氯氮平对谷氨酸功能低下精神分裂症小鼠模型的作用

目的 观察氯氮平对地卓西平马来酸盐（MK-801）所致谷氨酸功能低下精神分裂症小鼠模型的高活动性及刻板行为的作用。方法 昆明种小鼠130只。（1）取34只小鼠分为4组：溶媒空白对照组（腹腔注射溶媒，以下简称对照组）；3种氯氮平剂量（1．0，1．5，2．0mg／kg体质量，腹腔注射）组；每组8～10只，观察氯氮平对小鼠探究行为和自主活动的影响。（2）取46只小鼠分为5组，分别为对照组、MK-801模型组（溶媒＋MK-801，0．25mg／kg体质量，腹腔注射）及3种剂量（同上）氯氮平组分别加MK-801（0．25mg／kg体质量，腹腔注射），每组8～10只，观察氯氮平对MK-致801小鼠自主活动增加的影响。（3）取50只小鼠，每组10只，给药方案同“（2）”，观察氯氮平对MK-801引起的刻板行为的影响。结果 （1）与对照组比较，氯氮平剂量为1．5mg／kg体质量和2．0mg／kg体质量时，小鼠的探究行为及自主活动总路程减少（P均〈0．001）；但剂量为1．0mg／kg时，对小鼠的探究行为及自主活动均无影响（P均〉0．05）。（2）氯氮平剂量为1．0～2．0mg／kg体质量时，呈剂量依赖性抑制由MK-801引起的自主活动增加（均P〈0．05）。（3）氯氮平剂量为1．5～2．0mg／kg体质量时，呈剂量依赖性抑制MK-801引起的刻板行为（均P〈0．05）。但低剂量（1．0mg／kg体质量）氯氮平对MK-801引起的刻板行为无明显影响（P〉0．05）。结论 氯氮平对MK-801所致谷氨酸功能低下精神分裂症小鼠模型不同脑区的作用有选择性，低剂量时抑制由中脑边缘、中脑皮质系统介导的高活动性，较高剂量时抑制由中脑边缘、中脑皮质系统及黑质纹状体系统控制的高活动性及刻板行为。     

奥氮平对谷氨酸功能低下的精神分裂症小鼠模型的作用

目的 观察奥氮平对谷氨酸功能低下小鼠模型表现出的高活动性及前脉冲抑制(PPI)缺失的作用.方法 昆明种小鼠165只.(1)取36只小鼠分为4组:溶媒空白对照组(腹腔注射溶媒,以下简称对照组),3种奥氮平剂量(0.1 mg/kg体质量,0.2 mg/kg体质量,0.3 mg/kg体质量,腹腔注射)组,每组8～10只;观察奥氮平对小鼠探究行为和自主活动的影响.(2)取49只小鼠分为5组:对照组,地卓西平马来酸盐(MK-801)模型组(溶媒+MK-801,0.25 mg/kg体质量,腹腔注射),3种剂量(同上)奥氮平干预组(奥氮平+MK-801 0.25 mg/kg体质量,腹腔注射),每组9～10只;观察奥氮平对MK-801致小鼠自主活动增加的影响.(3)取80只小鼠分为8组:对照组,MK-801模型组(溶媒+MK-801,0.5 mg/kg体质量,腹腔注射),3种奥氮平剂量给药组(奥氮平+生理盐水,奥氮平剂量分别为0.3 mg/kg体质量,1 mg/kg体质量,3 mg/kg体质量),3种奥氮平剂量(同上)干预组(奥氮平+MK-801 0.5 mg/kg体质量,腹腔注射),每组10只;观察奥氮平对基线前脉冲抑制(PPI)及MK-801引起的PPI缺失的影响.结果 (1)与对照组比较,奥氮平剂量为0.2 mg/kg体质量和0.3mg/kg体质量时,小鼠的探究行为及自主活动总路程减少(P均＜0.05);但剂量为0.1 mg/kg时,对小鼠的探究行为(P=0.363)及自主活动(P=0.196)无影响.(2)奥氮平剂量为0.1～0.3 mg/kg体质量时,呈剂量依赖性抑制MK-801引起的自主活动增加(P均＜0.05).(3)奥氮平剂量为0.3～3mg/kg体质量时,对基线的PPI无影响(P均＞0.05),剂量为1～3 mg/kg时呈剂量依赖性修复了MK-801引起的PPI缺失(P均＜0.05).结论 奥氮平能够特异性地抑制谷氨酸功能低下小鼠模型表现出的高活动性和PPI缺失,与奥氮平的临床药理作用一致.     

