侧脑室注射IL—1ra后脑缺血大鼠下丘脑室旁核CRH的 …

目的 探讨白介素－１（ＩＬ－１）是否参与脑缺血大鼠下丘脑－垂体－肾上腺轴（ＨＰＡ）的激活。方法 选用成年ＳＤ大鼠，分为１７组（Ａ～Ｑ组）Ａ组为正常对照组，Ｂ～Ｏ组大鼠脑缺血时间分别为１，３，６，４２，４８，７２ｈ及１，２，３，４，５，６，７，８周，Ｐ组的处理为：用微量注射泵将ＩＬ－１受体拮抗剂（ＩＬ－１ｒａ）注入大鼠侧脑室，之后建立脑缺血模型；Ｑ组为Ｐ组的对照组，用微量注射泵将生理盐水注入大鼠侧脑     

局灶脑缺血鼠下丘脑室旁核促肾上腺皮质素释放激素的表达

目的探讨脑缺血对下丘脑垂体肾上腺轴的影响。方法动态观察局灶脑缺血鼠下丘脑室旁核（ＰＶＮ）促肾上腺皮质素释放激素（ＣＲＨ）的变化，采用免疫组化方法显示ＰＶＮＣＲＨ的表达。结果正常对照组鼠下丘脑ＰＶＮ有少量ＣＲＨ的表达，脑缺血２天内下丘脑ＰＶＮ无ＣＲＨ的表达，脑缺血第三天后ＣＲＨ的表达明显增多，且一直持续到脑缺血的第八周，而假手术组４周基本恢复正常。结论脑缺血后下丘脑ＰＶＮ的ＣＲＨ分泌细胞立即被激活；长期脑缺血使ＣＲＨ分泌细胞的活动增强。     

大鼠局灶性脑缺血IL-8变化的研究

目的 探讨ＩＬ－８在脑缺血损伤中的变化。方法 采用改良Ｚｅａ Ｌｏｎｇａ线栓法大鼠ＭＣＡＯ模型，将大脑中动脉（ＭＣＡ）闭塞不同的时间，应用双抗体夹心间接ＥＬＩＳＡ法检测缺血组和对照组大鼠受伤脑组织及血清ＩＬ－８浓度。结果 闭塞３ｈ缺血侧半球湿重大于非缺血侧（Ｐ〈０．０５），并维持至４８ｈ；缺血组病组织ＩＬ－８含量在ＭＣＡ闭塞３ｈ处于较低水平，随后逐渐升高，至６ｈ达高峰，随后又降低；血清中ＩＬ－８含     

大鼠脑缺血再灌注区ICAM-1表达与白细胞浸润的观察及丹参的影响

目的　观察细胞间粘附分子（ Ｉ Ｃ Ａ Ｍ１） 蛋白在大鼠脑缺血再灌注的不同时程脑组织中的表达与中性白细胞浸润程度的关系及丹参对它们的影响。方法　 Ｓ Ｄ大鼠分为３ 组：假手术组、对照组及丹参组。大脑中动脉缺血２ ｈ 再灌注２ ｈ 、１２ ｈ、２４ ｈ 、４８ ｈ 、７２ ｈ 、７ ｄ、１４ ｄ 后,分别进行 Ｉ Ｃ Ａ Ｍ１ 免疫组织化学及组织 Ｈ Ｅ染色。结果　在脑缺血再灌早期,脑微血管内皮细胞 Ｉ Ｃ Ａ Ｍ１ 免疫反应开始逐渐增加,再灌注４８ ｈ 达到高峰,再灌注１４ ｄ 接近正常水平,同时脑缺血区中性白细胞浸润也随之增加,在时程上与 Ｉ Ｃ Ａ Ｍ１ 表达同步。丹参组,再灌注４８ ｈ 后, Ｉ Ｃ Ａ Ｍ１ 免疫阳性血管数及中性白细胞的浸润比同时间对照组明显降低。结论　脑缺血 Ｉ Ｃ Ａ Ｍ１ 的表达与中性白细胞浸润密切相关,丹参能降低 Ｉ Ｃ Ａ Ｍ１ 的表达,抑制中性白细胞的浸润。     

