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。     

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.     

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.     

不同剂量博莱霉素致小鼠肺纤维化模型的比较

背景：经气管注射博莱霉素是制作动物肺纤维化模型最常用的方法,但博莱霉素最佳造模剂量目前国内外尚无统一定论。 目的：对比观察不同剂量的博莱霉素对小鼠肺纤维化模型的效果,寻找一种较为合理可靠的小鼠造模剂量。 设计、时间及地点：随机对照动物实验,于2007-09/2008-04在上海市发育生物学重点实验室完成。 材料：SPF级健康雌性C57BL/6J小鼠60只,体质量18~22 g,用于制备小鼠肺纤维化模型。 方法：60只小鼠随机数字表法分为博莱霉素组(n=45)和对照组(n=15),博莱霉素组各选15只动物分别气管内注射不同剂量(2,3.5,5 mg/kg)的博莱霉素,对照组气管内注射相同体积的生理盐水,所有小鼠于造模后第28天处死并取其左肺叶制作病理切片,右肺叶作羟脯氨酸含量测定。 主要观察指标：小鼠28 d 内的存活情况;光镜观察肺部炎症和纤维化程度;取右肺叶做羟脯氨酸测定。 结果：①实验开始后前7 d,博莱霉素组和对照组均无小鼠死亡,第8天博莱霉素组小鼠死亡率高于对照组(P < 0.05);博莱霉素3个剂量组之间死亡率由高到低分别为5,3.5,2 mg/kg 博莱霉素组,但差异无显著性意义(P > 0.05)。②光镜下可见对照组肺泡形态正常,间质中无炎症细胞浸润;博莱霉素组可见肺实变和胶原沉积,剂量越高,肺纤维化程度越重,以5 mg/kg 博莱霉素组最明显。③各组小鼠肺组织中羟脯氨酸含量从高到低依次为5 mg/kg 博莱霉素组、3.5 mg/kg 博莱霉素组、 2 mg/kg 博莱霉素组和对照组。 结论：经气管注射博莱霉素制作小鼠肺纤维化模型应兼顾造模效果和动物的存活率,3.5 mg/kg 是较为理想的小鼠造模剂量。     

壳寡糖及其衍生物对实验性糖尿病大鼠抗氧化能力及肾功能的影响

背景：壳寡糖和N-乙酰氨基单糖是高分子不溶性壳聚糖经水解的产物，具有水溶性。由于分子结构相似，壳寡糖和N-乙酰氨基单糖壳聚糖同样具有抗氧化等功效，同时由于其小分子可溶性和易被人体吸收的特性，在糖尿病及其并发症预防与治疗方面有更广阔的应用前景。 目的：观察不同剂量的壳寡糖，N-乙酰氨基单糖对链脲佐菌素诱导的糖尿病大鼠抗氧化能力的影响及对肾脏的保护作用。 设计、时间及地点：随机对照动物实验，于2008-07/09在中国海洋大学生物化学实验室完成。 材料：壳寡糖，N-乙酰氨基单糖由中国海洋大学生物化学实验室制备。81只Wistar大鼠随机分为9组：正常对照组，阴性对照组，二甲双胍组，壳寡糖和N-乙酰氨基单糖低、中、高剂量组，每组9只。 方法：正常对照组腹腔内注射柠檬酸缓冲液，其余各组按65 mg/kg体质量一次性腹腔内注射链脲佐菌素溶液制备糖尿病大鼠模型。壳寡糖和N-乙酰氨基单糖低、中、高剂量组分别按每日250，500，1 500 mg/kg灌胃壳寡糖和N-乙酰氨基单糖水溶液，正常对照组，阴性对照组按体质量灌胃等体积凉白开水(10 mL/kg)，二甲双胍组按每日200 mg/kg灌胃二甲双胍水溶液，连续60 d。 主要观察指标：①测定血清中谷胱甘肽过氧化物酶、超氧化物歧化酶、丙二醛浓度、总抗氧化能力和肾功能指标。②肾脏病理组织学检查。 结果：壳寡糖，N-乙酰氨基单糖可以增加糖尿病大鼠血清中总抗氧化能力及超氧化物歧化酶浓度，显著降低血清中丙二醛、尿素氮、N-乙酰氨基葡萄糖苷酶及尿液中总蛋白/肌酐、N-乙酰氨基葡萄糖苷酶/肌酐的水平。其中以壳寡糖中剂量组（500 mg/kg）和N-乙酰氨基单糖低剂量组（250 mg/kg）作用效果较好。 结论：适量壳寡糖及N-乙酰氨基单糖能够有效的降低链脲佐菌素诱导的糖尿病大鼠的抗氧化能力，从而对肾脏起到了保护作用。     

