吗啡与gp120致大鼠学习记忆障碍的作用及机制

 目的:探讨吗啡与gp120致大鼠学习记忆障碍的作用与机制。方法:4~6周的SD大鼠,侧脑室注射吗啡与gp120 V3环,Morris水迷宫评价空间记忆能力。TUNEL染色观察大鼠海马组织的阳性凋亡细胞数。Western blot法检测p-ERK的表达情况。结果:与对照组相比,100 μg/kg吗啡组、200 μg/kg吗啡组以及gp120 V3环组均能使大鼠的逃避潜伏期延长(P<0.05),目标象限停留时间以及穿越目标象限次数减少(P<0.05),海马区阳性细胞数增多(P<0.01),海马区p-ERK的表达增多(P<0.01);200 μg/kg吗啡+gp120 V3环组与200 μg/kg吗啡组或gp120 V3环组相比,逃避潜伏期延长(P<0.05),目标象限停留时间以及穿越目标象限次数减少(P<0.05),海马区阳性细胞数增多(P<0.01),海马区p-ERK的表达增多(P<0.01)。结论:侧脑室注射gp120 V3环可致大鼠学习与记忆障碍,吗啡能增强其效应,机制可能与增强海马区p-ERK的表达有关。     

米诺环素对CCI大鼠抑郁样行为的影响及机制研究

目的:观察海马CA1区注射米诺环素对坐骨神经慢性缩窄性损伤(CCI)大鼠的抑郁样行为、海马和前额叶皮层小胶质细胞激活的影响并分析其机制。方法:成年SD雄性大鼠随机分为:对照组、假手术组、CCI模型组、CCI+米诺环素组。糖水偏好及旷场实验检测大鼠抑郁样行为;免疫组化观察海马以及前额叶皮层Iba-1表达;取海马以及前额叶皮层组织,real-time PCR观察Iba-1、NLRP3和caspase1 mRNA表达,ELISA测定IL-1β和IL-18含量。结果:与假手术组相比,CCI大鼠7、10 d和14 d的糖水偏好明显降低(P 0. 05),旷场中央活动距离和中央活动时间明显减少(P 0. 05);与CCI组相比,CA1区注射米诺环素后CCI大鼠7 d和14 d的糖水偏好明显升高(P 0. 05),旷场中央活动距离和中央活动时间明显增加(P 0. 05)。与假手术组相比,CCI组大鼠海马CA1、CA3及DG区和前额叶皮层Iba-1阳性细胞数目显著增多(P 0. 05),Iba-1、NLRP3和caspase1 mRNA表达明显上调; IL-1β和IL-18含量也明显升高(P 0. 05)。与CCI组相比,注射米诺环素后,CCI大鼠海马CA1、CA3及DG区和前额叶皮层Iba-1阳性细胞数目减少(P 0. 05),Iba-1、NLRP3和caspase1 mRNA表达降低(P 0. 05),IL-1β和IL-18含量降低(P 0. 05)。结论:海马CA1区注射米诺环素明显抑制CCI大鼠的抑郁样行为;其机制可能是抑制海马和前额叶皮层小胶质细胞激活,下调NLRP3和caspase1表达,从而使IL-1β和IL-18产生减少。     

吗啡依赖小鼠海马神经元c-fos的表达

目的:探讨吗啡依赖小鼠海马不同亚区神经元c-fos表达的差异。方法:以剂量递增法皮下注射吗啡建立吗啡依赖小鼠模型,腹腔注射纳洛酮诱发戒断症状。根据小鼠戒断反应中出现的跳跃次数、体重下降等指标评定戒断反应强度。采用免疫组织化学法显示吗啡依赖小鼠和正常对照组小鼠海马神经元c-fos的表达。结果:吗啡依赖组海马CA1区和齿状回Fos阳性神经元数目明显增加(P<0.05),CA3区无明显改变(P>0.05)。纳洛酮催促戒断组海马CA1和CA3区Fos阳性神经元数目明显增加(P<0.05),齿状回Fos阳性神经元数目增加更为明显(P<0.01)。吗啡依赖组与纳洛酮催促戒断组CA3区阳性神经元数目有显著性差异(P<0.05)。结论:海马神经元c-fos的表达增强可能与吗啡依赖对神经元的损伤有关。     

