Kuipers S D, Trentani A, Westenbroek C, Bramham C R, Korf J, Kema I P, Ter Horst G J, Den Boer J A
Department of Psychiatry, Division of Biological Psychiatry, University Medical Center Groningen (UMCG), The Netherlands.
Neuropharmacology. 2006 Mar;50(4):428-40. doi: 10.1016/j.neuropharm.2005.10.006. Epub 2005 Nov 23.
Affective disorders are common psychiatric illnesses characterized by marked gender-related prevalence. Recent evidence links chronic stress and dysregulation of neurotrophin signaling with the development of depression, while novel theories suggest that antidepressants may act by promoting intracellular adaptations linked to neuroplasticity. Although selective serotonin reuptake inhibitors (SSRIs) efficaciously improve a variety of dysfunctions in males, their neuroendocrine effects and intracellular signaling patterns in females are not well determined. Here we show that chronic footshock stress (21 days) promotes HPA axis hyperactivity (as seen by the increased FOS-ir in the paraventricular hypothalamic nucleus (PVN), plasma corticosterone and adrenal hypertrophy), reduces hippocampal BrdU immunoreactivity and suppresses cortical-limbic CREB phosphorylation in female rats. Long-term citalopram treatment, in contrast, attenuates stress-induced elevation of corticosterone levels and adrenal hypertrophy, although it does not reverse footshock-mediated induction of FOS-ir in the PVN, inhibition of CREB phosphorylation and reduction of hippocampal BrdU-labeling. Moreover, citalopram administration was also associated with significant hypophagic effects and inhibition of CREB phosphorylation. These data suggest that, in female rats, normalization of chronic stress-induced HPA axis abnormalities may represent an initial phase of citalopram-mediated therapeutic actions and despite this SSRI's apparent lack of effects on neuroplasticity, we cannot exclude the possibility that some neurochemical adaptations occur in a later stage which may require more than 3 weeks of treatment to manifest.
情感障碍是常见的精神疾病，具有明显的性别相关患病率特征。最近的证据表明，慢性应激和神经营养因子信号失调与抑郁症的发生有关，而新理论认为，抗抑郁药可能通过促进与神经可塑性相关的细胞内适应性发挥作用。尽管选择性5-羟色胺再摄取抑制剂（SSRIs）能有效改善男性的多种功能障碍，但其对女性的神经内分泌作用和细胞内信号模式尚未明确。在此我们表明，慢性足部电击应激（21天）会促进雌性大鼠的下丘脑-垂体-肾上腺（HPA）轴功能亢进（如下丘脑室旁核（PVN）中FOS免疫反应性增加、血浆皮质酮水平升高和肾上腺肥大所示），降低海马区BrdU免疫反应性，并抑制皮质-边缘系统CREB磷酸化。相比之下，长期给予西酞普兰可减轻应激诱导的皮质酮水平升高和肾上腺肥大，尽管它不能逆转足部电击介导的PVN中FOS免疫反应性的诱导、CREB磷酸化的抑制以及海马区BrdU标记的减少。此外，给予西酞普兰还与显著的摄食减少效应和CREB磷酸化的抑制有关。这些数据表明，在雌性大鼠中，慢性应激诱导的HPA轴异常的正常化可能代表西酞普兰介导的治疗作用的初始阶段，尽管这种SSRI对神经可塑性明显缺乏作用，但我们不能排除在后期可能发生一些神经化学适应性变化的可能性，这可能需要超过3周的治疗才能显现出来。
