AIMTo investigate the possible involvement of glutamate(Glu) in the paraventricular nucleus (PVN) in the central regulation of baroreflex.

METHODSThe baroreflex was induced by intravenous injection of phenylephrine in conscious rats, and the extracellular concentration of Glu in the PVN region was measured by microdialysis and high performance liquid chromatography (HPLC) techniques. To determine whether the observed Glu release was involved in the baroreflex, NMDA and non-NMDA receptor antagonists, MK-801 and CNQX, were perfused in the PVN region during baroreflex.

RESULTSDuring baroreflex, the Glu concentration in the PVN region immediately increased to 384.82% +/- 91.77% of basal level (P < 0.01). (2) During baroreflex, direct perfusion of MK-801 and CNQX in the PVN were attenuated the increase of blood pressure and enhanced the decrease of HR (P < 0.01),resulting a significant increase in baroreflex sensitivity (P < 0.01).

CONCLUSIONGlutamate in PVN is involved in central regulation of baroreflex, which may inhibit baroreflex via ionothopic glutamate receptors.

6-Cyano-7-nitroquinoxaline-2,3-dione ; pharmacology ; Animals ; Baroreflex ; drug effects ; physiology ; Dizocilpine Maleate ; pharmacology ; Excitatory Amino Acid Antagonists ; pharmacology ; Male ; Paraventricular Hypothalamic Nucleus ; physiology ; Rats ; Rats, Wistar

To explore the facilitation of nociceptive response by dynorphin (Dyn ) A in a model of formalin test in rats, the effects of single intrathecal injection (i.t.) of normal saline (NS), MK-801 (antagonist of NMDA receptor), naloxone (antagonist of opioid receptor), or Dyn A (1-17) were observed, and the effects of i.t. MK-801 or naloxone followed by i.t. Dyn A (1-17) were observed as well. The nociceptive licking and biting induced by injection of formalin exhibited two phases. The first phase lasted for a relatively short period of 3-9 min, and the second phase lasted for a relatively longer period after a 3 to 6- min quietness. The results showed that there were no differences in the first phase in all groups; however, there were differences in the second phase as follows: (1) the duration of nociceptive response was significantly increased in Dyn A (1-17) group (489.5+/-22.5 s) as compared to that of NS group (344.7+/-12.9 s), MK-801 group (331.4+/-20.7 s) or naloxone group (352.5+/-18.4 s) (P<0.01 in three cases); (2) the duration of nociceptive response was significantly shortened in MK-801 plus Dyn A (1-17) group (285.7+/-19.4 s) as compared to that of Dyn A (1-17) group (P<0.01), but there were no significant differences as compared to that of MK-801 group; and (3) there was no significant difference in the second phase between naloxone plus Dyn A (1-17) group (473.8+/-17.8 s) and Dyn A (1-17) group, but the duration of nociceptive response was longer than that of NS group or naloxone group (P<0.01 in both). The results obtained suggest: (1) at the spinal cord, Dyn A (1-17) facilitates nociceptive responses; (2) NMDA receptors, but not opioid receptors, are possibly involved in the nociception by Dyn A (1-17).
Animals ; Dizocilpine Maleate ; pharmacology ; Dynorphins ; pharmacology ; Formaldehyde ; Injections, Spinal ; Naloxone ; pharmacology ; Nociceptors ; physiology ; Pain ; chemically induced ; physiopathology ; Rats ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; physiology

OBJECTIVETo establish an effective model for evaluating the spatial memory of rats.

METHODSThe adjacent left or right arm in Y-maze was defined as an initial arm or an objective one alternatively, and electro-stimulus to vola was used as a reinforcement. Meanwhile, the reliability of the model was validated by measuring the memory deficits induced by intraperitoneal (i.p.) injection of scopolamine (0.5 mg/kg) or bilaterally intrahippocampal (i.h.) microinjection of MK-801(0.2 microg/site).

RESULTSThe normal, sham-operated or saline-treated rats learned the left-right alternative memory model rapidly while injection of either scopolamine or MK-801 caused spatial memory deficits in Y-maze, including deficits in working and reference memory. Moreover,there was no appreciable difference in electricity intensity between the treated group and the control group.

