Hypothalamic-pituitary-adrenal-axis vs. the sympatho-adrenal medullary system in the acute response to psychological stress

[摘要] ENGLISH ABSTRACT: The hypothalamic-pituitary-adrenal-(HPA) axis has long been closely associated withpsychological stress-induced activation of the adrenal cortex and subsequent glucocorticoidproduction. Another, less known peripheral limb of the psychological stress response, is thesympatho adrenal medullary pathway.We hypothesized that the sympatho-adrenal medullary system constitutes the primary responseto acute psychological stress, with the HPA-axis functioning as a secondary response. We testedour hypothesis by manipulating a model of acute mild psychological stress (restraint) byblocking IL-6, a valuable constituent of the sympatho-adrenal medullary system.Serum corticosterone concentration increased in response to stress (7 ± 3 vs. 57 ± 4 ng/ml;P<0.0001), a response attenuated when IL-6 was blocked (17 ± 7 ng/ml). Stress increasedpituitary mass only when IL-6 was blocked (38 ± 3 vs. 65 ± 6 mg; P <0.001). Stress increasedleft adrenal mass only in the presence of IL-6 (34 ± 1 vs. 73 ± 8 mg; P <0.00001). Stress did notinfluence the circulating levels of TNF-α, IL-1β or IL-6 significantly. IL-1β and TNF-αconcentrations in the unstressed rats were lower when IL-6 was blocked.We then manipulated the stress model by administering S. frutescens extract to elucidate both thecentral and peripheral effects of acute S. frutescens administration on the psychological stressresponse.Restraint caused decreases in hippocampal GR levels when compared to respective controls. S.frutescens administration and exposure to restraint synergistically decreased hippocampalGABAAR levels. In addition, exposure to both stress and S. frutescens led to a noteworthyincrease in pituitary mass (P = 0.078), as well as pituitary ACTH levels (P < 0.01). Similarly,differences in circulating ACTH levels showed an effect of stress on ACTH secretion only in thepresence S. frutescens (P < 0.05). Adrenal mass was significantly increased in S. frutescenstreatedanimals that were also exposed to restraint (P < 0.05). Adrenal levels of ACTH showed areciprocal trend to pituitary and circulating ACTH levels. No statistically significant differenceswere seen in adrenal IL-6 content. However, marked increases in IL-6 levels were seen at thislevel with administration of S. frutescens stress exposure and a cumulative increase seen withboth S. frutescens-treatment and stress exposure.Hippocampal GABAAR, pituitary mass, pituitary ACTH and circulating ACTH levels showed asimilar trend towards a synergistic effect of S. frutescens and restraint in activation of thepsychological stress response, while adrenal ACTH levels showed an inverse trend.Hippocampal GR did not show any effect of stress or S. frutescens-treatment.The results from these two experiments indicate that the sympatho-adrenal medullary systemconstitutes the primary response to acute mild psychological stress and that the HPA-axis is onlyactivated during an exacerbated stress response or when the sympatho-adrenal medullarycontribution is inadequate. Furthermore, the acute administration of S. frutescens possibly led toa functional shift in GABAergic function, resulting in activation of the stress response. Theanecdotal reports of a 'docile effect of S. frutescens most likely results from activation of themesolimbic dopaminergic system by the hippocampus and amygdala. These results havedramatic consequence in GABA-based anxiety-treatments.

[发布机构] Stellenbosch University