NMDAR介导妊娠期慢性应激致子代雄鼠抑郁

目的探讨N-甲基-D-天冬氨酸受体(NMDAR)在妊娠期慢性应激致子代抑郁过程中发生的作用及其机制。方法将40只雌鼠随机分为孕期应激组(CPS)与孕期正常组(CON),待子鼠出生后,取子代雄鼠连续腹腔注射生理盐水或者不同剂量的NMDAR拮抗剂MK-801,观察子代抑郁程度,海马神经元病理变化,海马NMDAR水平及哺乳动物雷帕霉素靶蛋白(mTOR)和磷酸化哺乳动物雷帕霉素靶蛋白(p-mTOR)蛋白含量和信使RNA(m RNA)水平。结果妊娠期慢性应激可致子代抑郁程度增加,海马CA3区损伤的神经元数量增多,海马组织中NMDAR水平升高(P0.05),m TOR和p-m TOR表达量减少(P0.05);NMDAR拮抗剂MK-801不但可以改善妊娠期慢性应激致子代行为学和海马组织病理损伤,且上调海马组织m TOR和p-m TOR的蛋白水平,其中腹腔注射0.1mg·kg-1拮抗剂MK-801剂量组作用较强。结论 NMDAR介导了妊娠期慢性应激致子代抑郁,此作用可能与其抑制m TOR激活,导致子代海马CA3区神经元发生损伤有关。     

粉防已碱对戊四唑致癫大鼠脑透析液中Glu、Asp的影响

目的:探讨钙拮抗剂粉防已碱(Tet)的抗癫痫作用机制。方法:健康SD大鼠随机分为4组:对照组、Tet组3个剂量组(15mg/kg、30mg/kg、60mg/kg)。将大鼠制成微透析模型,并收取其腹腔注射戊四唑(Pentylenetetrazol,PTZ)前后的透析液,采用高效液相色谱和荧光检测相结合的方法测定大鼠海马细胞外谷氨酸(Glu)及天冬氨酸(Asp)的浓度。结果:对照组腹腔注射PTZ后海马细胞外Glu浓度明显升高(p<0.01),Tet三个剂量组腹腔注射PTZ后同对照组比较Glu、Asp浓度明显降低(p<0.01),且似具剂量依赖性。结论:Tet的抗癫痫作用与其降低癫痫大鼠海马细胞外Glu及Asp浓度有关,对Glu的作用更为显著。     

早期激素干预对急性一氧化碳中毒大鼠迟发性脑病的预防作用

目的观察早期激素干预对急性一氧化碳中毒大鼠迟发性脑病（DEACMP）的预防作用。方法将132只雄性Wistar大鼠随机分成3个实验组：CO中毒组（COP组）、CO中毒＋地塞米松10 mg/kg组（DSMS-10组）和CO中毒＋地塞米松30 mg/kg组（DSMS-30组）,每组40只。另设健康对照组（NC组）,12只。实验组按150 ml/kg腹腔内注射CO制备急性一氧化碳中毒动物模型,健康对照组大鼠注射等体积的空气。在中毒后30 min内DSMS-10组腹腔内注射地塞米松剂量为10 mg/kg/d,共7 d;DSMS-30组腹腔内注射地塞米松剂量为30 mg/kg/d,共7 d;NC组和COP组则注射等剂量生理盐水。监测中毒后90 min、7 d、14 d、21 d各组大鼠血清中髓鞘碱性蛋白（MBP）的含量,并在上述各时间点处死大鼠取脑组织,行HE及MBP免疫组化染色。采用Morris水迷宫实验评估动物的智力状态。结果 Morris水迷宫实验结果显示,COP组中有8只大鼠被判定为迟发性脑病;DSMS-10组中有6只被判定为迟发性脑病;而DSMS-30组和对照组未出现迟发性脑病。COP组大鼠血清中MBP含量增高最显著,DSMS-10组也有增高,DSMS-30组接近正常。差异在中毒后90 min、7 d最明显。病理学检查显示COP组中发生迟发性脑病的大鼠在中毒90 min~21 d后脑海马、皮质下出现神经元损伤、髓鞘碱性蛋白脱失等病理改变,上述病理改变在各实验组中均可观察到,但以COP组大鼠病变程度最重,DSMS-30组最轻。结论10 mg/kg地塞米松可降低急性一氧化碳中毒大鼠迟发性脑病的发生率。30 mg/kg地塞米松则可避免迟发性脑病的发生。     

