Neuroactive steroids attenuate oxytocin stress responses in late pregnancy

In late pregnant rats neuroendocrine stress responses, expressed as increased oxytocin secretion and activation of the hypothalamo-pituitary-adrenal axis, are attenuated. These adaptations preserve the oxytocin store for parturition and prevent pre-term birth, and protect the fetuses from adverse programming by exposure to excess glucocorticoid. Mechanisms of adaptations for oxytocin neurones are reviewed, using challenge with systemic interleukin-1beta, simulating activation of immune signaling by infection, as a stressor of special relevance in pregnancy. In virgin rats, systemic interleukin-1beta stimulates the firing of oxytocin neurones, and hence oxytocin secretion, but interleukin-1beta has no effects in late pregnant rats. This lack of response is reversed by naloxone treatment just before interleukin-1beta administration, indicating endogenous opioid suppression of oxytocin responses in late pregnancy. This opioid presynaptically inhibits noradrenergic terminals impinging on oxytocin neurones. Finasteride pretreatment, inhibiting progesterone conversion to allopregnanolone, a positive GABA(A) receptor allosteric modifier, also restores an oxytocin response to interleukin-1beta. This finasteride effect is reversed by allopregnanolone treatment. In virgin rats allopregnanolone attenuates the oxytocin response to interleukin-1beta, which is exaggerated by naloxone. The effects of naloxone and finasteride in late pregnant rats in restoring an oxytocin response to interleukin-1beta are not additive. Accordingly, allopregnanolone may both enhance GABA inhibition of oxytocin neurone responses to interleukin-1beta, and induce opioid suppression of noradrenaline release onto oxytocin neurones.     

解虑安神汤对社会隔离焦虑小鼠行为学 及脑内ALLO水平的影响

目的:通过观察解虑安神汤乙酸乙酯提取部位(J-A)对焦虑症动物模型行为学及脑内γ-氨基丁酸受体A亚型(GABAA-R)正性变构剂3α,5α-四氢孕酮(allopregnanolone,ALLO)的影响,探讨其抗焦虑的作用机制。方法:雄性小鼠随机分成隔离组和群养组。群养组每笼10只群养,作为正常对照组;隔离组小鼠单笼单只隔离饲养,复制社会隔离焦虑模型,随机分为正常对照组[0.5%聚氧乙烯山梨糖醇酐单油酸酯(吐温-80)]、模型组(0.5%吐温-80)、地西泮组(0.002 g·kg-1)、解虑安神汤乙酸乙酯提取部位组(J-A,0.21 g·kg-1)。从造模第3周开始ig给药,造模4周,于末次给药后1 h用高架十字迷宫(EPM)进行行为学测定,记录小鼠在EPM开臂、闭臂停留时间,进入开臂、闭臂次数,计算开放臂进入次数比例(OE%)及开放臂停留时间比例(OT%);行为学实验结束后,测定脑内ALLO的含量。结果:与模型组相比,J-A组可缩短小鼠在闭臂停留时间(186.14±50.86)s,(245.47±35.00)s、增加进入开臂次数的百分比(19.38±15.57)%,(7.34±9.68)%,差异有显著性意义(P<0.05);并具有延长小鼠在开臂停留时间,增加小鼠进入开臂次数、减少进入闭臂次数的趋势。脑内ALLO水平测定表明,与模型组相比,J-A组可增加小鼠脑内ALLO的水平,A依次为(0.90±0.13),(0.77±0.11),差异有显著性意义(P<0.05)。结论:解虑安神汤乙酸乙酯提取部位可能通过增加脑内ALLO的水平从而增强GABAA-R的功能发挥抗焦虑作用。     

A 17beta-derivative of allopregnanolone is a neurosteroid antagonist at a cerebellar subpopulation of GABA A receptors with nanomolar affinity