修治附子在吗啡诱导的大鼠条件性位置偏爱上的作用

目的: 探讨修治附子(PAT)在吗啡诱导的大鼠条件性位置偏爱(CPP)模型上的作用及其机制。方法: (1)40只SD大鼠分为5组(n=8):生理盐水组、吗啡组、吗啡+PAT处理1、2和3组。除生理盐水组外,其余4组连续8 d隔天交替皮下注射吗啡5 mg/kg或生理盐水建立CPP模型,并同时每日分别以蒸馏水或PAT(0.3或1.0或3.0g/kg)灌胃。(2)其余32只SD大鼠分为4组(n=8):吗啡组、nor-BNI(kappa受体拮抗剂)+吗啡组、吗啡+PAT组和nor-BNI+吗啡+PAT组。4组大鼠均采用上述方法建立CPP模型。各组大鼠均于吗啡注射前120 min皮下注射生理盐水或nor-BNI(5 mg/kg),PAT处理组每日PAT 3.0 g/kg灌胃,其余2组以蒸馏水灌胃。各组大鼠均于CPP训练前和训练后测定CPP值,训练后测定CPP值后取大鼠脑伏隔核并采用放射免疫法检测其所含强啡肽浓度。结果: (1)经CPP训练后,吗啡诱导引起了CPP值升高。(2)1.0或 3.0 g/kg的PAT剂量相关地降低了吗啡诱导引起的CPP升高(P<0.05)。(3)nor-BNI完全拮抗了PAT(3.0 g/kg)对吗啡CPP形成的抑制(P<0.05)。(4)PAT处理组大鼠脑伏隔核强啡肽的浓度比吗啡对照组高(P<0.05),也呈剂量相关。结论: PAT剂量相关地抑制吗啡诱导的CPP形成,具有抗成瘾作用,其抗成瘾作用可能与大鼠脑伏隔核强啡肽的浓度增加,从而激动kappa受体有关。     

GluN2亚基在海洛因诱导CPP模型大鼠PrL区的表达

目的:研究大鼠内侧前额叶皮质(mPFC)边缘前区(PrL)GluN2亚基在海洛因诱导条件位置性偏爱(CPP)及戒断状态的表达。方法:24只SD大鼠随机分为对照组(control)和海洛因诱导组。海洛因诱导组大鼠按实验进程分为两种状态,即海洛因诱导CPP状态(heroin)和海洛因戒断状态(withdrawal)。用小剂量递增法皮下注射海洛因,行大鼠海洛因诱导CPP建模,并自然戒断,免疫荧光染色检测各组大鼠PrL区GluN2亚基NR2A、NR2B、NR2C、NR2D的表达。结果:大鼠经过连续7 d小剂量递增法注射海洛因,形成了稳定的CPP;免疫荧光染色结果显示,大鼠CPP状态PrL区NR2B表达较对照组显著增强(P<0.01),其他亚基无明显变化。海洛因自然戒断7 d后,戒断状态大鼠PrL区NR2A、NR2C表达较对照组和CPP状态皆显著增强(P<0.01)。戒断状态NR2B表达水平显著高于对照组(P<0.01),但与CPP状态无显著差异。结论:大鼠海洛因依赖CPP的形成与PrL区NR2B亚基的活性密切相关,NR2A和NR2C可能参与药物戒断症状的调控。推测PrL区GluN2不同亚基在海洛因成瘾不同阶段作用不同,并可能成为临床海洛因成瘾干预和治疗的重要靶点。     