CONCLUSIONThe alternative Y-maze with electro-stimulus is a comparatively objective model which can evaluate the spatial memory in rats effectively.T

Animals ; Dizocilpine Maleate ; pharmacology ; Electric Stimulation ; Male ; Maze Learning ; drug effects ; Memory ; drug effects ; Rats ; Rats, Sprague-Dawley ; Scopolamine Hydrobromide ; pharmacology

BACKGROUND: It is emphasized that repetitive stimulation of small diameter afferent fibers produces a progressive increase in the action potential discharge and a prolonged increase in the excitability of neurons in the spinal cord following the stimulus and that this facilitatory component has a unique pharmacology. To investigate the behavioral parallels of this spinal facilitation, we evalusted the antinociceptive effects of intrathecal morphine, N-methyl-D-aspartate(NMDA), (+)-5-methyl-10,11- dihydro-5H-dibizo(a,d) cycloheptene-5, 10-imine hydrogen maleate(MK801) and (+/-)-3-(2-carboxy- piperazine-4-yl)-propyl-I-phosphonic acid(CPP), on the formalin test in rats. METHODS: Four to six days after chronic lumbar intrathecal catheterization, normal saline, morphine(0.1 to 30 ug), MK801(0.1 to 10 ug), CPP(0.1 to 5 ug) or NMDA(10 or 100 ng) were administered intrathecally before formalin injection. Spontanesous flinches were observed at 1-2 and 5-6 min(phase 1) and at 10 min intervals thereafter for 50 min(phase 2) after subcutaneous formalin injection into the dorsum of the right hind paw for each drug treated rats. RESULTS: Intrathecal morphine produced dose dependent inhibition of the phase 1 and phase 2 response(ED50=0.63 ug and 0.37 ug, respectively). Intrathecal MK801(0.1 to 10 ug) and CPP(0.1 to 5 ug) inhibited the phase 2 response more strongly than phase 1 response and inhibition of the phase 2 response(P<0.05 at any dose) was dose dependent(ED50=0.54 ug for MK801 and 0.15 ug for CPP). 1ntrathecal NMDA(10 or 100 ng) produced augmented responses in the intermediate and phase 2(P<0.05), but had no effect on the phase 1 response(P>0.7). Relative potencies of MK801 and CPP when compared with morphine were 1.34 and 0.41, respectively. CONCLUSIONS: This study suggests that intrathecal morphine and NMDA receptor antagonist(MK801 and CPP) have an antinociceptive effect on pathological pain mediated by central sensitization and that NMDA receptor antagonists can be utilized selectively in the treatment of components of central sensitization.
Action Potentials ; Analgesics ; Animals ; Catheterization ; Catheters ; Central Nervous System Sensitization ; Dizocilpine Maleate* ; Formaldehyde* ; Hydrogen ; Morphine* ; N-Methylaspartate* ; Narcotics ; Neurons ; Pain Measurement* ; Pharmacology ; Rats* ; Spinal Cord

OBJECTIVETo study the involvement of excitatory amino acid system in astrocytes activation caused by dimethoate.

METHODSPure-cultured astrocytes were gained by three passages from primary cultured rat nerve cells, then treated with 10(-6),10(-5),10(-4) mol/L dimethoate for 48 h, 50 micromol/L and 100 micromol/L MK801, a NMDA receptor blocker, was used to intervene the effects induced by 10(-4) mol/L dimethoate. HPLC-FLD was utilized to measure the concentrations of excitatory amino acid (EAA), RT-PCR was used to detect the expression levels of NR2B, GLT-1, GLAST, GFAP and S100beta mRNA, and immunofluorescence staining method was applied to measure the expression levels of GFAP and S100beta proteins.

RESULTSThe expression levels of GLAST mRNA in all exposure groups were 67.8%, 68.6% and 76.2% of control level, respectively, which were significantly lower than that of control group (P < 0.05); The concentrations of EAA significantly decreased in 10(-4) mol/L dimethoate group, as compared with control group (P < 0.01); the expression levels of GFAP mRNA in 10(-4) mol/L dimethoate group, of S100beta mRNA in 10(-5) mol/L dimethoate group, of GFAP protein in 10(-4) mol/L and 10(-5) mol/L dimethoate groups and S100beta protein in 10(-4) mol/L dimethoate group were significantly higher than those in control group (P < 0.01). The expression levels of GLT-1 and GLAST mRNA in 10(-4) mol/L dimethoate plus 50 micromol/L or 100 micromol/L MK801 groups increased significantly, as compared with 10(-4) mol/L dimethoate group (P < 0.01), the expression levels of NR2B mRNA in 10(-4) mol/L dimethoate plus 50 micromol/L or 100 micromol/L MK801 groups increased significantly, as compared with control group (P < 0.05 or P < 0.01); the concentration of Glu in 10(-4) mol/L dimethoate plus 100 micromol/L MK801 group increased significantly, as compared with 10(-4) mol/L dimethoate group (P < 0.01); the expression levels of GFAP mRNA and protein in 10(-4) mol/L dimethoate plus 50 micromol/L or 100 micromol/L MK801 groups decreased significantly (P < 0.01); S100beta protein expression level in 50 micromol/L MK801 intervention group was significantly higher than thatl in control group (P < 0.01).