链脲佐菌素剂量对C57BL/6J小鼠糖尿病神经病理性疼痛诱导效应的影响

目的观察不同剂量链脲佐菌素(STZ)对C57BL/6J小鼠糖尿病神经病理性痛诱导效应的影响,探讨其量效关系及最佳剂量。方法雄性C57BL/6J小鼠85只,随机分为正常对照组(n=10)和A～E 5个实验组(n=15,STZ腹腔注射剂量分别为80、100、120、140、160mg/kg),对照组腹腔注射等体积柠檬酸缓冲液。观察各组血糖、机械痛阈值、热刺痛阈值和28d生存率的变化,分析其与STZ剂量的关系。结果 A～E各组糖尿病成模率均>86.7%。C组神经病理性疼痛成模率(66.7%)均高于其余各组;E组28d生存率(46.7%)与A、B组间均存在显著差异(P<0.05)。结论 C57BL/6J小鼠腹腔注射STZ以120mg/kg为最佳剂量。     

尼莫地平对帕金森病模型小鼠黑质iNOS和COX-2表达的抑制作用

目的研究尼莫地平对1-甲基-4-苯基-1、2、3、6四氢吡啶(MPTP)所诱导的帕金森病(PD)模型小鼠黑质多巴胺能神经元的保护作用。方法雄性健康C57BL/6N小鼠随机分为对照组,腹腔注射生理盐水;模型组,腹腔注射MPTP(25 mg/kg);尼莫地平治疗组,每次注射MPTP前3 h灌胃给予尼莫地平(15 mg/kg)。观察各组小鼠行为学变化,免疫组织化学和免疫蛋白印迹法观察中脑黑质酪氨酸羟化酶(TH)、诱导型一氧化氮合酶(induciblenitricoxidesynthase,i NOS)和环氧化酶-2(Cyclooxygenase,COX-2)的表达变化。结果与对照组小鼠比较,MPTP模型组小鼠出现典型的PD症状,中脑黑质TH阳性神经元大量丢失,i NOS和COX-2阳性细胞显著增多,蛋白水平明显升高;经尼莫地平处理后,上述情况得到明显改善。结论在此PD小鼠模型中,尼莫地平通过抑制炎症因子i NOS和COX-2的表达,可对多巴胺能神经元起到一定的保护作用。     

N-Methyl-D-aspartate receptors mediate dopamine-induced changes in extrapyramidal and limbic dynorphin systems.

The N-methyl-D-aspartate (NMDA)-type glutamate receptor was shown to mediate dopamine-induced dynorphin A (Dyn) changes in extrapyramidal and limbic structures. MK801, a potent noncompetitive antagonist of the NMDA receptor, blocked increases in striatal and nigral Dyn content following single and multiple administrations of methamphetamine (METH). Significant attenuation of the METH-induced increases occurred with MK801 doses of 0.1 mg/kg/dose with complete blockade at 2.5 mg/kg/dose. Similar to METH, NMDA itself caused significant increases in striatal and nigral Dyn content. The NMDA-induced increase in striatal Dyn content was blocked by coadministration of an intermediate dose of MK801. The Dyn system associated with the nucleus accumbens responded in a similar manner in that MK801 totally blocked the METH-induced increases; moreover, NMDA elevated the Dyn content in this structure. The inability of MK801 to alter the quinpirole-induced decrease in striatal Dyn content suggests that the NMDA receptor is not involved in the D2 receptor regulation of striatal Dyn systems.     