解郁丸对WKY大鼠的抑郁样行为及海马和前额叶皮层BDNF表达的影响

目的:观察解郁丸对Wistar-Kyoto(WKY)大鼠抑郁样行为及脑源性神经营养因子(BDNF)在海马和前额叶皮层表达的影响,探讨其抗抑郁作用及相关机制。方法:成年雄性WKY大鼠为内源性抑郁动物模型,选取同品系Wistar大鼠作为空白对照组,WKY大鼠随机分为模型组、西酞普兰组和解郁丸组,分别灌胃给药21 d后,用糖水偏好实验及强迫游泳实验观察各组大鼠抑郁行为变化;采用免疫荧光法和Western blot法检测海马及前额叶皮层BDNF表达水平的变化。结果:WKY大鼠表现出明显的抑郁样行为,海马及前额叶皮层的BDNF表达量显著下降,且海马区神经元轴突减少(P0.01);在药物治疗后,WKY大鼠的抑郁样行为明显减少,BDNF在海马及前额叶皮层中的表达增加,且轴突数目也增加(P0.01)。结论:解郁丸能有效减少WKY大鼠的抑郁样行为;BDNF是其抗抑郁作用发挥的关键因子。本研究也进一步验证BDNF参与抑郁的发生发展过程。     

人参皂苷Rg1对癫痫大鼠海马神经元损伤和小胶质细胞活化的影响

目的探讨人参皂苷Rg1对癫痫大鼠海马神经元损伤和小胶质细胞活化的影响及其作用机制。方法 SD大鼠分为对照组(control组)、癫痫模型组(model组)、人参皂苷Rg1低剂量组(Rg1-L组)和人参皂苷剂量组(Rg1-H组),采用氯化锂-匹罗卡品腹腔注射制备癫痫大鼠模型;记录各组大鼠行为学发作情况;ELISA检测各组大鼠海马组织的氧化应激水平;qRT-PCR检测各组海马组织中炎症因子的表达;HE染色观察各组大鼠海马神经元结构和病理形态变化;免疫荧光组织化学染色检测各组大鼠小胶质细胞中iNOS、Arg-1蛋白表达。结果 model组大鼠症状达到Ⅲ级及Ⅲ级以上较control组显著增加,人参皂苷Rg1使大鼠的癫痫症状得到改善;与control组相比,model组大鼠海马组织中MDA(P<0.001)、TNF-αm RNA(P<0.001)、IL-1βmRNA(P<0.001)的表达水平上调,SOD(P<0.001)、IL-10 m RNA(P<0.001)的表达水平下调,而人参皂苷Rg1使大鼠海马组织中MDA(P<0.05)、TNF-αm RNA(P<0.05)、IL-1βmRNA(P<0.05)的表达水平下调,SOD(P<0.05)、IL-10 mRNA(P<0.05)的表达水平上调;model组大鼠海马神经元形态不完整,细胞间间隙增大和排列紊乱,人参皂苷Rg1组大鼠海马神经元形态明显改变,可见细胞排列较规则,大部分细胞形态正常;model组大鼠海马神经元凋亡率显著上升(P<0.001),人参皂苷Rg1组使大鼠海马神经元凋亡率下降(P<0.05);与control组相比,model组大鼠小胶质细胞数量显著增加(P<0.001),iNOS蛋白的表达显著升高(P<0.001),Arg-1蛋白表达显著降低(P<0.001),与model组相比,人参皂苷Rg1组大鼠小胶质细胞数量减少(P<0.05),iNOS蛋白的表达降低(P<0.05),Arg-1蛋白表达升高(P<0.05)。结论人参皂苷Rg1降低癫痫大鼠海马组织中iNOS蛋白的表达,增加Arg-1蛋白的表达,抑制小胶质细胞的激活,减轻氧化应激和炎症因子的表达,降低癫痫大鼠发作的等级。     

