Curtis Andre L, Bethea Thelma, Valentino Rita J
Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Neuropsychopharmacology. 2006 Mar;31(3):544-54. doi: 10.1038/sj.npp.1300875.
Stress-related psychiatric disorders are more prevalent in females than males, and this has been attributed to differences in stress sensitivity. As activation of the locus coeruleus (LC)-norepinephrine (NE) system is an important component of the stress response, this study compared LC responses to stress in female and male rats under different hormonal conditions in the halothane-anesthetized state. The mean basal LC discharge rate was similar between groups. However, the magnitude of LC activation elicited by hypotensive stress was substantially greater in females, regardless of hormonal status. The difference in stress sensitivity could be attributed to the differential postsynaptic sensitivity of LC neurons to corticotropin-releasing factor (CRF), which mediates LC activation by hypotension. CRF was 10-30 times more potent in activating LC neurons in female vs male rats. Interestingly, previous exposure to swim stress differentially regulated LC responses to CRF by sensitizing LC neurons of male, but not female, rats to CRF. The net effect of this was to abolish sex differences in LC sensitivity. Finally, CRF receptor (CRF-R) protein levels in the LC were greater in ovarectomized female vs male rats. This is the first study to demonstrate sex differences in the stress responsiveness of the brain noradrenergic system. Substantial sex differences were apparent in postsynaptic sensitivity to CRF and stress-induced regulation of postsynaptic sensitivity to CRF. These sex differences in the CRF regulation of the LC-NE system translate to a differential response to stress and may play a role in the increased vulnerability of females to stress-related psychiatric disorders.
与应激相关的精神障碍在女性中比男性更为普遍，这归因于应激敏感性的差异。由于蓝斑（LC）-去甲肾上腺素（NE）系统的激活是应激反应的重要组成部分，本研究比较了在氟烷麻醉状态下不同激素条件下雌性和雄性大鼠LC对应激的反应。各组之间的平均基础LC放电率相似。然而，无论激素状态如何，低血压应激引起的LC激活幅度在雌性中显著更大。应激敏感性的差异可能归因于LC神经元对促肾上腺皮质激素释放因子（CRF）的突触后敏感性差异，CRF通过低血压介导LC激活。与雄性大鼠相比，CRF激活雌性大鼠LC神经元的效力高10 - 30倍。有趣的是，先前暴露于游泳应激通过使雄性而非雌性大鼠的LC神经元对CRF敏感来差异调节LC对CRF的反应。其净效应是消除了LC敏感性的性别差异。最后，卵巢切除的雌性大鼠LC中的CRF受体（CRF-R）蛋白水平高于雄性大鼠。这是第一项证明大脑去甲肾上腺素能系统应激反应性存在性别差异的研究。在对CRF的突触后敏感性和应激诱导的对CRF的突触后敏感性调节方面，明显存在显著的性别差异。LC-NE系统的CRF调节中的这些性别差异转化为对应激的不同反应，并可能在女性对应激相关精神障碍易感性增加中起作用。
