奥氮平对谷氨酸功能低下的精神分裂症小鼠模型的作用

Objective To investigate the effects of olanzapine on hyperlocomotion and deficient prepusle inhibition (PPI) of hypoglutamatergic schizophrenia model in mice produced by dizocilpine maleate (MK-801), an N-methyl-D-aspartate (NMDA)antagonist.Methods (1) To investigate the effects of olanzapine on explorative behavior and spontaneous activity, three doses of olanzapine ( 0.1, 0.2, 0.3 mg/kg, i.p.) or vehicle was injected 30 min before the test.Locomotor activity was recorded for 30 min with an automated video tracking system, in which the components of the locomotor activity were divided into exploration (the first 10 min) and spontaneous activity (the second 20 min).(2) To examine the effects of olanzapine on MK-801-induced hyperlocomotion, mice were administered with olanzapine (0.1, 0.2 and 0.3 mg/kg) or vehicle 5 min before administration of MK-801 (0.25 mg/kg).After the second injection, locomotor activity was recorded for 90 min by the video tracking system.( 3 ) To explore the effects of olanzapine on intact and MK-801-disrupted sensorimotor gating, olanzapine (0.3, 1,3 mg/kg, i.p.) or the vehicle were injected 35 min before the start of the experiment, MK-801 (0.5 mg/kg, i.p.) or the same volume of saline was administered 5 min before the PPI experiment.Results ( 1 ) Olanzapine (0.2 and 0.3 mg/kg) significantly inhibited the explorative behavior and spontaneous activity (P ＜ 0.05 ) .Olanzapine at 0.1 mg/kg did not affect exploration ( P = 0.363 ) and spontaneous activity ( P = 0.196 ).Olanzapine (0.1 - 0.3 mg/kg) dose-dependently antagonized MK-801 -induced hyperlocomotion.(2) None of the olanzapine doses tested had a significant effect on baseline PPI.Olanzapine ( 1 - 3 mg/kg) dosedependently restored the MK-801-induced deficits in PPI.Conclusion Olanzapine specifically inhibited the MK-801-induced hyperlocomotion and deficits in PPI in mice and the results are also consistent with clinical findings.     

Dose-dependent and combined effects of N-methyl-D-aspartate receptor antagonist MK-801 and nitric oxide synthase inhibitor nitro-L-arginine on the survival of retinal ganglion cells in adult hamsters

This study investigated the effects of daily intraperitoneal injections of N-methyl-D-aspartate receptor antagonist MK-801 and nitric oxide synthase inhibitor nitro-L-arginine (L-NA) on the survival of retinal ganglion cells (RGCs) at 1 and 2 weeks after unilateral optic nerve transection in adult hamsters. The left optic nerves of all animals were transected intraorbitally 1 mm from the optic disc and RGCs were retrogradely labeled with Fluorogold before they received different daily dosages of single MK-801 or L-NA as well as daily combinational treatments of these two chemicals. All experimental and control animals survived for 1 or 2 weeks after optic nerve transection. Our results revealed that the mean numbers of surviving RGCs increased and then decreased when the dosage of MK-801 (1.0, 3.0 and 4.5 mg/kg) and L-NA (1.5, 3.0, 4.5 and 6.0 mg/kg) increased at both 1 and 2 weeks survival time points. Daily combinational use of 1.0 mg/kg MK-801 and 1.5 mg/kg L-NA lead to a highest RGC number that was even higher than the sum of the RGC numbers in 1.0 mg/kg MK-801 and 1.5 mg/kg L-NA subgroups at 2 weeks. These findings indicated that both MK-801 and L-NA can protect axotomized RGCs in a dose-dependent manner and combinational treatment of these chemicals possesses a potentiative and protective effect.     

Effects of dizocipine maleate on mitochondrial ultramicrostructure in neurons following traumatic brain injury in neonatal rats*★ A quantitative time-course analysis