吗啡成瘾戒断对大鼠海马CA1区P-CREB表达的影响

目的探讨吗啡成瘾戒断后大鼠海马CA1区P-CREB的表达变化。方法48只健康雄性成年SD大鼠,随机分为实验组和对照组:实验组腹腔注射吗啡起始剂量5mg/kg,1d2次,逐日递增,连续10d;对照组:以生理盐水代替吗啡。停药后7d、14d和21d处死。用免疫组织化学方法(ABC法)检测海马CA1区P-CREB的表达,图像分析系统测定阳性反应产物的平均灰度值。结果P-CREB表达在7d、14d实验组与对照组相比表达上调(P<0.05),21d与对照组比较无显著差异(P>0.05)。结论海马CA1区CREB磷酸化在吗啡依赖的形成中发挥作用。     

血管性痴呆大鼠海马synapsinⅠ及其磷酸化水平的动态变化

目的：观察血管性痴呆大鼠海马区突触结构和突触蛋白synapsin I及其磷酸化水平的变化，探讨血管性痴呆大鼠突触传递障碍的可能机制。方法: 采用双侧颈总动脉夹闭再灌注同时腹腔注射硝普纳建立血管性痴呆模型，在15 d、1月、2月和4月等时点，电镜观察大鼠海马CA1区突触结构的病理改变，应用免疫组织化学染色法测定血管性痴呆大鼠海马synapsinⅠ及其磷酸化水平的变化。结果: 假手术组大鼠海马CA1区未见明显病理改变，突触前小泡聚集成簇，模型组突触前后膜界限不清，突触后致密物减少，突触前囊泡分布分散、聚集囊泡簇减少，并随造模时间的延长，病理改变加重；模型组大鼠海马CA1区synapsin I阳性产物表达明显减少(P<0.01)，DG区分子层无明显变化(P>0.05)；模型组大鼠海马磷酸化synapsin I（p-synapsin I）阳性细胞明显减少(P<0.01,P<0.05)，15 d和1月时点大鼠海马DG区和CA1区p-synapsin I阳性细胞表达较假手术组增强(P<0.01)，2月和4月时点CA1区p-synapsin I阳性细胞表达较假手术组减弱(P<0.01)，而DG区无明显变化(P>0.05)。结论: VD模型大鼠海马突触结构受损，突触小泡簇减少；synapsinⅠ及其磷酸化水平表达降低，突触传递前机制受损可能是VD突触传递障碍的机制之一。     

吗啡精神依赖大鼠VTA-NAc-PFC神经环路NR1表达的变化

目的:研究吗啡诱导条件性位置偏爱(conditioned place preference,CPP)大鼠中脑腹侧被盖区-伏核-前额叶皮质(VTA-NAc-PFC)神经环路各核团中N-甲基-D-天冬氨酸受体NR1亚基(NR1)表达的变化。方法:20只大鼠随机分为生理盐水对照组和吗啡条件性位置偏爱模型组,模型组采用大鼠颈背部皮下吗啡剂量递增注射(起始剂量10 mg/kg,每天递增10 mg/kg,至注射10 d时为100 mg/kg),CPP训练10 d,末次训练后48 h CPP检测确认模型建立成功后取材,利用Western Blot方法检测VTA,NAc和PFC内NR1蛋白的表达情况。结果:经CCP检测,模型组大鼠在白箱(吗啡伴药箱)停留时间在训练前和训练后分别为408±93 s和528±81 s,与生理盐水组比较(训练前和训练后分别为393±81 s和416±58 s)明显有所延长(P0.05)。Western Blot检测到吗啡诱导条件性位置偏爱大鼠的NAc核团NR1表达水平较生理盐水组显著增加(P0.05),而VTA和PFC两个核团的NR1表达水平则未见明显改变。结论:NR1在吗啡精神依赖过程中NAc核团中表达增加,而在VTA和PFC核团中没有增加。     