谷氨酸载体在鼠脑缺血神经元死亡中的作用

目的研究谷氨酸载体在脑缺血神经元死亡中的作用。方法用原位杂交和免疫组织化学方法观察大鼠脑缺血后脑内谷氨酸载体ＧＬＡＳＴｍＲＮＡ和胶质纤维酸性蛋白（ＧＦＡＰ）表达的变化，用药理分析手段观察谷氨酸载体摄取抑制剂Ｌ反式吡咯烷２，４二羧酸（ＬｔｒａｎｓＰＤＣ）对脑缺血致神经元损伤的影响。结果脑缺血后２４小时，大脑皮层缺血周边区ＧＬＡＳＴｍＲＮＡ和ＧＦＡＰ表达无显著变化；而缺血后７２小时，缺血周边区ＧＬＡＳＴｍＲＮＡ和ＧＦＡＰ表达都显著增加，脑缺血后２４小时和７２小时，缺血侧海马ＣＡ１区ＧＬＡＳＴｍＲＮＡ表达则无显著变化；与侧脑室注射生理盐水组相比，侧脑室注射１μｇ或２μｇＬｔｒａｎｓＰＤＣ有使脑梗塞体积增大的趋势，但差异无显著意义；侧脑室注射５μｇＬｔｒａｎｓＰＤＣ使脑梗塞体积显著增大。结论脑缺血后谷氨酸载体功能可能呈代偿性增强，提示谷氨酸载体在限制脑缺血时谷氨酸神经毒中起重要作用。     

大鼠全脑缺血再灌流后脑组织P53及P21蛋白的表达

目的　探讨大鼠全脑缺血再灌流后Ｐ５３、Ｐ２１蛋白的表达及其与迟发性神经元死亡（ＤＮＤ）的关系。方法　在４ 血管闭塞法全脑缺血模型上,采用ＨＥ及ＬＳＡＢ染色法,观察脑组织病理改变,检测脑组织Ｐ５３、Ｐ２１蛋白的表达,以及蛋白合成抑制剂放线菌酮对其的影响。结果　全脑缺血１５ ｍ ｉｎ 再灌流后,脑组织Ｐ５３、Ｐ２１蛋白表达增加,且两者分布接近。海马结构、丘脑、下丘脑等白质区（再灌流后６ ｈ）较皮层、海马的神经细胞核（２４ ｈ）先检测到Ｐ５３、Ｐ２１蛋白,７２ ｈ 表达达高峰。并且以缺血损伤最严重的海马ＣＡ１ 区Ｐ５３、Ｐ２１蛋白表达为强。另外,放线菌酮可抑制脑组织Ｐ５３、Ｐ２１蛋白的表达,并对ＤＮＤ具有一定的保护作用。结论　全脑缺血再灌流损伤后,脑组织Ｐ５３、Ｐ２１蛋白表达增加,放线菌酮可抑制其表达,并对ＤＮＤ起保护作用,提示Ｐ５３、Ｐ２１蛋白参与了全脑缺血后ＤＮＤ的凋亡机制,并对其起促进作用     

人参皂甙对手术应激大鼠下丘脑—垂体—肾上腺轴？…

目的和方法 为探讨手术应激大鼠下丘脑－垂体－肾上腺轴（ＨＰＡＡ）和脾脏中肾上腺皮质激素释放素（ＣＲＦ）和促肾上腺皮质激素（ＡＣＴＨ）阳性细胞数及人参皂甙的调节作用。采用了免疫酶组化和免疫荧光检测方法。结果 应激后１５～３０ｍｉｎ，下丘脑，垂体中ＣＲＦ和ＡＣＴＨ阳性细胞数较正常对照组减少，ＣＲＦ阳性细胞在６０ｍｉｎ后逐渐增多，６ｈ时达正常水平，ＡＣＴＨ阳性细胞于３ｈ开始增多，１２ｈ时至正常水平，而肾     

急性缺血性脑血管病患者血ICAM—1,VCAM—1,CD62p的改变？…

目的 探讨急性缺血性脑血管病患者中性粒细胞表面细胞间粘附分子（ＩＣＡＭ－１）、血管粘附分子（ＶＣＡＭ－１）和血小板Ｐ选择素（ＣＤ６２ｐ）的改变及其临床意义。方法应用流式细胞术测定１２１例缺血患者发病４８小时内ＩＣＡＭ－１、ＶＣＡＭ－１、ＣＤ６２ｐ的改变。结果 （１）各种急性脑缺血患者ＩＣＡＭ－１均较对照组升高，Ｐ〈０．０１）；脑血全形成和腔隙性脑梗死ＣＤ６２ｐ升高，Ｐ〈０．０５；脑血栓形成ＶＣＡＭ     

