Systems mediating acute glucocorticoid effects on memory consolidation and retrieval

It is well established that glucocorticoid hormones, secreted by the adrenal cortex after a stressful event, influence cognitive performance. This article reviews recent findings from this laboratory on the acute effects of glucocorticoids in rats on specific memory phases, i.e., memory consolidation and memory retrieval. Posttraining activation of glucocorticoid-sensitive pathways involving glucocorticoid receptors (GRs) enhances memory consolidation in a dose-dependent manner. Glucocorticoid influences on memory consolidation depend on noradrenergic activation of the basolateral complex of the amygdala (BLA) and interactions of the BLA with other brain regions. By contrast, memory retrieval processes are usually impaired with high circulating levels of glucocorticoids or following infusions of GR agonists into the hippocampus. Although the BLA does not appear to be a site of glucocorticoid action in influencing memory retrieval, an intact BLA is required for enabling glucocorticoid effects on memory retrieval. The BLA appears to be a key structure in a memory-modulatory system that regulates, in concert with other brain regions, stress and glucocorticoid effects on both memory consolidation and memory retrieval.     

Subtype-specificity of the presynaptic α2-adrenoceptors modulating hippocampal norepinephrine release in rat

In vivo brain microdialysis and high-performance liquid chromatography with electrochemical detection were used to study the effect of different selective α₂-antagonists on hippocampal norepinephrine (NE) release in freely moving awake rat. Systemic administration (0.5 mg/kg i.p.) of either the α_2AD-antagonist BRL 44408 or the α-_2BC-antagonist ARC 239 did not significantly change the basal release of NE. At a higher dose (5 mg/kg i.p.) ARC 239 was still ineffective, whereas BRL 44408 caused a significant increase of the extracellular level of NE. Similar results were obtained from in vitro perfusion experiments. Rat hippocampal slices were loaded with [³H]NE and the electrical stimulation-evoked release of [³H]NE was determined. The α₂-antagonists were applied in a concentration range of 10⁻⁸ to 10⁻⁶ M. ARC 239 was ineffective, whereas BRL 44408 significantly increased the electrically induced release of [³H]NE. In agreement with the data of microdialysis and perfusion experiments. BRL 44408 displaced [³H]yohimbine from hippocampal and cortical membranes of rat brain with high affinity whereas ARC 239 was less effective. The pK_i values of eight different α₂-adrenergic compounds showed a very good correlation (r = 0.98, slope = 1.11 P < 0.0001) in hippocampus and frontal cortex where the α₂-adrenoceptors have been characterized as α_2D-subtype. Our data indicate that hippocampal NE release in rat is regulated by α_2D-adrenoceptors, a species variation of the human α_2A-subtype.     

去甲肾上腺素预处理对大鼠供心肌细胞凋亡及凋亡蛋白表达的影响

目的 探讨去甲肾上腺素预处理是否可诱导心肌热休克蛋白70（HSP70）的合成,并进一步研究其对大鼠供心缺血再灌注后心肌细胞凋亡及凋亡蛋白表达的影响.方法 雄性Wistar大鼠18只,随机分为2组：对照组（n=9）,腹腔注射生理盐水0.5 ml,24 h后取离体心脏灌注HTK心肌保护液,4℃保存3 h.然后行Langendorff离体心脏灌注,灌注Krebs-Henseleit（K-H）液2 h.实验组（n=9）,腹腔注射重酒石酸去甲肾上腺素（溶于生理盐水中）3.1 μmol/kg（0.53 mg/kg）,腹腔注射24 h后取离体心脏,处理方法同对照组.心脏灌流结束后取材测定各组心肌HSP70表达,TUNEL法测定心肌细胞凋亡率,免疫组化法测定凋亡蛋白Bcl-2、Bax的表达,并对相关指标做统计学处理比较.观察心肌细胞光镜结构和电镜下的超微结构.结果 实验组心肌组织HSP70表达明显高于[（17.78±1.82）%]对照组[（5.22±1.05）%],心肌细胞凋亡率明显低于[（5.57±1.05）%]对照组[（9.44±1.27）%],凋亡相关蛋白Bcl-2明显高于[（41.88±5.09）%]对照组[（31.36±3.27）%],Bax明显低于[（22.61±3.49）%]对照组[（40.52±4.17）%].实验组心肌组织光镜下结构以及电镜下超微结构的损伤较对照组明显减轻.结论 去甲肾上腺素预处理能诱导心肌组织HSP70高表达,HSP70对离体大鼠心脏经过缺血再灌注后具有明显的保护效应,去甲肾上腺素预处理能够明显保护心肌的结构和功能,抑制心肌细胞凋亡.     