慢性吗啡处理及戒断后大鼠前额皮质、海马和杏仁核中Parvalbumin的表达变化

为了观察慢性吗啡处理及戒断后大鼠前额皮质、海马和杏仁核中parvalbumin(PV)的表达变化,为其功能的研究提供形态学依据,本实验将30只雄性SD大鼠随机分为吗啡依赖组和生理盐水对照组。吗啡依赖组大鼠腹膜腔注射吗啡,2次/d,起始剂量为5mg/kg,逐日递增5mg,至第10d为50mg/kg;对照组注射同体积的生理盐水。于末次注射后动物分别存活3h、3d和14d。用免疫组化方法和相对平均灰度值检测前额皮质、海马和杏仁核内PV的表达。结果显示:在生理盐水处理组各存活时间点,前额皮质、海马和杏仁核内PV的表达相同。和生理盐水对照组相比,3h时海马和杏仁核内PV的表达明显增加(P<0.05),但前额皮质内PV的表达减少。第3d时,海马CA1、CA3、CA4、齿状回和杏仁核内PV的表达减少,但CA2区PV表达继续增加,而前额皮质的表达开始恢复。至第14d时,CA2区PV的表达开始恢复,但CA1、CA4和杏仁核内PV的表达又开始增加,明显高于第3d组(P<0.05)。以上结果提示慢性吗啡处理及戒断后PV的表达具有区域特异性和时相特异性;这种变化在戒断早期可能主要与躯体依赖相关,而戒断晚期主要与精神依赖相关。     

衰老晚期大鼠脑组织丙二醛及非水溶性蛋白的变化

选用SD大白鼠青年组(3个月)、衰老晚期组(34～36个月)各10只,测定各组大鼠海马、前额皮质、小脑皮质丙二醛(MDA)和蛋白质含量的变化.结果如下:与青年组比较,衰老晚期鼠海马、前额皮质、小脑皮质MDA和非水溶性蛋白、组织总蛋白含量均明显增多,海马的非水溶性蛋白在2个年龄组均高于其余2个脑区.衰老晚期前额皮质非水溶性蛋白含量明显高于小脑皮质.本文对MDA和非水溶性蛋白在衰老晚期的改变的意义进行了讨论.     

Contribution of the suprachiasmatic nucleus to day:night variation in cocaine-seeking behavior

Recent work has shown that time-of-day influences drug-seeking behavior. The present experiments tested the hypothesis that the master circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus (SCN) is required for generating day:night differences in drug-seeking behavior, specifically the acquisition, extinction, and reinstatement of cocaine-induced conditioned place preference (CPP). Sham and SCN-lesioned (SCNx) rats were trained for cocaine-induced CPP behavior at either ZT4 (Zeitgeber time 4, 4 h after lights-on) or ZT12 (lights-off). After being tested for side preference, rats were allowed to extinguish CPP. This was followed by cocaine-induced reinstatement with 5 mg/kg and 10 mg/kg of cocaine. SCNx animals exhibited no 24-h locomotor activity rhythm. Acquisition of CPP behavior did not vary with time-of-day, but was greater in SCNx animals. Sham rats tested at ZT12 took significantly longer to extinguish CPP behavior compared to ZT4, an effect completely abolished by SCN lesions. Cocaine-induced reinstatement of CPP did not vary with time of day in sham rats. However, SCNx animals tested at ZT4 trended towards greater reinstatement to the low dose of cocaine, and displayed significantly less reinstatement to the higher dose of cocaine than sham rats. Additionally, SCNx rats tested for reinstatement to the lower dose of cocaine displayed greater reinstatement at ZT4 than at ZT12. We conclude that: 1) acquisition of CPP behavior does not vary between the two times of day tested but is influenced tonically by the SCN, 2) extinction of cocaine CPP varies with time-of-day and this variation depends critically on the SCN, and 3) reinstatement of cocaine CPP does not vary between the two times of day tested. However, day:night differences in reinstatement are unmasked in animals lacking an SCN, suggesting the possibility that an extra-SCN oscillator is responsible for generating variation in this cocaine-seeking behavior.     