BACKGROUND： The effects of N-methyl-D-aspartic acid （NMDA） receptor antagonist on neurodegeneration in the immature brain following traumatic brain injury （TBI） are still widely unknown. OBJECTIVE： To study the effects of dizocipine maleate （MK-801）, a non-competitive NMDA receptor antagonist, on mitochondrial ultramicrostructure of neurons in the ipsilateral cingulate cortex and hippocampus after TBI in neonatal rats, and to analyze the optimal time interval of MK-801 administration （1 mg/kg）. DESIGN： Completely randomized controlled study.
SETTING： Shanghai Jiao Tong University.
MATERIALS： Eight 7-day-old neonatal SD rats, irrespective of gender, were provided by Experimental Animal Center, Medical College of Fudan University. The experiment was approved by a local ethics committee. MK-801 was provided by Sigma. A CM-120 transmission electron microscope （Philips, Holland） was used for tissue analysis.
METHODS： This study was performed at the Departments of Anatomy, Neuromorphology, and Biophysics, Medical College of Shanghai, Jiaotong University, between October 2006 and January 2007. Focal models of contusion and laceration of brain were established by the free-falling impact method. Eight rats were randomly divided into a normal control group （n = 2 ） and a MK-801 group （n = 6）. Rats in the normal control group did not receive model establishment and administration, and they were only analyzed by an electron microscope. In the MK-801 group, the cingulate cortex was damaged using a contusion device. MK-801 （1 mg/kg） was intraperitoneally injected 30 minutes before lesion, immediately after lesion, and 30 minutes after lesion （n = 2 for each time point）.
MAIN OUTCOME MEASURES： The cingulate cortex and hippocampal tissues from the injured side were removed 24 hours after lesion and routinely processed for analysis of neuronal ultramicrostructure using transmission electron microscopy. RESULTS： Differential therapeutic effects of MK-801 （1 mg/kg） at d     

A short-chain α-neurotoxin from Naja naja atra produces potent cholinergic-dependent analgesia

Objective To investigate the analgesia induced by cobrotoxin (CT) from venom of Naja naja atra, and the effects of atropine and naloxone on the antinociceptive activity of CT in rodent pain models. Methods CT was administered intraperitoneally (33.3,50,7μg/kg) , intra-cerebral venticularly (2.4μg /kg) or microinjected into periaque-ductal gray (PAG,1.2μg /kg). The antinociceptive action was tested using the hot-plate test and the acetic acid writhing test in mice and rats. The involvement of cholinergic system and the opioid system in CT-induced analgesia was examined by pretreatment of animals with atropine (0.5mg/kg, im or 10mg/kg, ip) or naloxone (3mg/kg,ip) . The effect of CT on motor activity was tested using the Animex test. Results CT (33.3,50 and 75μg/kg,ip) exhibited a dose-dependent analgesic action in mice as determined with hot-plate test and acetic acid writhing test. In the mouse acetic acid writhing test, the intra-cerebral ventricle administration of CT 2.4μg/kg (1/23th of a systemic dose) produced marked analgesic effects. Microinjection of CT 1.2μg/kg (1/46th of systemic dose) into the PAG also elicited a robust analgesic action in the hot-plate test in rats. Atropine at 0.5 mg/kg (im) or naloxone at 3 mg/kg (ip) failed to block the analgesic effects of CT, but atropine at 10 mg/kg (ip) did antagonize the analgesia mediated by CT in the mouse acetic acid writhing test. At the highest effective dose of antinociception (75μg/kg) , CT did not change the spontaneous mobility of mice. Conclusion These results suggest that CT from Naja naja atra venom has analgesic effects. Central nervous system may be involved in CT' analgesic effects and the PAG may be the primary central site where CT exerts its effects. The central cholinergic system but not opioid system appears to be involved in the antinociceptive action of CT.     

A short-chain α-neurotoxin from Naja naja atra produces potent cholinergic-dependent analgesia

Objective To investigate the analgesia induced by cobrotoxin （CT） from venom of Naja naja atra, and the effects of atropine and naloxone on the antinociceptive activity of CT in rodent pain models. Methods CT was administered intraperitoneally （33.3, 50, 75 μg/kg）, intra-cerebral venticularly （2.4 μg/kg） or microinjected into periaqueductal gray （PAG, 1.2 μg/kg）. The antinociceptive action was tested using the hot-plate test and the acetic acid writhing test in mice and rats. The involvement of cholinergic system and the opioid system in CT-induced analgesia was examined by pretreatment of animals with atropine （0.5 mg/kg, im or 10 mg/kg, ip） or naloxone （3 mg/kg, ip）. The effect of CT on motor activity was tested using the Animex test. Results CT （33.3, 50 and 75 μg/kg, ip） exhibited a dosedependent analgesic action in mice as determined with hot-plate test and acetic acid writhing test. In the mouse acetic acid writhing test, the intra-cerebral ventricle administration of CT 2.4 μg/kg （1/23th of a systemic dose） produced marked analgesic effects. Microinjection of CT 1.2 μg/kg （1/46th of systemic dose） into the PAG also elicited a robust analgesic action in the hot-plate test in rats. Atropine at 0.5 mg/kg （ira） or naloxone at 3 mg/kg （ip） failed to block the analgesic effects of CT, but atropine at 10 mg/kg （ip） did antagonize the analgesia mediated by CT in the mouse acetic acid writhing test. At the highest effective dose of antinociception （75 μg/kg）, CT did not change the spontaneous mobility of mice. Conclusion These results suggest that CT from Naja naja atra venom has analgesic effects. Central nervous system may be involved in CT＇ analgesic effects and the PAG may be the primary central site where CT exerts its effects. The central cholinergic system but not opioid system appears to be involved in the antinociceptive action of CT.     

