Effects of Repeated Stress on the Ying-Yang of Catecholamines and Glucocorticoids in the Regulation of Brain Cytokines

Today, an overwhelming amount of research suggests that pro-inflammatory cytokines (i.e. IL-1β, TNF-a, IL-6), particularly IL-1β, play an important role in the pathophysiology of depression, yet the specific relationship between chronic stress, immune regulation, sex, and depression is not well understood. Stress, which is known to precipitate depression, can induce the production of pro-inflammatory cytokines within the brain. In response to stress both the sympathetic nervous system (SNS) and the hypothalamic-pituitary adrenal (HPA) axis are responsible for a highly orchestrated regulation of brain pro-inflammatory cytokines. Stimulation of b-adrenergic receptors via catecholamines induce the production of pro-inflammatory cytokines and mediate depressive-like behaviors. In contrast, cortisol (corticosterone in rats) production, as a result of HPA-axis activation, is well known for its anti-inflammatory mechanisms. However, it remains unknown as to how the regulation of brain pro-inflammatory cytokines by catecholamines and glucocorticoids is altered in response to chronic stress. In addition, the prevalence of anxiety and depression disorders are higher in females with the mechanisms underlying these discrepancies going largely unstudied. Briefly, male and female F-344 rats were exposed to four days of repeated mild stress and on the fifth day were administered vehicle, propranolol (b-AR antagonist), metyrapone (corticosterone synthesis inhibitor), or combination of both propranolol and metyrapone. 24h following drug administration, limbic brain regions were dissected and processed for measurement of IL-1β mRNA. Preliminary findings show differences in IL-1b regulation between males and females and help to better understand the mechanisms of stress on neuro-inflammatory disorders such as depression.