舒芬太尼复合艾司洛尔对全麻患者气管插管时心血管反应的影响

目的评价舒芬太尼复合艾司洛尔对全麻患者气管插管时心血管反应的影响。方法择期上腹部手术患者60例,年龄26～50岁,体重48～75kg,ASAⅠ或Ⅱ级,随机分为3组（n=20）：舒芬太尼0.5μg/ks组（Ⅰ组）、芬太尼5μg/kg＋艾司洛尔1 mg/kg组（Ⅱ组）和舒芬太尼0.5μg/kg＋艾司洛尔1 mg/kg组（Ⅲ组）。3组均静脉注射试验用药、异丙酚1.5 mg/kg和维库溴铵0.1 mg/kg麻醉诱导后气管插管,机械通气。分别于麻醉诱导前（T1）、麻醉诱导后1min（T2）、气管插管后即刻（T3）、气管插管后1 min（T4）、3min（T5）及10min（T6）记录HR,收缩压（SP）、舒张压（DP）,并于T1、T2、T4时采集桡动脉血7 ml,测定血浆肾上腺素（Ad）和去甲肾上腺素（NA）的浓度。结果与Ⅰ组比较,Ⅱ组和Ⅲ组HR、SP、DP及血浆Ad和NA的浓度降低（P〈0.05）;与Ⅱ组比较,Ⅲ组HR、SP、DP降低（P〈0.05）。与T1比较,T2时3组HR、SP、DP及血浆Ad和NA浓度降低（P〈0.05）,Ⅰ组T3时HR、SP、DP升高,T4时HR升高,Ⅱ组、Ⅲ组差异无统计学意义（P〉0.05）。结论舒芬太尼0.5μg/kg复合艾司洛尔1mg/kg可更好地预防全麻患者气管插管时的心血管反应。     

Immunomodulatory effects of morphine withdrawal in the rat are time dependent and reversible by clonidine

Rationale: It is well established that opioids can modulate the immune status following both acute and chronic administration and that tolerance develops to some of these immunomodulatory effects. Few studies, however, have investigated opioid withdrawal-induced immunomodulation and the mechanism by which that process may be mediated. Objectives: The present study examines the immunomodulatory properties of morphine withdrawal alone and in the presence of the α₂-adrenergic agonist, clonidine. Methods: Rats drank a morphine solution for 20 days; withdrawal was induced on day 21 by replacing the morphine solution with plain tap water. Measurements of withdrawal-induced weight change and immunomodulation were obtained at several time points after withdrawal induction. Immune status was assessed by determining concanavalin A (Con-A), toxic shock syndrome toxin (TSST-1), and lipopolysaccharide (LPS)-stimulated splenocyte proliferation, splenic ConA-stimulated interferon (IFN)-γ production, and splenic natural-killer (NK) cell activity. In a separate series of experiments, systemic injections of clonidine (0.001–0.01 mg/kg) were administered during a 12-h withdrawal episode and all measures of immune status were reassessed. Results: Weight change was time dependent, with peak decreases in weight occurring 24 h following withdrawal induction. Rats also exhibited a time-dependent suppression of immune status in all assays except LPS-stimulated proliferation; immunomodulation was most evident 12 h following withdrawal induction. Clonidine dose dependently prevented withdrawal-induced suppression of Con-A and TSST-1-stimulated splenocyte proliferation, Con-A-stimulated splenocyte IFN-γ production, and splenic NK cell activity. Conclusions: These findings demonstrate that opioid withdrawal significantly suppresses a subset of immune parameters and that these effects can be prevented by clonidine. Received: 21 February 1999 / Final version: 14 May 1999     

去甲肾上腺素对烧伤大鼠脑组织血管内皮细胞生长因子表达的影响

目的 观察去甲肾上腺素（NE）对烧伤大鼠脑组织血管内皮细胞生长因子（VEGF）表达的影响。方法 用40％总体表面积（TBSA）Ⅲ度烫伤大鼠，观察NE对烧伤大鼠血脑屏障通透性的影响。用免疫组织化学法、实时荧光定量聚合酶链反应（PCR）法，观察NE对烧伤大鼠脑组织VEGF表达的影响。结果 （1）烧伤大鼠和NE刺激后的烧伤大鼠血脑屏障通透性增加，与对照组比较差异有统计学意义（P〈0．01）。随着烧伤前注入NE剂量的加大，BN2、BN3组脑组织的血脑屏障通透性增加明显，与烧伤组比较，差异有统计学意义（P〈0．01）；（2）大剂量NE刺激时，脑组织VEGF的表达增加，烧伤后VEGF的表达明显增加，与对照、N1、N2组比较，差异有统计学意义（P〈0．01）。随NE刺激剂量增大，烧伤后VEGF表达增强，BN2、BN3组与烧伤组比较，差异有统计学意义（P〈0．05）。结论 NE能够诱导严重烧伤大鼠脑组织VEGF表达，可能是烧伤后促进脑水肿形成的一个重要因素。     