Combined action of MK-801 and ceftriaxone impairs the acquisition and reinstatement of morphine-induced conditioned place preference, and delays morphine extinction in rats

Objective It is well established that glutamate and its receptors, particularly the N-methyl-D-aspartate receptor (NMDAR), play a significant role in addiction and that the inhibition of glutamatergic hyperfunction reduces addictive behaviors in experimental animals. Specifically, NMDAR antagonists such as MK-801, and an inducer of the expression of glutamate transporter subtype-1 (GLT-1) (ceftriaxone) are known to inhibit addictive behavior. The purpose of this study was to determine whether the combined action of a low dose of MK-801 and a low dose of ceftriaxone provides better inhibition of the acquisition, extinction, and reinstatement of morphine-induced conditioned place preference (CPP) than either compound alone. Methods A morphine-paired CPP experiment was used to study the effects of low doses of MK-801, ceftriaxone and a combination of both on reward-related memory (acquisition, extinction, and reinstatement of morphine preference) in rats. Results A low dose of neither MK-801 (0.05 mg/kg, i.p.) nor ceftriaxone (25 mg/kg, i.p.) alone effectively impaired CPP behaviors. However, when applied in combination, they reduced the acquisition of morphine-induced CPP and completely prevented morphine reinstatement. Their combination also notably impaired the extinction of morphine-induced CPP. Conclusion The combined action of a low dose of an NMDAR antagonist (MK-801) and GLT-1 activation by ceftriaxone effectively changed different phases of CPP behavior.     

Stimulation of D2 receptors in the prefrontal cortex reduces PCP-induced hyperactivity,acetylcholine release and dopamine metabolism in the nucleus accumbens

Summary. The aim of the present study was to investigate the effects of stimulation of D2 receptors in the prefrontal cortex (PFC) on spontaneous motor activity and the hyperactivity induced by the psychomimetic phencyclidine (PCP). In addition, the effects of prefrontal D2 stimulation under PCP treatment on dialysate concentrations of acetylcholine, choline, dopamine, DOPAC and HVA in the nucleus accumbens were also investigated. Sprague-Dawley male rats were implanted with guide cannulae to perform bilateral injections into the medial PFC of the D2 agonist quinpirole (1.5 and 5 μg/side). Horizontal and vertical spontaneous motor activity and the motor activity induced by systemic injections of the PCP (5 mg/kg i.p.) were monitored in the open field. PFC injections of quinpirole (1.5 and 5 μg/side) significantly decreased horizontal and vertical spontaneous motor activity in a dose-related manner. These effects were blocked by the D2 antagonist raclopride (5 μg/side). Microinjections of quinpirole (1.5 and 5 μg/side) into the PFC also significantly attenuated the hyperactivity produced by PCP (5 mg/kg i.p.). PCP also increased dialysate concentrations of acetylcholine, and dopamine metabolites in the nucleus accumbens. These increases were also reduced by injections of quinpirole (5 μg/side) into the PFC. These results suggest that the stimulation of prefrontal D2 receptors plays an inhibitory role in regulating spontaneous and PCP-induced motor activity and also in the neurochemical changes produced by PCP in the nucleus accumbens.     

Synergistic effects of ginseng stem and leaf-extracted ginsenoside and choline on improving learning and memory in rats Association verification experiment in animals with multiple learning and memory Disorders