CONCLUSIONExcitatory amino acid system involved in astrocytes activation caused by dimethoate. MK801 was useful to control astrocytes gliosis.

Animals ; Astrocytes ; drug effects ; metabolism ; Cells, Cultured ; Dimethoate ; toxicity ; Dizocilpine Maleate ; pharmacology ; Excitatory Amino Acids ; metabolism ; Rats ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors

OBJECTIVETo study changes in the expression levels of parvalbumin (PV), glutamate decarboxylase 67 (GAD67) and K+-Cl- cotransporter 2 (KCC2) in the brain tissue of rats with schizophrenia (SZ) induced by dizocilpine (MK-801), and to investigate the mechanism involving gamma-aminobutyric acid (GABA) by which NMDA receptor blocker induces SZ in the perinatal period.

METHODSThirty-six neonatal male Sprague-Dawley rats were randomly assigned to two batches on postnatal day 6. Each batch was divided into normal control (treated by 0.9% normal saline), SZ-development model (treated by subcutaneous injection of 0.1 mg/kg MK-801 on postnatal days 7-10; bid), and SZ-chronic medication model groups (treated by intraperitoneal injection of 0.2 mg/kg MK-801 on postnatal days 47-60; qd). On postnatal day 63, the brain tissue of the first batch of rats was obtained and then fixed with paraform for histological sections; expression levels of PV and GAD67 in the medial prefrontal cortex (mPFC) and hippocampus CA1 were measured by immunohistochemistry. Simultaneously, the second batch of rats was sacrificed and the mPFC and hippocampus were obtained and homogenized; expression levels of KCC2 in the mPFC and hippocampus were measured by Western blot.

RESULTSExpression levels of PV and GAD67 in the mPFC and hippocampus CA1 were significantly lower in the SZ-development and chronic medication model groups than in the normal control group (P<0.05). Expression levels of KCC2 in the mPFC and hippocampus were significantly lower in the SZ-development model group than in the SZ-chronic medication model and normal control groups (P<0.05).

CONCLUSIONSThe expression changes of PV and GAD67 in SZ can be simulated using the SZ development model induced by MK-801, which might affect the development of the GABA system in the PFC and hippocampus by downregulating KCC2 expression.

Animals ; CA1 Region, Hippocampal ; chemistry ; Dizocilpine Maleate ; pharmacology ; Glutamate Decarboxylase ; analysis ; Immunohistochemistry ; Male ; Parvalbumins ; analysis ; Prefrontal Cortex ; chemistry ; Rats ; Rats, Sprague-Dawley ; Schizophrenia ; etiology ; metabolism ; Symporters ; analysis

The purpose of this study was to investigate the expression of c-fos in the spinal cord during the development of allodynia, induced by peripheral nerve injury. Following tight ligation of the left L5 and L6 spinal nerves of Sprague- Dawley rat, the lumbar spinal cord was postfixed following perfusion. Frontal frozen sections of 40nm were immunostained according to the peroxidase-antiperoxidase method. The allodynic threshold was checked with 8 calibrated von Frey filaments. MK-801 (0.3 mg/kg), morphine (3 mg/kg) and saline (as a placebo) were administered subcutaneously 30 min before, and 24 and 48 hrs after surgery. The tactile threshold decreased below 3 g since 2 days after surgery in the saline and morphine groups, but delayed a little in the MK-801 group. In the superficial layer the number of Fos-like immunoreactive neurones (Fos-LI) peaked at 2 hours and decreased thereafter, and reached normal levels 24 hrs following operation, for all groups. In the deep layer they were biphasic, - peaking at 2 and 24 hrs - in the saline group, but were suppressed in the morphine and MK-801 groups until 7 days following operation. The above discrepancy between the number of Fos-LI and the allodynic threshold showed that central sensitizations are not critically involved in the development of nerve injury induced tactile allodynia.
Analgesics, Opioid/*pharmacology ; Animal ; Dizocilpine Maleate/*pharmacology ; Excitatory Amino Acid Antagonists/*pharmacology ; Hyperesthesia/etiology/*metabolism ; Ligation ; Male ; Morphine/*pharmacology ; Proto-Oncogene Proteins c-fos/*metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*metabolism ; Spinal Nerves/injuries ; Wounds and Injuries/complications

AIMTo evaluate the effects of melatonin on antioxidant enzyme levels and histopathologic changes in dizocilpine (MK-801)-induced psychosis model rat testis.