MK-801建立谷氨酸功能低下精神分裂症小鼠模型的研究

目的用谷氨酸N-甲基-D-天冬氨酸(NMDA)受体非竞争性拮抗剂地卓西平马来酸盐(MK-801)建立谷氨酸功能低下精神分裂症小鼠模型,评价MK-801不同剂量时对这种模型的行为学改变,探讨其适宜剂量。方法根据文献及预试验,确定MK-801的实验剂量,用DigBehv自发活动视频分析系统测定腹腔注射MK-801不同剂量组小鼠的自发活动,用评分量表评价小鼠的刻板行为,并与注射生理盐水组比较。结果MK-801(0．125～0．50 mg／kg)呈剂量依赖性增加小鼠的自发活动和刻板行为。MK-801剂量为0．25 mg／kg时能显著增加小鼠的自发活动和刻板行为,而且从行为学方面评定,没有明显的神经毒性作用。0．50 mg/kg剂量组出现了后肢肌力障碍和明显的共济失调等神经毒性表现。结论0．25 mg／kg的MK-801可作为谷氨酸功能低下小鼠模型的最适宜剂量,引起的行为学改变能够客观量化。     

氟哌啶醇对MK-801致小鼠高活动性与前脉冲抑制损害的作用

目的观察氟哌啶醇对谷氨酸功能低下小鼠模型表现出的高活动性及前脉冲抑制(prepulse inhibition,PPI)损害的作用。方法昆明种小鼠152只分组(n=8或n=10)进行下述对照观察:观察不同剂量氟哌啶醇(0.03、0.1、0.3 mg/kg)腹腔注射对昆明种小鼠探究行为和自主活动的影响;以0.25 mg/kg MK-801诱导小鼠自主活动增加,观察上述剂量氟哌啶醇对MK-801致小鼠高活动性的影响;以0.5 mg/kg MK-801诱导小鼠PPI损害,观察氟哌啶醇(0.1、0.3、1 mg/kg)对基线水平PPI以及MK-801损害后PPI的作用。结果与对照组比较,氟哌啶醇剂量为0.1 mg/kg和0.3 mg/kg时,小鼠的探究行为及自主活动总路程减少(P<0.05);但剂量为0.03 mg/kg时,对小鼠的探究行为及自主活动均无影响(P>0.05)。氟哌啶醇剂量为0.1~0.3 mg/kg时,呈剂量依赖性抑制由MK-801引起的自主活动增加(F=27.23,P<0.01),0.1mg/kg的氟哌啶醇的抑制程度为22%(P<0.01),0.3 mg/kg的氟哌啶醇的抑制程度为65%(P<0.00...     

