.

Estrogen signaling in the medial amygdala decreases emotional stress responses and obesity in ovariectomized rats.

Declining estradiol (E2), as occurs during menopause, increases risk for obesity and psychopathology (i.e., depression, anxiety). E2 modulates mood and energy homeostasis via binding to estrogen receptors (ER) in the brain. The often comorbid and bidirectional relationship between mood and metabolic disorders suggests shared hormonal and/or brain networks. The medial amygdala (MeA) is abundant in ERs and regulates mood, endocrine, and metabolic stress responses; therefore we tested the hypothesis that E2 in the MeA mitigates emotional and metabolic dysfunction in a rodent model of surgical menopause. Adult female rats were ovariectomized (OVX) and received bilateral implants of E2 or cholesterol micropellets aimed at the MeA. E2-MeA decreased anxiety-like (center entries, center time) and depression-like (immobility) behaviors in the open field and forced swim tests (FST), respectively in ovariectomized rats. E2-MeA also prevented hyperphagia, body weight gain, increased visceral adiposity, and glucose intolerance in ovariectomized rats. E2-MeA decreased caloric efficiency, suggestive of increased energy expenditure. E2-MeA also modulated c-Fos neural activity in amygdalar (central and medial) and hypothalamic (paraventricular and arcuate) brain regions that regulate mood and energy homeostasis in response to the FST, a physically demanding task. Given the shared neural circuitry between mood and body weight regulation, c-Fos expression in discrete brain regions in response to the FST may be due to the psychologically stressful and/or metabolic demands of the task. Together, these findings suggest that the MeA is a critical node for mediating estrogenic effects on mood and energy homeostasis.