METHODSA total of 24 adult male Wistar-Albino rats were divided into three groups with 8 in each. Group I was used as control. Rats in Group II were injected with MK-801 (0.5 mg/kg body weight i.p. for 5 days). In addition to MK-801, melatonin (50 mg/kg body weight i.p. once a day for 5 days) was injected into the rats in Group III. The testes were harvested bilaterally for biochemical and histopathological examinations. Antioxidant enzyme activities, malondialdehyde, protein carbonyl and nitric oxide (NO) levels in testicular tissues were analyzed using spectrophotometric analysis methods. Histopathological examinations of the testes were also performed.

RESULTSMK-801 induced testicular damage, which resulted in significant oxidative stress (OS) by increasing the levels of antioxidant enzymes. The malondialdehyde, protein carbonyl and NO levels were increased in testicular tissues of rats. Treatment with melatonin led to significant decrease in oxidative injury. Administration of melatonin also reduced the detrimental histopathologic effects caused by MK-801.

CONCLUSIONThe results of the present study showed that MK-801 cause OS in testicular tissues of rats and treatment with melatonin can reduce the harmful effects of MK-801.

Animals ; Antioxidants ; pharmacology ; Disease Models, Animal ; Dizocilpine Maleate ; adverse effects ; pharmacology ; Male ; Malondialdehyde ; Melatonin ; pharmacology ; Mental Disorders ; chemically induced ; Nitric Oxide ; Oxidative Stress ; drug effects ; Protein Carbonylation ; Psychotropic Drugs ; adverse effects ; pharmacology ; Rats ; Rats, Wistar ; Testis ; drug effects ; enzymology ; pathology

Schizophrenia is one of the common mental diseases. Because the mechanism of the schizophrenia is significantly complicated, the cause is still unknown. N-methyl-D-aspartate receptor antagonist can simulate the positive and negative symptoms, as well as the cognitive disorder of schizophrenia. Thus it has been widely used to establish the animal models of schizophrenia. The relationship of the three blocking agents of ion channels (phencyclidine, MK-801, ketamine) and the establishment of schizophrenia animal models is reviewed in this article.
Animals ; Behavior, Animal/drug effects* ; Brain/physiopathology* ; Consciousness Disorders/physiopathology* ; Disease Models, Animal ; Dizocilpine Maleate/pharmacology* ; Excitatory Amino Acid Antagonists/pharmacology* ; Humans ; Ketamine/pharmacology* ; Mice ; Phencyclidine/pharmacology* ; Rats ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; Schizophrenia/physiopathology*

AIMTo investigate protective effects of ginkgolide B (GB) in different administration modes on glutamate-induced neuronal damage.

METHODSEssential GB were obtained by supercritical CO2 fluid extraction. Glutamate excitotoxicity were examined in primary cultures from neonatal Wistar rat, by using of Trypan blue dye staining, testing the lactate dehydrogenase leakage from cultured neurons and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) method. The protective effects of GB in different administration modes (pre-treatment and post-treatment) were adopted and compared with the NMDA receptor uncompetitive antagonist-MK-801 in acute-treatment.

RESULTSTreatment with GB in two administration modes both could increase ratio of surviving neuron, decrease LDH efflux and reduce ratio of neuron apoptosis in different degree, depended on dose in certain range. The protective effect of pre-treatment was superior to post-treatment, but inferior to MK-801.

CONCLUSIONGB can protect neurons against glutamate damage, and preventive using has more efficiency. The potential mechanism of its neural protection may be not only related to PAF receptor. If the predominant protection effect of GB in pretreatment is considered, precautionary intervention to high-risk population could have more value.

Animals ; Cells, Cultured ; Dizocilpine Maleate ; pharmacology ; Ginkgolides ; administration & dosage ; pharmacology ; Glutamic Acid ; adverse effects ; Hippocampus ; drug effects ; metabolism ; Lactones ; administration & dosage ; pharmacology ; Neurons ; drug effects ; metabolism ; Rats ; Rats, Wistar