帕利哌酮对地卓西平马来酸盐引起大鼠自发活动增加及感觉门控功能异常的作用

目的探讨利培酮及其活性代谢产物帕利哌酮对地卓西平马来酸盐(dizocipline maleate,MK-801)引起的大鼠自发活动增加及感觉门控功能异常的作用,分析二者药理学作用的异同。方法成年雄性Sprague-Dawley(SD)大鼠共96只。选取SD大鼠48只,根据体重分层随机分为对照组、MK-801模型组、帕利哌酮0.10 mg/kg组、帕利哌酮0.50 mg/kg组、帕利哌酮1.00mg/kg组及利培酮组,每组8只,观察不同剂量帕利哌酮及利培酮(0.1 mg/kg)对MK-801(0.40 mg/kg)引起的大鼠自发活动增加的影响;选取SD大鼠48只,根据体重分层随机分组,每组8~10只,观察不同剂量帕利哌酮(0.10、0.50和1.00 mg/kg)及利培酮(0.5 mg/kg)对MK-801(0.25 mg/kg)引起大鼠前脉冲抑制(prepulse inhibition,PPI)功能异常的影响。结果利培酮及帕利哌酮均不同程度地逆转MK-801引起的大鼠自发活动增加(P0.05),而帕利哌酮的对抗作用随着给药剂量的增加而减弱;帕利哌酮各剂量组均不同程度地提高大鼠基线PPI,组间差异具有统计学意义(P0.05),但未能逆转MK-801引起的PPI减低效应,组间差异无统计学意义(P0.05);而利培酮(0.5 mg/kg)可逆转MK-801对大鼠PPI的破坏作用(P0.05)。结论利培酮和帕利哌酮不同程度地逆转了MK-801引起大鼠自发活动增加及感觉门控功能异常,说明帕利哌酮虽为利培酮活性代谢产物,但二者药理学作用不尽相同。     

地卓西平马来酸盐对雄性大鼠自发活动和前脉冲抑制及再认记忆的影响

目的 观察急性腹腔注射N-甲基-D-天冬氨酸(NMDA)受体拮抗剂地卓西平马来酸盐(MK-801)刘大鼠自发活动、感觉运动门控和物体再认记忆的影响,探讨MK-801模拟精神分裂症不同内表现型的适宜剂量.方法 成年雄性SD大鼠共104只,按照体质量采用分层随机化方法进行分组.(1)取SD大鼠48只,分为MK-801小剂量组、MK-801中剂量组、MK-801高剂量组和对照组,每组12只,观察不同剂量MK-801 (0.1、0.2、0.4 mg/kg)对大鼠自发活动的影响;(2)取SD大鼠32只,分为MK-801小剂量组、MK-801中剂量组、MK-801高剂量组和对照组,每组8只,观察不同剂量MK-801(0.1、0.2、0.4 mg/kg)对大鼠前脉冲抑制(PPI)的影响;(3)取SD大鼠24只,分为MK-801小剂量组和对照组,每组12只,观察小剂量MK-801 (0.1 mg/kg)对大鼠物体辨别测试的影响.结果 (1)中高剂量MK-801 (0.2,0.4 mg/kg)呈剂量依赖性诱导大鼠自发活动的增加以及PPI的损害(P＜0.05或P＜0.01),小剂量(0.1 mg/kg)组在自发活动和PPI上与对照组差异无统计学意义(P＞0.05).(2)小剂量MK-801组在物体辨别测试中对新物体的偏爱指数显著低于对照组[(57.79±10.66)％比(73.34±18.52)％,P＜0.05].结论 中高剂量MK-801可引起自发活动和感觉运动门控功能异常,而小剂量在排除运动系统异常的前提下可特异性地破坏大鼠的再认记忆,提示MK-801模拟精神分裂症的不同内表现型时应根据研究目的选择适宜剂量.     