Cocaine-induced convulsions: pharmacological antagonism at serotonergic, muscarinic and sigma receptors

The concurrent influence of multiple neurotransmitter systems in mediating cocaine-induced convulsions is predicted by the results of previous receptor binding studies. The present results demonstrate that pharmacological manipulations of these predicted neurotransmitter systems alters the occurrence of cocaine-induced convulsions. The 5-HT reuptake inhibitor fluoxetine enhanced the occurrence and severity of convulsions produced by 100 mg/kg (−) cocaine, while the 5-HT₂ receptor antagonists cinanserin, ketanserin and pirenperone antagonized cocaine-induced convulsions in a dose-dependent manner. Further, the M₁ receptor antagonist pirenzepine antagonized cocaine-induced convulsions, but atropine did not. In addition, both the (+) and (−) stereoisomers of the sigma ligand SKF 10047 significantly attenuated cocaine-induced convulsions. (+)SKF 10047 was more potent than (−)SKF 10047 in this effect, suggesting a stereoselective effect at sigma receptor sites. In contrast, DA and NE neurotransmission do not appear to modulate the proconvulsant effects of cocaine in a specific, dose-dependent manner. Thus, of the CNS binding sites with which cocaine is known to interact, the results are consistent with the conclusion that 5-HT transporters and 5-HT₂ receptor sites appear to be direct and primary sites related to cocaine-induced convulsions, while M₁ and sigma binding sites appear to play important but secondary and modulatory roles in this response. Received: 8 July 1996/Final version: 24 September 1996     

Dissociation between in vivo hippocampal norepinephrine response and behavioral/neuroendocrine responses to noise stress in rats

The behavioral and extracellular hippocampal norepinephrine responses to audiogenic stress were concomitantly characterized in freely moving rats using in vivo microdialysis. Noise stimulation produced a rapid, but short-lived increase in norepinephrine release from the hippocampus during the first 20 min of noise presentation that declined to baseline levels for the duration of the noise stimulation and following noise offset. In contrast, the behavioral response persisted throughout the duration of the noise stimulation. In a separate group of similarly treated animals, neuroendocrine indices of stress were monitored during exposure to noise. Consistent with the behavioral response, corticosterone and adrenocorticotropic hormone remained elevated for the duration of noise presentation. These findings support a dissociation between the hippocampal norepinephrine response and the behavioral and neuroendocrine response patterns and suggest that other systems may be involved in the regulation of behavioral responsiveness to aversive stimuli.     

Noradrenergic response to acute ethanol administration in heathly subjects: comparison with intravenous yohimbine

The effects of oral administration of ethanol [1.1 ml/kg 95% ethanol administered as a 20% (by volume) solution] and intravenous administration of the alpha₂ adrenergic receptor antagonist yohimbine hydrochloride (0.4 mg/kg), alone and in combination, were compared using a double-blind, placebo-controlled design. Twelve healthy subjects completed 4 test days during which drug effects on subjective measures of intoxication and anxiety, plasma levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and cortisol, and cardiovascular indices were assessed. Acutely administered oral ethanol significantly increased the subjective measures of intoxication and anxiety, plasma MHPG, and sitting systolic blood pressure compared with placebo. Intravenous yohimbine significantly increased subjective measures of intoxication and anxiety, plasma MHPG and cortisol, and blood pressure relative to placebo. The ethanol-induced increase in plasma MHPG was significantly greater than that following yohimbine, whereas yohimbine resulted in significantly greater increases in anxiety, plasma cortisol, and blood pressure measurements than ethanol. The combined administration of ethanol and yohimbine had a clear additive effect of increasing the severity of acute intoxication compared with ethanol or yohimbine alone, and resulted in a significantly greater plasma MHPG response compared with either drug given alone. Although the pharmacokinetic effects of ethanol administration on NE metabolism must be considered, these findings suggest that the intoxicating and anxiogenic effects of acute ethanol administration may be associated with increased NE turnover, as measured by plasma MHPG, in healthy human subjects. In addition, these results indicate that ethanol and yohimbine may act additively to increase ethanol intoxication and that they may increase NE turnover through different physiological mechanisms.