实验性脑血管痉挛时一氧化氮与超氧化物歧化酶对脑血流的作用研究

目的 探讨一氧化氮（ＮＯ）、超氧化物歧化酶（ＳＯＤ）分别及联合使用对大鼠实验性蛛网膜下腔出血（ＳＡＨ）后脑血管痉挛（ＣＶＳ）时脑血流（ＣＢＦ）的作用。方法 将３０只大鼠随机分成５组（每组６只）。Ａ组：假手术＋盐水,Ｂ组：ＳＡＨ＋盐水;Ｃ组：ＳＡＨ＋ＳＯＤ;Ｄ组：ＳＡＨ＋ＮＯＣ１２;Ｅ组：ＳＡＨ＋ＳＯＤ、ＮＯＣ１２。模拟制成４８ｈ后,通过Ｌａｓｅ－Ｄｏｐｐｌｅｒ血液仪观察各种药物持续静脉注射１ｈ内Ｃ     

谷氨酸对急性脑缺血再灌注大鼠皮层乙酰胆碱活性影响的在体动态电化学研究

为了研究脑缺血时兴奋性氨基酸与胆碱能神经的关系，采用双侧颈总动脉夹闭（ＣＣＡＯ）的脑缺血动物模型，用乙酰胆碱离子选择性微电极（ＡＣｈ－ＩＳＭｓ）检测皮层ＡＣｈ释放量，观察脑缺血再灌注时谷氨酸对大鼠皮层ＡＣｈ释放量的影响。结果表明：１０－１ｍｏｌ／ＬＧｌｕ对ＡＣｈ－ＩＳＭｓ无干扰作用，在生理状态下不能显著地促进皮层ＡＣｈ的释放，但可使脑缺血３ｍｉｎ时皮层ＡＣｈ释放量较未加Ｇｌｕ组增加５８．１％（Ｐ＜０．０１），再灌注后皮层ＡＣｈ活性恢复减慢。结果提示：Ｇｌｕ协同ＡＣｈ释放的效应在脑缺血时明显放大，推测Ｇｌｕ和ＡＣｈ可能在缺血性脑损伤中有放大的协同作用。     

Systemic Interleukin-1beta stimulates the simultaneous release of norepinephrine in the paraventricular nucleus and the median eminence

Interleukin-1beta (IL-1beta), a cytokine with pronounced central effects such as fever, anorexia, analgesia, etc., is also known to activate the hypothalamo-pituitary-adrenal (HPA) axis. Corticotropin releasing hormone (CRH) neurons located in the hypothalamus are important for HPA activation. The cell bodies of CRH neurons are located in the paraventricular nucleus (PVN) and their terminals are present in the median eminence (ME). Although the catecholamines, norepinephrine (NE) and dopamine (DA) are believed to be crucial factors in the stimulation of CRH neurons, it is not clear if they affect the cell bodies or terminals of these neurons to cause HPA activation. This study was done to determine if IL-1beta affects NE and DA release at the level of CRH cell bodies or their terminals. Adult male Sprague-Dawley rats were implanted with two push-pull cannulae, one in the PVN and another in the ME, and were subjected to push-pull perfusion. They were treated either with 0, 1 or 5 microg of IL-1beta. Perfusates were collected for 2 h after treatment and analyzed for NE concentrations using HPLC-EC. NE levels in the control and low dose groups did not change significantly during the entire period of observation both in the PVN and ME. In contrast, treatment with 5 microg of IL-1beta produced a marked increase in NE release in the PVN at 20 and 40 min post-treatment. NE release in the ME increased from 10 to 140 min post-treatment. There were no significant changes in the release of DA from both these areas. These results indicate that IL-1beta increases NE levels both in the PVN and in the ME and this could be a possible mechanism by which it stimulates the HPA axis.     

