Skelton K H, Nemeroff C B, Knight D L, Owens M J
Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
J Neurosci. 2000 Feb 1;20(3):1240-8. doi: 10.1523/JNEUROSCI.20-03-01240.2000.
In view of the substantial preclinical evidence that supports a seminal role of central corticotropin-releasing factor (CRF) neuronal systems in the physiology and pathophysiology of stress and anxiety, it is reasonable to suggest that the anxiolytic properties of benzodiazepines are mediated, at least in part, via regulation of CRFergic function. To begin to test this complex hypothesis, we examined the effects of acute and chronic administration of the triazolobenzodiazepine agonist alprazolam on CRF peptide concentrations, receptor-binding density, and mRNA expression in the CNS. Additionally, we measured mRNA expression for urocortin, a recently discovered neuropeptide that is generally considered to be a second endogenous ligand for CRF receptors. Both acute and chronic alprazolam administration was found to decrease CRF concentrations within the locus coeruleus. Furthermore, chronic alprazolam decreased basal activity of the hypothalamic-pituitary-adrenal axis, CRF mRNA expression in the central nucleus of the amygdala, and CRF(1) mRNA expression and receptor binding in the basolateral amygdala. In marked contrast, urocortin mRNA expression in the Edinger-Westphal nucleus and CRF(2A) receptor binding in the lateral septum and ventromedial hypothalamus were increased. Similar findings of an inverse relationship between the CRF(1) and CRF(2A) receptor systems have been reported in an anxiety model based on adverse early-life experience, suggesting the intriguing possibility that CRF neuronal systems may be comprised of two separate, but interrelated, subdivisions that can be coordinately and inversely regulated by stress, anxiety, or anxiolytic drugs.
鉴于大量临床前证据支持中枢促肾上腺皮质激素释放因子（CRF）神经元系统在应激和焦虑的生理及病理生理过程中起关键作用，有理由认为苯二氮䓬类药物的抗焦虑特性至少部分是通过调节CRF能功能介导的。为了开始验证这一复杂假说，我们研究了三氮唑苯二氮䓬激动剂阿普唑仑急性和慢性给药对中枢神经系统中CRF肽浓度、受体结合密度和mRNA表达的影响。此外，我们测量了尿皮质素的mRNA表达，尿皮质素是一种最近发现的神经肽，通常被认为是CRF受体的第二种内源性配体。结果发现，阿普唑仑急性和慢性给药均能降低蓝斑内的CRF浓度。此外，慢性阿普唑仑降低了下丘脑-垂体-肾上腺轴的基础活性、杏仁核中央核中的CRF mRNA表达以及基底外侧杏仁核中的CRF(1) mRNA表达和受体结合。与之形成鲜明对比的是，动眼神经背核中的尿皮质素mRNA表达以及外侧隔区和腹内侧下丘脑的CRF(2A)受体结合增加。在基于早期不良生活经历的焦虑模型中也报道了类似的CRF(1)和CRF(2A)受体系统呈负相关的发现，这表明CRF神经元系统可能由两个独立但相互关联的亚群组成，它们可被应激、焦虑或抗焦虑药物协同和反向调节，这一可能性很有意思。
