Ethanol-Induced Extracellular Signal Regulated Kinase: Role of Dopamine D1 Receptors

Background:  Addictive drugs activate extracellular signal regulated kinase (ERK) in brain regions critically involved in their affective and motivational properties. The aim of this study was to demonstrate the ethanol-induced activation of ERK in the nucleus accumbens (Acb) and in the extended amygdala [bed nucleus of the stria terminalis lateralis (BSTL) and central nucleus of the amygdala (CeA)] and to highlight the role of dopamine (DA) D₁ receptors in these effects.
Methods:  Ethanol (0.5, 1, and 2 g/kg) was administered by gavage and ERK phosphorylation was determined in the nucleus Acb (shell and core), BSTL, and CeA by immunohistochemistry. The DA D₁ receptor antagonist, SCH 39166 (SCH) (50 μg/kg), was administered 10 minutes before ethanol (1 g/kg).
Results:  Quantitative microscopic examination showed that ethanol, dose-dependently increased phospho-ERK immunoreactivity (optical and neuronal densities) in the shell and core of nucleus Acb, BSTL, and CeA. Pretreatment with SCH fully prevented the increases elicited by ethanol (1 g/kg) in all brain regions studied.
Conclusions:  The results of this study indicate that ethanol, similar to other addictive drugs, activates ERK in nucleus Acb and extended amygdala via a DA D₁ receptor-mediated mechanism. Overall, these results suggest that the D₁ receptors/ERK pathway may play a critical role in the motivational properties of ethanol.     

七氟醚对幼鼠获取空间学习记忆能力及海马pERK1/2表达的影响

目的探讨七氟醚对幼鼠获取空间学习记忆能力及海马p ERK1/2表达的影响。方法出生后14 d SD幼鼠54只,随机分为对照组(C组)、七氟醚5%组(Sevo组)、假手术组(Sham组)各18只。C组不做任何处理,Sevo组幼鼠暴露于5%的七氟醚4 h,Sham组幼鼠吸入氧气4 h,1周、3周、6周后于上午8:00~11:00应用Morris水迷宫对幼鼠进行7 d的行为学观察,记录逃避潜伏期,行为学结束后随即取出6只幼鼠用免疫组化法测定海马CA1区神经元p ERK1/2的表达。结果与Sham组比较,Sevo组逃避潜伏期和探索时间明显延长(P<0.01),Sevo组海马CA1区神经元p ERK1/2的表达明显减少(P<0.01);Sham组与C组逃避潜伏期时间差异无统计学意义,海马CA1区神经元p ERK1/2的表达之间差异无统计学意义。结论七氟醚对幼鼠获取空间学习记忆能力的影响与抑制海马p ERK1/2表达有关。     

结直肠癌中pERK1/2和pAKT表达模式的临床病理意义以及预测预后的价值

目的 探讨磷酸化蛋白pERK1/2、pAKT在结直肠癌中表达的意义以及它们用于预测预后的价值.方法 运用免疫组化法检测84例结直肠癌手术标本、癌旁正常黏膜pERK1/2、pAKT表达模式,13例腹部创伤手术患者的正常结直肠黏膜做为对照.分析pERK1/2、pAKT表达模式与临床病理特征以及生存预后的关系.结果 pERK1/2、pAKT表达率从癌灶（65.5％、58.3％）到癌旁（45.2％、44.0％）和对照组（30.8％、15.4％）依次降低,P＜0.05;它们与肿瘤的大小、浸润深度、分化程度、T和N分期显著正相关;pERK1/2和pAKT双阳性表达病例、单阳病例、双阴病例的5年生存率和中位生存时间在趋势上依次升高,但差异无统计学意义,P ＞0.05.结论 ERK1/2、pAKT异常激活是结直肠癌的一个特征变化,二者磷酸化表达水平上调与肿瘤进展、侵袭性增强相关,但是目前的数据尚不支持pERK1/2、pAKT可以作为预测预后的独立因子.     

Role of dopamine D1 receptors in caffeine‐mediated ERK phosphorylation in the rat brain

The aim of this research was to study the role of dopamine D₁ receptors in caffeine elicited ERK phosphorylation in the prefrontal and other cortical (cingulate and motor) and subcortical (shell and core of the nucleus accumbens) regions. To this end, caffeine (3 and 10 mg/kg) was administered before phosphoERK immunohistochemistry. Caffeine dose‐dependently increased the number of phosphoERK‐positive neurons in the prefrontal and cingulate cortices but not in the secondary motor cortex and in the nucleus accumbens shell and core. The dopamine D₁ receptor antagonist, SCH 39166 (50 μg/kg), fully prevented phosphoERK activation by caffeine (10 mg/kg) in the superficial and deep layers of the prefrontal cortex but failed to prevent it in the cingulate cortex. Given that phosphoERK can be regarded as a postsynaptic marker of neuronal activation, the present results indicate that psychotropic properties of caffeine may result from the activation of prefrontal, via dopamine D₁ receptors, and cingulate cortices. Failure of caffeine to activate ERK in the nucleus accumbens further supports, indirectly, the observation that caffeine fails to activate dopamine transmission in this structure and is consistent with the tenet that caffeine lacks of true addictive properties. Synapse 64:341–349, 2010. © 2009 Wiley‐Liss, Inc.     