A single administration of interleukin-1 or amphetamine induces long-lasting increases in evoked noradrenaline release in the hypothalamus and sensitization of ACTH and corticosterone responses in rats

Single administration of the cytokine interleukin-1beta (IL-1) or the psychostimulant amphetamine causes long-term sensitization of the hypothalamus pituitary adrenal (HPA) axis, i.e. enhanced adrenocorticotropine hormone (ACTH) and corticosterone responses weeks later. HPA responses to these stimuli involve activation of hypothalamic corticotropin-releasing hormone (CRH) neurons by noradrenergic projections to the paraventricular nucleus (PVN). In search of the underlying mechanisms, we studied the temporal pattern of HPA sensitization in relation to (1) the reactivity of noradrenergic projections to the PVN and (2) altered secretagogue production in hypothalamic CRH neurons. Single exposure to IL-1 or amphetamine induced cross-sensitization of ACTH and corticosterone responses 11 and 22 days later, but not after 42 days. Amphetamine-induced HPA sensitization was not accompanied by increased costorage of arginine vasopressin (AVP) in CRH terminals, as found previously after IL-1 pretreatment. The reactivity of noradrenergic terminals was assessed by measuring the electrically evoked release of [3H]-noradrenaline from superfused PVN slices. Single administration of amphetamine and IL-1 induced a long-lasting (up to 22 days) increase (up to 165%) of evoked noradrenaline release. This indicates that single exposure to psychostimulants or to cytokines can induce a long-lasting increase in stimulus-secretion coupling in brainstem noradrenergic neurons that innervate the PVN. This common, long-lasting functional change may underlie, at least in part, IL-1- and amphetamine-induced HPA cross-sensitization. In addition, increased AVP signalling by hypothalamic CRH neurons appears to play a role in IL-1-induced, but not in amphetamine-induced, HPA sensitization.     

Brain Angiotensin II Modulates Sympathoadrenal and Hypothalamic Pituitary Adrenocortical Activation during Stress

Angiotensin II (Ang II) type-1 (AT₁) receptors are present in areas of the brain controlling autonomic nervous activity and the hypothalamic-pituitary-adrenal (HPA) axis, including CRH cells in the hypothalamic paraventricular nucleus (PVN). To determine whether brain AT₁ receptors are involved in the activation of the HPA axis and sympathetic system during stress, we studied the effects of acute immobilization stress on plasma catecholamines, ACTH and corticosterone, and mRNA levels of CRH and CRH receptors (CRH-R) in the PVN in rats under central AT₁ receptor blockade by the selective antagonist, Losartan. While basal levels of epinephrine, norepinephrine and dopamine in plasma were unaffected 30 min after icv injection of Losartan (10 μg), the increases after 5 and 20 min stress were blunted in Losartan treated rats (P<0.05 for norepinephrine, and P<0.01 for epinephrine and dopamine, vs controls). Basal or stress-stimulated plasma ACTH and corticosterone levels were unaffected by icv Losartan treatment. Using in situ hybridization studies, basal levels of CRH mRNA and CRH-R mRNA in the PVN were unchanged after icv Losartan. While Losartan had no effect on the increases in CRH-R mRNA levels 2 or 3 h after 1 h immobilization, it prevented the increases in CRH mRNA. The blunted plasma catecholamine responses after central AT₁ receptor blockade indicate that endogenous Ang II in the brain is required for sympathoadrenal activation during immobilization stress. While Ang II appears not to be involved in the acute secretory response of the HPA axis, it may play a role in regulating CRH expression in the PVN.     

Brainstem Hemisection Decreases Corticotropin-Releasing Hormone mRNA in the Paraventricular Nucleus but not in the Central Amygdaloid Nucleus

Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus and in the central nucleus of the amygdala (ACE) participate in neurohumoral and behavioral responses to stress. To understand better the central regulation of CRH, the present study assessed the effects of ipsilateral surgical hemisection of the brainstem on expression of CRH mRNA in the PVN and the ACE. In situ hybridization was used to demonstrate PVN CRH mRNA expression in hemisected, sham-operated or intact rats before and after 3  h of immobilization (IMMO). In addition, hypothalamic-pituitary-adrenocortical (HPA) axis activity at baseline and during IMMO was assessed by measurements of plasma concentrations of ACTH and corticosterone. IMMO markedly increased CRH mRNA expression in the PVN in all experimental groups. Rats with brainstem hemisections had lower PVN CRH mRNA expression ipsilateral to the lesion and markedly blunted responses after IMMO, compared to values in sham-operated rats. In contrast, neither hemisection nor IMMO affected CRH mRNA expression in the ACE. Lesioned and SHAM-operated groups did not differ in baseline or IMMO-induced increases in plasma ACTH or corticosterone levels. The present results indicate that baseline levels and IMMO-induced increments in CRH mRNA expression in the PVN, but not in the ACE, depend on ipsilaterally ascending medullary tracts and that IMMO-induced HPA activation does not depend on these pathways.     

