Leonard B E
Pharmacology Department, National University of Ireland, Galway, Ireland.
Eur Psychiatry. 2005 Oct;20 Suppl 3:S302-6. doi: 10.1016/s0924-9338(05)80180-4.
The impact of acute and chronic stress on the hypothalamic-pituitary-adrenal (HPA) axis is reviewed and evidence presented that corticotrophin releasing factor (CRF) is the stress neurotransmitter which plays an important role in the activation of the central sympathetic and serotonergic systems. The activity of CRF is expressed through specific receptors (CRF 1 and 2) that are antagonistic in their actions and widely distributed in the limbic regions of the brain, as well as in the hypothalamus, and on immune cells. The mechanism whereby chronic stress, via the CRF induced activation of the dorsal raphe nucleus, can induce a change in the serotonergic system, involves an increase in the 5HT2A and a decrease in the 5HT1A receptor mediated function. Such changes contribute to the onset of anxiety and depression. In addition, the hypersecretion of glucocorticoids that is associated with chronic stress and depression desensitises the central glucocorticoid receptors to the negative feedback inhibition of the HPA axis. This indirectly results in the further activation of the HPA axis. The rise in pro-inflammatory cytokines that usually accompanies the chronic stress response results in a further stimulation of the HPA axis thereby adding to the stress response. While CRF would appear to play a pivotal role, evidence is provided that simultaneous changes in the serotonergic and noradrenergic systems, combined with the activation of peripheral and central macrophages that increase the pro-inflammatory cytokine concentrations in the brain and blood, also play a critical role in predisposing to anxiety and depression. Neurodegenerative changes in the brain that frequently occur in the elderly patient with major depression, could result from the activation of indoleaminedioxygenase (IDO), a widely distributed enzyme that converts tryptophan via the kynenine pathway to for the neurotoxic end product quinolinic acid.
本文综述了急性和慢性应激对下丘脑-垂体-肾上腺（HPA）轴的影响，并提供证据表明促肾上腺皮质激素释放因子（CRF）是应激神经递质，在中枢交感神经系统和血清素能系统的激活中起重要作用。CRF的活性通过特定受体（CRF 1和2）表达，这些受体的作用相互拮抗，广泛分布于大脑边缘区域、下丘脑以及免疫细胞上。慢性应激通过CRF诱导中缝背核激活从而引起血清素能系统变化的机制，涉及5HT2A受体介导功能增加和5HT1A受体介导功能降低。这些变化促使焦虑和抑郁的发生。此外，与慢性应激和抑郁相关的糖皮质激素分泌过多会使中枢糖皮质激素受体对HPA轴的负反馈抑制不敏感。这间接导致HPA轴进一步激活。通常伴随慢性应激反应出现的促炎细胞因子增加会进一步刺激HPA轴，从而加重应激反应。虽然CRF似乎起着关键作用，但有证据表明，血清素能和去甲肾上腺素能系统的同时变化，以及外周和中枢巨噬细胞的激活导致大脑和血液中促炎细胞因子浓度增加，在引发焦虑和抑郁方面也起着关键作用。老年重度抑郁症患者大脑中经常出现的神经退行性变化，可能是由于吲哚胺双加氧酶（IDO）的激活所致，IDO是一种广泛分布的酶，它通过犬尿氨酸途径将色氨酸转化为神经毒性终产物喹啉酸。