Effects of NMDA glutamate receptor antagonist drugs on the volitional consumption of ethanol by a genetic drinking rat

The ability of drugs that reduce NMDA receptor activity on the volitional consumption of ethanol in the genetic drinking rat, mHEP line, was investigated. After the consumption of ethanol solutions and water by each male or female mHEP rat had stabilized on its preferred concentration, different doses of LY 274614, a competitive NMDA antagonist, MK 801, a non-competitive NMDA antagonist, (+)-HA-966 or ACPC (1-aminocyclopropane-1-carboxylic acid), antagonists of the glycine site were administered daily for three days. The dose of 3.0 mg/kg i.p. LY 274614 reduced the consumption of ethanol by 64% compared to the pre-treatment baseline, while 0.3 mg/kg of MK 801 reduced consumption by 44%, 20 mg/kg (+)-HA-966 reduced consumption by 47% and 300 mg/kg of ACPC reduced consumption by 30%. These doses of LY 274614 and MK 801 reduced the ability of Sprague-Dawley rats to walk on a rotorod. Effects of these drugs on food intake were small except for the 20 mg/kg dose of (+)-HA-966. Therefore, the drugs did not have an anti-caloric effect and manipulations of the glutamatergic system through NMDA receptors may modify the consumption of ethanol. This interaction should be explored further for its therapeutic potential and to better understand the control by central neuronal systems of the consumption of ethanol.     

地卓西平马来酸盐动物行为模型研究

目的 制作灵长类动物从氨酸Ｎ－甲基－天冬氨酸受体非竞争性拮抗剂地产马来酸盐（ＭＫ－８０１）功能低下行为模型：研究奥氮平治疗谷氨酸功能低下的疗效。方法：给Ｃｅｂｕｓ Ａｐｅｌｌａ猴皮下注射ＭＫ－８０１（０．０６ｍｇ／ｋｇ,０．０８ｍｇ／ｋｇ,０．１０ｍｇ／ｋｇ）或／和奥氮平（０．０２ｍｇ／ｋｇ,０．０４ｍｇ／ｋｇ,０．０８ｍｇ／ｋｇ）,用自编７分量表评定药物所致动物的行为变化。结果 注射药物３ｈ内动     

Effects of antipsychotic treatments and D-serine supplementation on the electrophysiological activation of midbrain dopamine neurons induced by the noncompetitive NMDA antagonist MK 801

The acute administration of the noncompetitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK 801) is known to increase central dopaminergic activity in rats and to elicit schizophreniform behavior in human. The current study was undertaken to compare the effects of different acute or chronic neuroleptic treatments, on the response of ventral tegmental area dopamine (DA) neurons to MK 801, using the in vivo electrophysiological paradigm in anesthetized preparations. Sprague Dawley male rats were treated, acutely or chronically during 3 weeks, with saline, olanzapine (10 mg/kg), haloperidol (1 mg/kg) or the combination of haloperidol with D-serine (1 mg/kg/300 mg/kg), a gliotransmitter coagonist of the NMDA receptor that has been shown to improve the efficacy of typical neuroleptics. In control animals, the acute administration of MK 801 (0.5 mg/kg, i.v.) increased significantly both the firing and burst activity of DA neurons by 20 and 26%, respectively, the latter effect being partially reversed by the selective 5-HT2A antagonist M 100,907 (0.4 mg/kg, i.v.). The acute preadministration of haloperidol (1 mg/kg, i.p.) and olanzapine (10 mg/kg, i.p.) failed to prevent or reverse the activatory effect of MK 801 on firing activity. On the other hand, MK 801-induced burst activity, was partially prevented by olanzapine, but not by haloperidol pretreatment. All antipsychotic treatments, when administered chronically, prevent the activatory effect of MK 801 on both firing and burst activity, and occasionally convert the response to MK 801 on burst activity to an inhibitory response, the latter occurring more predominantly in rats treated with the combination haloperidol/D-serine. These results suggest that a chronic antipsychotic regime alters the function of the NMDA receptors that tonically control the firing activity of midbrain dopaminergic neurons.     

Motor responses to dopamine D1 and D2 agonists in the reserpine-treated mouse are affected differentially by the NMDA receptor antagonist MK 801

Summary The akinesia induced by reserpine in mice was effectively reversed by the dopamine D₁ receptor agonists SKF 38393 (5–30 mg/kg IP) and CY 208-243 (1–5 mg/kg IP), and by the mixed D₁/D₂ agonist pergolide (5 mg/kg SC), but less well by the D₂ agonists lisuride, PHNO, LY 171555 and RU 24213 (each at 5 mg/kg SC) and not at all by the NMDA receptor antagonist MK 801 (0.1–10 mg/kg IP). MK 801 potentiated D₁-dependent locomotion, but always suppressed rearing and grooming. D₂-dependent locomotion was inhibited by MK 801. The D₂ agonist RU 24213 was antagonised by as little as 6.25 g/kg MK 801, while PHNO and LY 171555 were antagonised by 0.1 mg/kg MK 801. Lisuride was not inhibited by up to 1.6 mg/kg MK 801.Importantly, all animals showed signs of incapacitation with MK 801 in certain elements of their behaviour, most notably ataxia and hind limb abduction. Thus whilst NMDA receptor blockade can facilitate the restoration of movement by dopamine D₁ (though not D₂) agonists in monoamine-depleted mice, the fluency of the motor response is adversely affected.     