Contribution of the Ventral Subiculum to Inhibitory Regulation of the Hypothalamo-Pituitary-Adrenocortical Axis

Anatomical studies indicate that the ventral subiculum is in a prime position to mediate hippocampal inhibition of the hypothalamo-pituitary-adrenocortical (HPA) axis. The present study evaluated this hypothesis by assessing HPA function following ibotenic acid lesion of the ventral subiculum region. Rats with lesions of the ventral subiculum (vSUB) or ventral hippocampus (vHIPPO) did not show changes in basal corticosterone (CORT) secretion at either circadian peak or nadir time points when compared to sham-lesion rats (SHAM) or unoperated controls. However, rats with vSUB lesions exhibited a prolonged glucocorticoid stress response relative to all other groups. Baseline CRH mRNA levels were significantly increased in the medial parvocellular paraventricular nucleus (PVN) of the vSUB group relative to controls. CRH mRNA differences were particularly pronounced at caudal levels of the nucleus, suggesting topographic organization of vSUB interactions with PVN neurons. Notably, the vHIPPO group, which received large lesions of ventral CA1, CA3 and dentate gyrus without significant subicular damage, showed no change in stress-induced CORT secretion, suggesting that the ventral subiculum proper is principally responsible for ventral hippocampal actions on the HPA stress response. No differences in medial parvocellular PVN AVP mRNA expression were seen in either the vSUB or vHIPPO groups. The results indicate a specific inhibitory action of the ventral subiculum on HPA activation. The increase in CRH biosynthesis and stress-induced CORT secretion in the absence of changes in baseline CORT secretion or AVP mRNA expression suggests that the inhibitory actions of ventral subicular neurons affect the response capacity of the HPA axis.     

Effect of repeated lipopolysaccharide administration on tissue cytokine expression and hypothalamic-pituitary-adrenal axis activity in rats

The effects of chronic immune challenge on cytokine expression and hypothalamic-pituitary-adrenal axis (HPA) axis responses to stress were studied in Wistar rats after administration of increasing doses of lipopolysaccharide (LPS). Repeated LPS (R-LPS) decreased body weight and increased adrenal weight and pituitary pro-opiomelanocortin mRNA levels. LPS injection increased plasma adrenocorticotropic hormone (ACTH) and corticosterone but the effect was attenuated in R-LPS. Plasma corticosterone but not ACTH responses to restraint were also reduced in R-LPS. Basal and restraint-stimulated corticotropin releasing hormone (CRH) mRNA levels were lower in R-LPS, but responses to a new LPS injection were similar to controls. In contrast, type 1 CRH receptor (CRH-R1) mRNA responses to both LPS and restraint were blunted in R-LPS. Vasopressin mRNA levels in parvocellular neurones were higher in R-LPS, and increased further after restraint but not after a new LPS injection. Glucocorticoid receptor (GR) levels in the paraventricular nucleus (PVN) increased after a single LPS or R-LPS (24 h after the last injection) but declined after a new injection in R-LPS. Interleukin (IL)-1beta and IL-6 mRNAs increased in the pituitary, spleen and circumventricular organs after single or R-LPS, suggesting that cytokines may contribute to the activation of the HPA axis though pathways from the circumventricular organs as well as paracrine effects in the pituitary. The data show that (i) adaptation of the HPA axis during repeated LPS injection involves increases in vasopressin : CRH expression ratios in parvocellular neurones; (ii) that hypothalamic CRH and vasopressin responses to acute stimulation are independent of CRH-R1 expression in the PVN; and (iii) there is a dissociation between pituitary and adrenal responses to acute stress suggesting a decrease of adrenal sensitivity to ACTH.     