慢性间歇低氧对幼鼠认知及相关脑区CREB的影响

目的:观察慢性间歇低氧(CIH)对幼鼠认知的影响并探讨其潜在的机制。方法:取八臂迷宫训练成功的SPF级健康雄性SD幼鼠40只,随机分为:间歇低氧2周(2IH)、4周组(4IH),对照2周(2C)、4周组(4C),建立IH幼鼠模型,低氧结束后进行八臂迷宫测试,观察海马和前额叶皮层超微结构变化及cAMP反应元件结合蛋白(CREB)mRNA和磷酸化CREB蛋白的表达。结果:4组幼鼠的记忆错误次数比较均有显著差别(均P0.05);IH各组海马及前额叶皮层神经元均出现早期凋亡和变性,尤以4IH组最为明显,对照组则基本正常;与相应对照组相比,2IH、4IH组幼鼠海马和前额叶皮层CREB mRNA和p-CREB蛋白的表达水平显著降低(均P0.05),且以4IH组最低(均P0.01),差异显著,两对照组之间无显著差异(P0.05)。结论:慢性间歇低氧诱导海马和前额叶皮层神经元超微结构改变,还下调CREB的基因转录和抑制CREB蛋白磷酸化,抑制记忆相关蛋白的合成,这可能是引起学习记忆能力下降的重要机制之一。     

Cognitive dysfunction and glutamate reuptake: Effect of EAAT2 polymorphism in schizophrenia

A disturbance of glutamatergic transmission has been suggested to contribute to the development of schizophrenic pathophysiology, based primarily on the ability of glutamate receptor antagonists to induce schizophrenic-like symptoms. The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate uptake. It also contributes to energy metabolism in the brain, by transporting glutamate into astrocytes for conversion into glutamine. A dysregulation of its level of expression has been associated with multiple neurological disorders. Blocking glutamate uptake by EAAT2 in cultured oligodendrocytes leads to cell death, demyelination and axonal damage, suggesting that it is crucial for normal oligodendrocyte function. Different studies focused on EAAT2 alterations among subjects affected by schizophrenia, reporting a decreased expression in the parahippocampal region and in the dorsolateral prefrontal cortex. Moreover, subjects with the high-risk metabotropic glutamate receptor 3 (GRM3) haplotype associated with schizophrenia had lower EAAT2 expression in the prefrontal cortex and also showed impaired cognitive performances for measures of verbal list learning and verbal fluency. EAAT2 protein activity is regulated by a SNP rs4354668 (−181 T/G) which falls in the gene promoter region, with the G allele resulting in a lower activity of the transporter. Based on these data, we assessed possible effects of the −181 T/G EAAT2 polymorphism on two core prefrontal cognitive performances, known to be impaired in schizophrenia, in a sample of 211 clinically stabilized patients. We observed better executive functions (WCST, no. of categories) and working memory (N-back: 1-back, 2-back) performances in subjects homozygous for the T allele, compared to the G carriers group. These observations suggest that the presence of the G allele is associated, among patients with schizophrenia, with a disadvantageous effect on core cognitive functions that depend on prefrontal cortex activity. These results are preliminary and need to be replicated by future and larger studies, however they suggest that EAAT2 inefficiency may represent a target of interest for development of pharmacological strategies aimed to improve prefrontal performances by compensating the impaired glutamate reuptake.     

Lesions of the medial prefrontal cortex prevent the acquisition but not reinstatement of morphine-induced conditioned place preference in mice

In order to further investigate the role of the mPFC in morphine reward and drug priming induced relapse, the present study examined the effects of the mPFC lesions on the acquisition and morphine priming induced reinstatement of conditioned place preference (CPP). In the first experiment, mice received sham or bilateral kainic acid lesions of the mPFC and were subsequently tested for the acquisition of a morphine-induced CPP. In the second experiment, each mouse received lesions of mPFC following the establishment of morphine-induced CPP. Nine days later, a priming injection of morphine was given (2 mg/kg, i.p.) to reinstate the extinguished CPP. The results showed that pre-conditioning lesions of the mPFC blocked the acquisition of morphine-induced CPP, while post-conditioning lesions of the mPFC failed to prevent morphine priming induced reinstatement of CPP. These results provide the first direct evidence that the mPFC may be involved in the acquisition, but not morphine priming induced reinstatement of CPP.     