Acetaldehyde elicits ERK phosphorylation in the rat nucleus accumbens and extended amygdala

Recent advances suggest that acetaldehyde mediates some of the neurobiological properties of ethanol. In a recent study, we have shown that ethanol elicits the phosphorylation of extracellular signal‐regulated kinase (pERK) in the nucleus accumbens and extended amygdala, via a dopamine D₁ receptor‐mediated mechanism. The aim of this study was to determine whether acetaldehyde and ethanol‐derived acetaldehyde elicit the activation of ERK in the nucleus accumbens and extended amygdala. The effects of acetaldehyde (10 and 20 mg/kg) and ethanol (1 g/kg), administered to rats intragastrically, were assessed by pERK peroxidase immunohistochemistry. To establish the role of ethanol‐derived acetaldehyde, the alcohol dehydrogenase inhibitor, 4‐methylpyrazole (90 mg/kg), and the acetaldehyde‐sequestering agent, D ‐penicillamine (50 mg/kg), were administered before ethanol. Acetaldehyde increased pERK immunoreactivity in the nucleus accumbens and extended amygdala. Inhibition of ethanol metabolism and sequestration of newly synthesized acetaldehyde completely prevented ERK activation by ethanol. In addition, to establish the role of D₁ receptors stimulation in acetaldehyde‐elicited ERK phosphorylation, we studied the effect of the D₁ receptor antagonist, SCH 39166. Pretreatment with the D₁ receptor antagonist (50 μg/kg) fully prevented acetaldehyde‐elicited ERK activation. Overall, these results indicate that ethanol activates ERK by means of its metabolic conversion into acetaldehyde and strengthen the view that acetaldehyde is a centrally acting compound with a pharmacological profile similar to ethanol. Synapse 64:916–927, 2010. © 2010 Wiley‐Liss, Inc.     

脊髓ERK1/2的激活参与福尔马林所致家兔胆囊痛的形成

ERK是丝/苏氨酸蛋白激酶(MAPK)家族的成员,很多刺激可使其激活成为pERK,在细胞生长、分化、增殖等过程中起着重要作用。ERK1/2激活后为pERK1/2,后者可在核内发挥蛋白激酶的作用,磷酸化下游的转录因子,这些转录因子再启动基因的转录。在神经系统中,ERK1/2在学习、记忆和突触可塑     

Acute changes of coagulation and fibrinolysis parameters after experimental thromboembolic stroke and thrombolytic therapy

Thrombolysis is the only effective pharmaceutical therapy in acute ischemic stroke in humans but has a high risk of intracerebral hemorrhage. We aimed to establish an animal model to study changes of coagulation and fibrinolytic parameters during thromboembolic ischemic stroke and thrombolysis with recombinant tissue plasminogen activator (rt-PA). We used a thromboembolic stroke model in the rat. Animals were treated with rt-PA thrombolysis (n=10) and compared with untreated (n=10), sham operated (n=10) and control animals (n=20). Coagulation parameters (APTT, PT, TT, fibrinogen, AT III, TAT) and fibrinolytic parameters (t-PA antigen concentration, t-PA activity, PAI-1 concentration, PAI activity, plasminogen, antiplasmin) were measured at two time points (2.5 and 5h after stroke induction) with a battery of commercially available test kits. We observed an (1) initiation of coagulation and inhibition of fibrinolysis by the operation procedure itself, (2) simultaneous activation of fibrinolysis and its inhibitors after stroke induction and (3) potent initiation of fibrinolysis and consumption of fibrinolysis inhibitors after rt-PA therapy of stroke. We established a model system to monitor coagulation and fibrinolysis during thrombolytic therapy of stroke in the rat. This model may be used to study the influence of these parameters on hemorrhagic stroke transformation and outcome in experimental stroke in future.     

Estradiol treatment in preadolescent females enhances adolescent spatial memory and differentially modulates hippocampal region-specific phosphorylated ERK labeling

Estrogen levels in rats are positively correlated with enhanced memory function and hippocampal dendritic spine density. There is much less work on the long-term effects of estradiol manipulation in preadolescent rats. The present work examined how injections of estradiol during postnatal days 19–22 (p19–22; preadolescence) affected water maze performance and hippocampal phosphorylated ERK labeling. To investigate this, half of the estradiol- and vehicle-treated female rats were trained on a water maze task 24 h after the end of estradiol treatment (p23–27) while the other half was not trained. All female rats were tested on the water maze from p40 to p44 (adolescence) and hippocampal pERK1/2 labeling was assessed as a putative marker of neuronal plasticity. During adolescence, preadolescent-trained groups showed lower latencies than groups without preadolescent training. Retention data revealed lower latencies in both estradiol groups, whether preadolescent trained or not. Immunohistochemical detection of hippocampal pERK1/2 revealed elevations in granule cell labeling associated with the preadolescent trained groups and reductions in CA1 labeling associated with estradiol treatment. These results show a latent beneficial effect of preadolescent estradiol treatment on adolescent spatial performance and suggest an organizational effect of prepubescent exogenously applied estradiol.     

急性低血压对清醒大鼠前庭内侧核区pERK1/2表达的影响

[目的]探讨在清醒大鼠诱发急性低血压对前庭内侧核（MVN）区pERK1/2表达的影响.[方法]股动脉插管观察大鼠血压,股静脉插管注射给予硝普钠（SNP）诱发急性低血压,使血压下降约30%左右后,利用免疫组织化学方法观察MVN区pERK1/2表达的变化,并结合化学损伤单侧前庭器官观察可能的外周机制.[结果]股静脉注射给予清醒大鼠SNP诱发急性低血压后5,10,20,40 min时,双侧MVN区均可见明显的pERK1/2蛋白表达,而5,10 min时表达增多最明显,与对照组比较差异具有统计学意义.在单侧前庭器官损伤组（24 h）诱发急性低血压后的各个时间段,前庭器官损伤同侧MVN区pERK1/2阳性神经元的表达明显减少,但损伤对侧MVN区的pERK1/2表达明显增多.[结论]静脉注射给予清醒大鼠SNP诱发急性低血压可致MVN区兴奋,此作用可被破坏外周前庭器官所阻断.