Acute glucocorticoid pretreatment suppresses stress-induced hypothalamic-pituitary-adrenal axis hormone secretion and expression of corticotropin-releasing hormone hnRNA but does not affect c-fos mRNA or fos protein expression in the paraventricular nucleus of the hypothalamus

Corticosterone regulates both basal and stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity in a negative-feedback fashion. However, the cellular and molecular mechanisms of this negative feedback have yet to be explicitly characterized. By comparing stress-induced c-fos and corticotropin-releasing hormone (CRH) expression in the paraventricular nucleus (PVN), we may be able to determine whether acute glucocorticoid treatment affects the net neural excitatory input to the PVN (represented primarily by c-fos mRNA expression) or directly affects the ability of cells in the PVN to respond to that input (represented primarily by CRH hnRNA expression). In the following studies, we observed the effect of acute glucocorticoid (RU28362) treatment on subsequent HPA axis reactivity by measuring stress-induced plasma hormone concentration [corticosterone and adrenocorticotropic hormone (ACTH)] and gene expression (c-fos and CRH) in the PVN. First, we examined the dose-response relationship between systemically administered RU28362 (1-150 microg/kg, i.p) and suppression of the stress-induced corticosterone response. We then confirmed central nervous system access of the maximally suppressive dose of RU28362 (150 microg/kg) by an ex vivo radioligand binding assay. RU28362 selectively occupied the majority of glucocorticoid receptors in the hippocampus and hypothalamus while having no effect on mineralocorticoid receptors. In separate studies, RU28362 (150 microg/kg) and corticosterone (5 mg/kg) were injected i.p. 1 h before restraint stress. Compared to vehicle-treated controls, rats treated with RU28362 and corticosterone had substantially blunted stress-induced corticosterone and ACTH production, respectively. Furthermore, treatment with RU28362 significantly blunted stress-induced CRH hnRNA expression in the PVN. By contrast, neither RU28362 nor corticosterone treatment had an effect on stress-induced neuronal activation as measured by c-fos mRNA and its protein product in the PVN. This dissociation between c-fos and CRH gene expression suggests that glucocorticoid suppression of HPA activity within this time-frame is not a result of decreased excitatory neural input to the PVN, but instead depends on some direct effect of RU28362 on cells intrinsic to the HPA axis.     

Effect of interleukin 1beta on the HPA axis in H1-receptor knockout mice

OBJECTIVES AND METHODS: Circulating cytokines such as interleukin-1 (IL-1), and tumor necrosis factor-alpha as well as lipopolysaccharide (LPS) are potent ACTH secretagogues, acting via stimulation of corticotropin-releasing hormone (CRH) and vasopressinergic neurons in the paraventricular nucleus of the hypothalamus (PVN). Histamine (HA) has been shown to stimulate ACTH secretion in rats, an effect in part mediated by CRH and arginine vasopressin (AVP). We have previously shown that inhibition of neuronal HA synthesis or central blockade of H(1) receptors (H(1)R) decreased the ACTH response to LPS in male rats. To further elucidate the role of neuronal HA in cytokine-induced activation of the HPA axis, we compared the effect of H(1)R knockout on IL-1beta-induced ACTH secretion in adult male mice. RESULTS: In H(1)R knockout mice, ACTH secretion increased from basal levels of 261 to 492 pmol/l in response to IL-1beta whereas the cytokine-induced ACTH secretion increased from 140 to 406 pmol/l in wild-type mice. Plasma corticosterone (CORT) rose from basal levels of 99 to 831 nmol/l in knockout mice upon IL-1beta stimulation, whereas in wild-type mice CORT levels rose from 112 to 841 nmol/l. There was no significant difference in IL-1beta-stimulated plasma ACTH or CORT levels between wild-type and knockout mice. Furthermore, there was no significant difference in basal or IL-1beta-stimulated hypothalamic levels of histamine and tele-methyl-histamine between wild-type and knockout mice. HDC gene expression was significantly lower in knockout mice than in wild-type mice both under basal and IL-1beta-stimulated conditions, while there were no significant differences in CRH gene expression in the PVN in knockout mice under basal and IL-1beta-stimulated conditions. Increased basal expression of AVP in the PVN of knockout mice was observed in this study compared to wild-type mice. CONCLUSION: We conclude that the lack of the gene for histamine H(1)R does not seem to be crucial for the ACTH and CORT response to IL-1beta, either due to possible functional compensation in the H(1)R knockout mouse or due to activation of pathways other than the neuronal histaminergic system.