米帕明和丁螺环酮抗隔离小鼠攻击行为的药理作用

目的　研究米帕明和丁螺环酮对小鼠探究行为、自主活动以及隔离攻击行为的影响。方法　雄性昆明种小白鼠隔离饲养 38～ 45天 ,建立隔离小鼠攻击模型。急性腹腔注射生理盐水或米帕明或丁螺环酮 ,30min后测定小鼠的攻击行为。采用XZC 4A自主活动测定仪 ,测定群居小鼠的探究行为和自主活动性。结果　 (1)米帕明各剂量组 (0mg/kg ,2 5mg/kg ,5 0mg/kg ,10 0mg/kg)攻击行为的潜伏期 ( x±s)分别为 (5 2± 2 8)s ,(6 7± 47)s ,(132± 87)s ,(2 2 8± 94)s;呈剂量依赖性延长隔离小鼠攻击行为的潜伏期 ,拮抗其攻击行为。然而 ,同等剂量的米帕明对群居小鼠的自主活动和探究行为无明显影响。 (2 )丁螺环酮 2 5mg/kg,5 0mg/kg ,10 0mg/kg剂量组的攻击行为潜伏期 ( x±s)分别为(2 15± 74)s,(134± 10 3)s和 (30 0± 0 )s。与生理盐水组 (18± 7)s相比较 ,差异有显著性 (P <0 0 5 ) ,可明显抑制隔离小鼠的攻击行为。给小鼠腹腔注射相同剂量丁螺环酮 ,呈剂量依赖性减少群居小鼠的自主活动和探究行为。结论　米帕明和丁螺环酮均具有抗隔离小鼠攻击行为的药理活性。     

急慢性注射地卓西平马来酸盐对小鼠额叶microRNA-181b表达的影响

目的研究急慢性注射地卓西平马来酸盐(MK-801)对小鼠额叶中与精神分裂症相关的微小RNA(microRNA,miRNA)-181b表达的影响,探讨其参与精神分裂症病理学的可能机制。方法急性注射实验中40只小鼠随机分成四组,分别腹腔注射不同剂量(0.125 mg/kg,0.25 mg/kg,0.50 mg/kg)的MK-801和生理盐水(简称急性对照组),15 min后用实时荧光定量PCR(real-time PCR)技术检测额叶miRNA-181b的相对表达量;慢性注射实验中22只小鼠随机分成两组,分别腹腔注射0.25 mg.kg-1.d-1的MK-801和生理盐水(简称慢性对照组),连续14 d,然后检测miRNA-181b的相对表达量。结果急性注射0.125 mg/kg、0.25 mg/kg、0.50 mg/kgMK-801的各组小鼠额叶miRNA-181b的相对表达水平分别为0.65±0.05、0.61±0.05和0.91±0.08。前两个剂量组miRNA-181b的表达明显低于对照组(1.00±0.13),P<0.05,而0.5 mg/kg的MK-801则对miRNA-181b表达无影响(P>0.05)。慢性MK-801注射组miRNA-181b的相对表达量为1.86±0.19,显著高于慢性对照组(1.00±0.10),P<0.05。结论急性和慢性MK-801对额叶中miRNA-181b表达的影响不同,结合miR-181b的分子功能,提示miRNA-181b在急性和慢性模型鼠的构建中起到不同的作用。     

MK-801建立精神分裂症的感觉运动门控障碍的小鼠模型研究

目的 观察N-甲基-D-天冬氨酸(NMDA)受体拮抗剂地革西平马来酸盐(MK-801)对小鼠感觉运动门控功能的影响,确定建立精神分裂症的感觉运动门控障碍小鼠模型的适宜剂量.方法 采用不同剂量(0.125 mg/kg、0.25mg/kg、0.50 mg/kg)的MK-801建立感觉运动门控障碍的小鼠模型,用SR-LAB惊反射测试系统测定小鼠前脉冲抑制(PPI)、惊反射幅度和习惯化等行为学指标以比较不同剂量的药理作用.结果 ①前脉冲刺激的强度高于背景12 dB时,MK-801 0.125 mg/kg、0.25 mg/kg、0.50 mg/kg各剂量组PPI的数值分别为(28.7%±4.8%)、(27.6%4±5.6%)、(9.2%±4.0%).与对照组(53.6%±4.5%)的差异均有统计学意义(P<0.01),呈剂量依赖性破坏了小鼠的PPI.②MK-801剂量为0.5 mg/kg时,惊反射的幅度明显大于对照组(P＜0.001),增加的幅度为53%.③MK-801 0.5 mg/kg剂量组的习惯化为(-2.6%±10%),与正常对照组(43.7%±7.6%)相比,引起了习惯化明显损害(P＜0.001).结论 MK-801能够引起小鼠PPI的缺失,且能增加小鼠对惊反射刺激的反应性.0.50 mg/kg的MK-801可作为建立精神分裂症的感觉运动门控障碍的小鼠模型的适宜剂量.     