Locomotor effects of amantadine in the mouse are not those of a typical glutamate antagonist

Summary Amantadine has been shown to displace [³H]MK 801 from its binding site on the NMDA receptor. We have therefore studied the motor effects of amantadine in normal and 24h reserpine-treated mice to determine whether the behavioural profile of this drug resembles that of other NMDA receptor antagonists (e.g. MK 801). In common with the latter, amantadine (5–40 mg/kg IP) produced a modest dose-dependent sedation in dopamineintact mice, with a reduction in locomotion and other species-typical behaviours (e.g. rearing and grooming), but with no signs of the hyperactivity, stereotypy, ataxia or loss of muscle tone commonly seen with MK 801. Amantadine (5–80 mg/kg IP) effected a small incrase in motility in akinetic reserpine-treated mice by itself, but this response was highly variable and not statistically significant. As with MK 801, amantadine significantly inhibited the locomotion induced by the selective D₂ agonist RU 24213 (5 mg/kg SC) and the mixed D₁/D₂ agonist apomorphine (0.5 mg/kg SC) in monominedepleted mice, without altering the animals' responsiveness to threshold doses of these drugs. However, amantadine did not facilitate the locomotion induced by threshold (3 mg/kg IP) or fully active doses (30 mg/kg IP) of the selective D₁ agonist SKF 38393, which distinguishes amantadine from other NMDA receptor blockers. Since the potentiation of dopamine D₁-dependent locomotion may be a major factor in the antiparkinson activity of MK 801 and other glutamate receptor antagonists the inability of amantadine to potentiate SKF 38393 in this study suggests the mechanism of its anti-akinetic activity differs, from that of conventional glutamate blocking drugs.     

Fluoxetine prevents PCP- and MK801-induced HSP70 expression in injured limbic cortical neurons of rats.

BACKGROUND: N-Methyl-D-aspartate (NMDA) receptor antagonists, including phencyclidine (PCP) and dizocilpine (MK801), cause schizophrenialike psychosis in humans, and produce vacuolated neurons in the cingulate and retrosplenial cortices of the rat brain. Since psychotically depressed patients and schizophrenic depressed patients may require treatment with selective serotonin reuptake inhibitors (SSRIs), it is of interest to examine the relationship between SSRIs and NMDA antagonist neurotoxicity. METHODS: The neurotoxicity of PCP and MK801 was assessed using heat shock protein (HSP70) immunocytochemistry and HSP70 Western blots because HSP70 is expressed in the injured, vacuolated neurons. Female rats were given fluoxetine (0, 5, 10, and 20 mg/kg IP) followed 1 hour later by MK801 (1 mg/kg IP) or PCP (50 mg/kg IP). RESULTS: Pretreatment with fluoxetine (20 mg/kg IP) 1 hour before MK801 prevented the induction of HSP70 by MK801 in the cingulate and retrosplenial cortices. Pretreatment with fluoxetine (10 or 20 mg/kg IP) 1 hour before PCP also prevented the HSP70 induction by PCP. CONCLUSIONS: Fluoxetine prevents the neurotoxicity of NMDA receptor antagonists in rat brain. This suggests the possibility that SSRIs could modulate psychosis, and may provide a model for examining the link between the hallucinogenic properties of PCP and lysergic acid diethylamide.     

Effect of an NMDA receptor antagonist on the wind-up of neurons in the trigeminal oralis subnucleus