BACKGROUND AND PURPOSE: High-affinity, subtype-selective antagonists of the neurosteroid binding sites of GABA(A) receptors are not available. We have characterized an allopregnanolone derivative as an antagonist of cerebellar GABA(A) receptors with nanomolar affinity. EXPERIMENTAL APPROACH: Receptor binding and electrophysiological methods were used for the allosteric modulation of cerebellar GABA(A) receptors by an allopregnanolone derivative, (20R)-17beta-(1-hydroxy-2,3-butadienyl)-5alpha-androstane-3alpha-ol (HBAO). GABA(A) receptors of rat cerebellar membranes were labelled with the chloride channel blocker [(3)H]ethynylbicycloorthobenzoate (EBOB). The ionophore function of GABA(A) receptors was studied by whole-cell patch clamp electrophysiology in cultured rat cerebellar granule and cortical cells. KEY RESULTS: Partial displacement of cerebellar [(3)H]EBOB binding by nanomolar HBAO was attenuated by 0.1 mM furosemide, an antagonist of alpha(6) and beta(2-3) subunit-containing GABA(A) receptors. Displacement curves of HBAO were reshaped by 30 nM GABA and shifted to the right. However, the micromolar potency of full displacement by allopregnanolone was not affected by 0.1 mM furosemide or 30 nM GABA. The nanomolar, but not the micromolar phase of displacement of [(3)H]EBOB binding by GABA was attenuated by 100 nM HBAO. Submicromolar HBAO did not affect [(3)H]EBOB binding to cortical and hippocampal GABA(A) receptors. HBAO up to 1 microM did not affect chloride currents elicited by 0.3-10 microM GABA, while it abolished potentiation by 1 microM allopregnanolone with nanomolar potency in cerebellar but not in cortical cells. Furosemide attenuated cerebellar inhibition by 100 nM HBAO. CONCLUSIONS AND IMPLICATIONS: HBAO is a selective antagonist of allopregnanolone, a major endogenous positive modulator via neurosteroid sites of cerebellar (probably alpha(6)beta(2-3)delta) GABA(A) receptors.     

四氢孕酮和地西泮对暴露于架高十字迷宫小鼠的作用

目的比较孕酮的还原性代谢产物四氢孕酮和地西泮抗焦虑作用。方法C57小鼠腹腔注射四氢孕酮、地西泮或赋形剂 ,20min后观察在架高十字迷宫试验中的表现 ,测定其自发活动。结果腹腔注射四氢孕酮0.1mg·kg-1,明显缩短小鼠进入十字迷宫开臂的潜伏期[从(31.30±8.39)s减少到(8.80±6.00)s ,P<0.001] ,并显著增加进入十字迷宫开臂的次数(从1.20±0.42增到4.80±1.75,P<0.001)及在开臂的滞留时间占总时间的百分比 (从7.13 %增加到32.50 %,P<0.001)。而腹腔注射地西泮0.25mg·kg-1的抗焦虑作用弱于四氢孕酮。自发活动实验显示 ,0.5mg·kg-1地西泮明显减少小鼠自发活动 (P<0.01) ,而0.1mg·kg-1地西泮和0.25mg·kg-1 的四氢孕酮均不影响小鼠自发活动。结论试验结果提示神经甾体和地西泮对小鼠行为有不同的作用。四氢孕酮具选择性抗焦虑作用而不影响自发活动 ,可望成为地西泮抗焦虑的代用品     

The role of progesterone in memory bias during spatial navigation in females

Rats can use several memory systems to navigate a maze toward a reward. Two of these are place memory and response memory and female rats can be biased to predominantly use one over another. Both progesterone and estrogens have been shown to alter memory bias. Although the effects of estrogens have been well documented, the effects of progesterone remain somewhat unexplored. Mechanisms through which progesterone may be acting to exert its effects are reviewed here. Converging evidence suggests that the actions of progesterone differ depending on the presence of estrogens, frequently acting in opposition to estrogens when administered together. The hippocampus, dorsal striatum, and prefrontal cortex are likely involved, as is the progesterone metabolite, allopregnanolone. There is a need for more research on progesterone and memory bias, especially considering current formulations of hormonal contraceptives include progestins.