清幻灵对谷氨酸功能低下小鼠模型自主活动及学习记忆的影响

目的观察清幻灵对谷氨酸功能低下小鼠模型自主活动及学习记忆的影响。方法将昆明种小鼠60只随机分为5组，其中一组作为空白组，其余4组连续腹腔注射2周MK-801造模。2周后随机编为模型组、清幻灵小剂量组、清幻灵中剂量组、清幻灵大剂量组，给予相应药物灌胃1个月，同时采用自主活动仪、避暗仪、跳台仪分别观察5组的偏好行为、学习记忆的变化。结果模型组与空白组相比，自主活动明显增多，差异具有统计学意义（34．2±4．9次VS10．2±4．0次，t=5．54，P〈0．05）；避暗法实验结果显示：在第2周末，清幻灵各剂量组与空白组相比，潜伏期有所延长，但差异无统计学意义（P〉0．05）。在第6周末，清幻灵小、中、大剂量组的潜伏期与空白组相比，有不同程度的延长[（269．9±23．7）S，（270．0±17．5）S，（264．6±45．4）SVS（241．2±7．8）s]。其中，在第6周末清幻灵中剂量组、大剂量组潜伏期比第2周末分别延长了15．1s、19．3S。结论清幻灵对小鼠高活动性有正常调节作用，同时对小鼠学习记忆能力具有增强和改善作用，并且呈剂量依赖性。     

Epilepsy and anomalies of neuronal migration: MRI and clinical aspects

Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.     

Classification of methods in transcranial Electrical Stimulation (tES) and evolving strategy from historical approaches to contemporary innovations

Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.     

Hepatic Considerations in the Use of Antiepileptic Drugs

Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.     

Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms

Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.     

Neonatal Seizures: Problems in Diagnosis and Classification

Summary: The clinical identification of neonatal seizures is critical for the recognition of brain dysfunction; however, diagnosis is often difficult because of the poorly organized and varied nature of these behaviors. Current classification systems are limited in their ability to communicate motor, autonomic, and electroencephalo-graphic features of seizures precisely and to provide a basis for uniform effective diagnosis, therapy, and determination of prognosis. Recent investigations of neonates, utilizing bedside electroencephalographic/polygraphic/ video monitoring techniques, have provided the basis for improved diagnosis and classification of seizures in the newborn. These studies have demonstrated that not all clinical phenomena currently considered to be seizures require electrocortical epileptiform activity for their initiation or elaboration. In addition, the specific clinical character of the phenomena considered to be seizures, the clinical state of the infant, and the character of the EEG indicate the probable pathophysiological mechanisms involved and suggest probable etiologies, prognosis, and therapy. Similarities between animal models that demonstrate reflex physiology and neonates with motor automatisms and tonic posturing suggest that these clinical behaviors may not be epileptic in origin but, rather, primitive movements of progression and posture mediated by brainstem mechanisms. Although not all clinical behaviors currently considered to be neonatal seizures may have similar pathophysiological mechanisms, they are clinically significant because they all indicate brain dysfunction.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Un nouveau cadre conceptuel de travail pour la psychiatrie

In an attempt to place psychiatric thinking and the training of future psychiatrists more centrally into the context of modern biology, the author outlines the beginnings of a new intellectual framework for psychiatry that derives from current biological thinking about the relationship of mind to brain. The purpose of this framework is twofold. First, it is designed to emphasize that the professional requirements for future psychiatrists will demand a greater knowledge of the structure and functioning of the brain than is currently available in most training programs. Second, it is designed to illustrate that the unique domain which psychiatry occupies within academic medicine, the analysis of the interaction between social and biological determinants of behavior, can best be studied by also having a full understanding of the biological components of behavior.