Extracellular recordings of convergent neurons of the oralis subnucleus of the trigeminal sensory complex were performed in paralysed rats under halothaneN₂OO₂ anesthesia using glass micropipettes. The effects of MK801, a noncompetitive NMDA receptor antagonist, were observed on the increased cell activity (wind-up), triggered by the repetition, at a low frequency (0.66 Hz) and high intensity (3 times the threshold of C-fiber response), of electrical stimulation of the receptive field. Successive cumulative doses (up to 1 mg/kg) of MK801 i.v. resulted in a dose-dependent decrease in the responses related to C-fiber input (11 cells). A single dose of 1 mg/kg applied in four cells had effects similar to the 1 mg/kg dose given cumulatively. Three units were either weakly or not modified by MK801. In a second experiment, recordings were performed in 12 cells for 80 min after an injection of a small dose of MK801 (0.15 mg/kg). C input was not significantly modified by the antagonist. The effects of MK801 on the first part of the wind-up response (wind-up proper) peaked between 15 and 50 min and returned to control values at about 80 min. The effects on the postdischarge followed approximately the same time course. It is concluded that despite being devoid of substantia gelatinosa, the oralis subnucleus contains neurons that display an NMDA receptor-linked wind-up similar to the phenomenon described in the dorsal horn of the spinal cord.     

Comparative effects of N and MK-801 on the abstinence syndrome in morphine-dependent mice

The effects of N^{G-monomethyl-l-arginine} (l-NMMA), an inhibitor of nitric oxide (NO) synthase and MK-801, an NMDA receptor antagonist on abrupt and naltrexone-precipitated abstinence symptoms were determined in male Swiss-Webster mice rendered dependent on morphine by subcutaneous implantation of a pellet containing 75 mg of morphine base for 3 days. Mice which served as controls were implanted with placebo pellets. Six hours after pellet removal, mice were injected intraperitoneally with either the vehicle or MK-801 (0.03, 0.1 and 0.3 mg/kg). Thirty minutes later the animals were injected with naltrexone subcutaneously (50 μg/kg) and the intensity of abstinence symptoms were determined. Of the three doses of MK-801 used, only 0.1 mg/kg dose inhibited the jumping behavior precipitated by naltrexone in morphine-dependent mice. Whereas the lower dose (0.03 mg/kg) of MK-801 increased, the higher doses of MK-801 (0.1 and 0.3 mg/kg) displayed a decrease in the formation of fecal boli. Administration of MK-801 did not affect the body weight loss observed during abrupt withdrawal (induced by removal of the pellets) in morphine-dependent mice. MK-801 at 0.1 mg/kg dose further decreased the body temperature during abrupt withdrawal in morphine-dependent mice. Other two doses of MK-801 (0.03 and 0.3 mg/kg) did not modify the hypothermia observed during abrupt morphine withdrawal. On the other hand, l-NMMA (0.02 to 4.0 mg/kg) injected intraperitoneally 15 min prior to the naltrexone administration blocked the stereotyped jumping response in a dose-dependent manner. Higher doses of l-NMMA 2.0 and 4.0 mg/kg also decreased the number of fecal boli formation. l-NMMA (0.2 to 4.0 mg/kg) also significantly reduced the abrupt withdrawal-induced body weight loss in morphine-dependent mice. Thus MK-801 has very little effect, which is not dose-dependent, on abrupt and antagonist-precipitated withdrawal in morphine-dependent mice. However, the l-NMMA has more profound dose-dependent effects on both the abrupt and antagonist-precipitated withdrawal in morphine-dependent mice. It is concluded that the inhibitors of NO synthase may be more beneficial than NMDA receptor antagonists in managing the symptoms of morphine abstinence syndrome.     

Involvement of NMDA receptor mechanisms in the modulation of serotonin release in the lateral parabrachial nucleus in the rat

Microdialysis was employed to investigate whether N-methyl-d-asparatate (NMDA) glutamate receptor mechanisms are involved in the modulation of serotonin (5-hydoxytryptamine, 5-HT) release in the region of the lateral parabrachial nucleus (LPBN) in freely moving rats. Perfusion of NMDA (10 and 50 microM) through the microdialysis probe significantly enhanced extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the LPBN area. Local perfusion of the NMDA antagonist dizocilpine (MK801, 10 and 50 microM) did not change the basal 5-HT and 5-HIAA levels in the LPBN area. MK801 (10 microM) administered together with NMDA antagonized the stimulant effect of NMDA (10 microM). The intake of 0.3M NaCl and water induced by subcutaneous injections of the diuretic furosemide (FURO, 10 mg/kg) and the angiotensin converting enzyme inhibitor captopril (CAP, 5 mg/kg) produced significant increases in the 5-HT and 5-HIAA concentrations in the LPBN area. The increased levels of 5-HT and 5-HIAA caused by the combined treatment with FURO and CAP were attenuated by perfusion of MK801 (10 microM). These results indicate the participation of NMDA receptors in the control of 5-HT release in the LPBN area.