BACKGROUND:Ginsenoside extracted from the stem and leaf of ginseng(GSL)and choline have both been shown to improve learning and memory functions; however,further studies are needed to understand the synergistic effects of a combination of both.OBJECTIVE:To verify the combined improved synergistic effects of GSL and choline on learning and memory disorders in rats.DESIGN:Control observation.SETTING:Taishan Medical College.MATERIALS:A total of 150 male Kunming mice weighing(20±2)g and 40 healthy male Wistar rats weighing(220±20)g were provided by the Experimental Animal Department of Jilin University.Animal experimentation received confirmed consent from the local ethic committee.GSL was provided by the Department of Chemistry,Norman Bethune Medical University,and choline was provided by the Third Experiment Factory,Shanghai.METHODS:This study was performed at the Life Science Institute,Taishan Medical College from October 2006 to February 2007.①Scopolamine-induced learning and memory disorders in rats:Forty rats were randomly divided into control group,model group,combination group(400 mg/kg GSL 200 mg/kg choline),GSL(400 mg/kg)group,and choline(200 mg/kg)group,8 rats/group.Rats were perfused and administrated in the morning,once a day for 14 successive days.Rats in the control group and model group were perfused with 20 mL/kg distilled water and underwent Morris water maze spatial resolution test 1 hour after perfusion on the 10th,11th,and 12th days after administration.Rats also underwent passive step-down avoidance test 1 hour after reperfusion on the 13th and 14th days after administration.Thirty minutes prior to experimentation,rats in the remaining three groups were intraperitoneally(I.p)injected with 2 mg/kg scopolamine,and rats in the control group were I.p.injected with 2 mL/kg saline.②Scopolamine-induced learning disorder and memory acquired disorder in mice:Fifty mice were randomly divided into control group,model group,combination group(400 mg/kg GSL 200 mg/kg choline),GSL(400 mg/kg)group,and choline(200 mg/kg)group,with 10 mice/group.Mice were perfused and administrated in the morning,once a day for 9 successive days.Mice in the control group and model group were perfused with 20 mL/kg distilled water and underwent passive step down avoidance test 1 hour after reperfusion on the 8th and 9th day after administration.Twenty minutes prior to training,mice in the remaining three groups were I.p.injected with 2 mg/kg scopolamine,and mice in the control group were I.p.injected with 10 mL/kg saline.③ Sodium nitrite-induced memory consolidation disorder in mice:Grouping,administration,and testing were the same as mentioned above.After training,mice in the remaining three groups were immediately subcutaneously injected with 120 mg/kg sodium nitrite,and mice in the control group were subcutaneously injected with 20 mL/g saline.④Ethanol-induced memory reconsotidation disorder in ice:Grouping,administration,and testing were the same as mentioned above.At 24 hours after training and 20 minutes before retraining,mice in the remaining four groups were perfused with 10 mL/kg ethanol(0.3 volume fraction),and mice in the control group were perfused with 10 mL/kg saline.MAIN OUTCOME MEASURES:Synergistic effects of GSL and choline on learning and memory deficits induced by scopolamine,sodium nitrite,and ethanol in experimental animals.RESULTS:All 40 rats and 150 mice were included in the final analysis.①Synergistic effects of GSL and choline on learning and memory disorders induced by scopolamine in rats:During passive step-down avoidance and Morris water maze spatial resolution tests,the number of error responses and length of maze training in the model group were significantly greater than in the control group(P＜0.01); while the number of error responses and length of maze training in the combination group were significantly less than in the model group,GSL group,and choline group(P＜0.05-0.01 ).The Q value was＞1 after combining administration,which suggests that the combination of GSL and choline had synergistic effects.② Synergistic effects of GSL and choline on learning disorder and memory-acquired disorder induced by scopolamine in mice:During passive step-down avoidance test,the number of error responses in the model group were significantly greater than in the control group(P＜0.01); while the number of error responses in the combination group were significantly less than in the model group,GSL group,and choline group(P＜0.05-0.01).The Q value was＞1 after combining administration,which suggests GSL and choline had synergistic effects.③Synergistic effects of GSL and choline on memory sodium nitrate-induced consolidation disorder in mice:During passive step down avoidance test,the number of error responses in the model group were significantly less than in the control group(P＜0.01 ); while the number of error responses in the combination group were significantly less than in the model group,GSL group,and choline group(P＜0.05-0.01).The Q value was＞1 after combined administration,which suggests GSL and choline had synergistic effects.④Synergistic effects of GSL and choline on ethanol-induced memory reconsolidation disorder in mice:During passive step down avoidance test,the number of error responses in the model group were significantly greater than in the control group(P＜0.01); while the number of error responses in the combination group were significantly less than in the model group,GSL group,and choline group(P＜0.05-0.01).The Q value was＞1 after combined dministration,which suggests GSL and choline had synergistic effects.CONCLUSION:GSL and choline have synergistic effects on learning and memory functions.     

黄连解毒汤对APP/PS1双转基因阿尔茨海默病模型小鼠脑组织的保护

Huanglian Jiedu decoction(HLJDD) has been shown to improve cerebral blood flow,and reduce lipid peroxidation damage to the brain and its energy metabolism.The present study was designed to observe the cerebroprotective effect of HLJDD on an Alzheimer’s disease rodent model,prese-nilin-1/amyloid protein precursor double transgenic mice.HLJDD reduced serum interleukin-6 and interleukin-1β levels,decreased β-amyloid precursor protein gene and senile plaque expression,resisted oxidation,and reduced free radical-induced injury,thereby improving the learning and memory of these mice.Moreover,HLJDD at 433 mg/kg per day exhibited better effects compared with that at 865 or 216 mg/kg per day,and donepezil hydrochloride at 30 mg/kg per day.Thus,these results suggest that HLJDD may have protective effects against Alzheimer’s disease.