褪黑素通过抑制△FosB的表达拮抗大鼠可卡因条件性位置偏爱的复燃

目的研究褪黑素对大鼠可卡因条件性位置偏爱复燃的作用及机制。方法建立大鼠可卡因诱导的条件性位置偏爱模型,在可卡因戒断后/复燃前给予褪黑素,检测实验大鼠条件性位置偏爱的变化,并应用Western blot和共聚焦激光扫描显微镜技术观察褪黑素对△FosB表达的影响;另外进行松果体摘除术,观察去除内源性褪黑素对可卡因诱导的条件性位置偏爱和△FosB表达的影响。结果褪黑素对大鼠条件性位置偏爱效应的复燃具有抑制作用,褪黑素下调了可卡因复燃诱导的△FosB在相关脑区的高表达。松果体摘除抑制了可卡因诱导的条件性位置偏爱的形成,但是对复燃诱导的条件性位置偏爱的强化无明显作用,松果体摘除组大鼠除了在海马表现出△FosB的低表达外,在其它脑区未观察到明显变化。结论褪黑素可能通过抑制可卡因复燃诱导的△FosB的高表达拮抗大鼠可卡因奖赏效应的强化。     

吗啡对大鼠心理依赖相关脑区超微结构和突触数量的影响

目的：观察不同时程吗啡依赖大鼠心理依赖相关脑区超微结构和突触数量的变化。方法：建立不同时程吗啡依赖大鼠模型,应用透射电镜对相关脑区皮质超微结构和突触进行观察计数。结果：吗啡依赖大鼠海马、杏仁核、豆状核和额叶皮质神经细胞线粒体肿胀、畸形,内质网扩张,多聚核糖体解聚,轴突、树突及突触数量增多;吗啡依赖4周组大鼠突触数量的增多与其他短时期或对照组大鼠相比,具有显著性差异;而8周组则具有高度显著性差异。结论：吗啡依赖大鼠心理依赖相关脑区神经细胞呈缺血缺氧性及退行性改变;突触数量增多,并随吗啡依赖时限的延长而更加明显。     

Manipulation of dopamine d1-like receptor activation in the rat medial prefrontal cortex alters stress- and cocaine-induced reinstatement of conditioned place preference behavior

These studies examined the ability of the dopamine D1-like agonist SKF 81297 and D1-like antagonist SCH 23390 in the medial prefrontal cortex to alter the reinstatement of cocaine-induced conditioned place preference behavior. Male Sprague-Dawley rats were fitted with bilateral cannulae over the medial prefrontal cortex and subsequently trained in a conditioned place preference task. Animals were trained in this task using four pairings of cocaine (12 mg/kg, i.p.). Conditioned place preference was demonstrated in all animals, and this behavior was then extinguished over a 5-10-day period before testing for reinstatement. Just prior to reinstatement by immobilization stress or a cocaine priming injection (5 mg/kg, i.p.), a microinjection of the D1-like receptor antagonist SCH 23390 (0.01, 0.1 or 1.0 microg/side), or the D1-like receptor agonist SKF 81297 (0.1, 0.3 or 1.0 microg/side) was given into the medial prefrontal cortex. SCH 23390 blocked both stress- and cocaine-induced reinstatement of conditioned place preference after the two higher doses were administered into the medial prefrontal cortex. The highest dose of SKF 81297 (1.0 microg/side) prevented immobilization stress- but not cocaine-induced reinstatement. The highest dose of these drugs given in the absence of stress or cocaine did not produce reinstatement. The results indicate that immobilization stress given within the place-preference chamber is capable of producing reinstatement of cocaine-seeking behavior. The microinjection studies suggest that D1-like receptor antagonism within the prefrontal cortex is sufficient to block reinstatement by stress and cocaine. Furthermore, the results from D1-like receptor activation in the medial prefrontal cortex point to utilization of different neural pathways for stress- and cocaine-induced reinstatement.