Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Pocatello, ID, USA.
J Neuroendocrinol. 2010 Jan;22(1):24-32. doi: 10.1111/j.1365-2826.2009.01934.x. Epub 2009 Nov 14.
Systemic ethanol (EtOH) administration activates the hypothalamic-pituitary-adrenal (HPA) axis of rats in a sexually dimorphic manner. The present studies tested the role played by the central nervous system (CNS) in this phenomenon. To localise the effects of the drug to the brain, we utilised an experimental paradigm whereby a small, nontoxic amount of the drug was delivered via intracerebroventricular (i.c.v.) injection. EtoH administered i.c.v. rapidly diffuses throughout the cerebrospinal fluid and brain, and does not cause neuronal damage or have any long-term physiological or behavioural effects. Experimental groups included intact males, intact cycling females, and ovariectomised (OVX) animals with or without replacement oestradiol (E(2)). Intracerebroventricular EtOH-induced HPA hormonal activation was determined by measuring plasma adrenocorticotrophin (ACTH) levels. Activation of brain areas that both regulate HPA function and are responsive to gonadal hormones was determined using expression of the transcription factor c-fos (Fos) as a marker of neuronal activity. We observed sex- and oestrous cycle- dependent differences in HPA activation by EtOH as measured by both these parameters. ACTH secretion was highest in females in pro-oestrus or oestrus, just prior to or after the endogenous peak of E(2), as was Fos expression in the paraventricular nucleus of the hypothalamus (PVN) and the locus coreuleus (LC) of the brainstem. In OVX animals, E(2) replacement caused an increase in PVN and LC Fos expression in response to i.c.v. EtOH compared to OVX controls, but a decrease in ACTH secretion. Taken together, these results indicate that at the level of the CNS, EtOH stimulates HPA activity more robustly at times when the effects of E(2) are high, but that E(2) alone is not responsible for this effect. The data further suggest that the LC plays an important role in the circuitry, which appears to be different from that activated following the systemic administration of EtOH.
系统性乙醇（EtOH）给药以性别二态的方式激活大鼠的下丘脑-垂体-肾上腺（HPA）轴。本研究测试了中枢神经系统（CNS）在这一现象中的作用。为了将药物的作用定位于大脑，我们利用了一种实验范式，通过该范式，通过脑室内（i.c.v.）注射给予小剂量的非毒性药物。EtOH 经 i.c.v. 给药后迅速扩散到脑脊液和大脑中，不会引起神经元损伤，也不会产生任何长期的生理或行为影响。实验组包括完整的雄性、完整的循环雌性和去卵巢（OVX）动物，具有或不具有替代雌二醇（E(2)）。通过测量血浆促肾上腺皮质激素（ACTH）水平来确定 i.c.v. EtOH 诱导的 HPA 激素激活。通过作为神经元活动标志物的转录因子 c-fos（Fos）的表达来确定调节 HPA 功能和对性腺激素有反应的脑区的激活。我们观察到 EtOH 激活的性别和动情周期依赖性差异，这两个参数均有体现。ACTH 分泌在动情前期或发情期的雌性中最高，即在内源性 E(2) 高峰之前或之后，下丘脑室旁核（PVN）和脑桥蓝斑核（LC）中的 Fos 表达也是如此。在 OVX 动物中，与 OVX 对照组相比，E(2) 替代导致 LC 和 PVN 中的 Fos 表达增加，以响应 i.c.v. EtOH，但 ACTH 分泌减少。总之，这些结果表明，在中枢神经系统水平，当 E(2) 的作用较高时，EtOH 更强烈地刺激 HPA 活性，但 E(2) 本身并不是这种作用的原因。数据进一步表明，LC 在电路中起着重要作用，该电路似乎与系统给予 EtOH 后激活的电路不同。
