Several decades of research attempting to explain schizophrenia regarding dopamine hyperactivity hypothesis have produced disappointing results. New hypotheses focusing on serotonin-dopamine interactions and hypofunction of the NMDA glutamate transmitter system have been emerging as potentially more promising concepts. The next generation of treatments for schizophrenia, whether they are based on dopamine, serotonin, or glutamate etc., should be effective on negative symptoms and cognitive deficits as well as positive symptoms. In this article, I review the brief overview of these hypotheses and new drugs based on the hypotheses.
Dopamine ; Glutamic Acid* ; N-Methylaspartate ; Receptors, Glutamate* ; Schizophrenia ; Serotonin

Metabotropic glutamate receptors (mGluRs), classified into three groups (group I, II, III), play a critical role in modulation of synaptic transmission at central and peripheral synapses. In the present study, extracellular field potential recording techniques were used to investigate effects of mGluR agonists on excitatory synaptic transmission at thalamic input synapses onto the lateral amygdala. The non-selective mGluR agonist t-ACPD (100 microM) produced reversible, short-term depression, but the group III mGluR agonist L-AP4 (50 microM) did not have any significant effects on amygdala synaptic transmission, suggesting that group I and/or II mGluRs are involved in the modulation by t-ACPD. The group I mGluR agonist DHPG (100 microM) produced reversible inhibition as did t-ACPD. Unexpectedly, the group II mGluR agonist LCCG-1 (10 microM) induced long-term as well as short-term depression. Thus, our data suggest that activation of group I or II mGluRs produces short-term, reversible depression of excitatory synaptic transmission at thalamic input synapses onto the lateral amygdala. Considering the long-term effect upon activation of group II mGluRs, lack of long-term effects upon activation of group I and II mGluRs may indicate a possible cross-talk among different groups of mGluRs.
Amygdala* ; Depression ; Receptors, Metabotropic Glutamate* ; Synapses ; Synaptic Transmission*

Disease Progression ; Humans ; Neoplasms ; diagnosis ; metabolism ; Receptors, Metabotropic Glutamate ; metabolism

Intraplantar injection of melittin has been known to induce sustained decrease of mechanical threshold and increase of spontaneous flinchings. The present study was undertaken to investigate how the melittin-induced nociceptive responses were modulated by changes of metabotropic glutamate receptor (mGluR) activity. Changes in paw withdrawal threshold (PWT), number of flinchings and paw thickness were measured at a given time point after injection of melittin (10microgram/paw) into the mid-plantar area of rat hindpaw. To observe the effects of mGluRs on the melittin-induced nociceptions, group I mGluR (AIDA, 100microgram and 200microgram), mGluR1 (LY367385, 50microgram and 100microgram) and mGluR5 (MPEP, 200microgram and 300microgram) antagonists, group II (APDC, 100microgram and 200microgram) and III (L-SOP, 100microgram and 200microgram) agonists were intrathecally administered 20 min before melittin injection. Intraplantar injection of melittin induced a sustained decrease of mechanical threshold, spontaneous flinchings and edema. The effects of melittin to reduce mechanical threshold and to induce spontaneous flinchings were significantly suppressed following intrathecal pre-administration of group I mGluR, mGluR1 and mGluR5 antagonists, group II and III mGluR agonists. Group I mGluR antagonists and group II and III mGluR agonists had no significant effect on melittin-induced edema. These experimental findings indicate that multiple spinal mGluRs are involved in the modulation of melittin-induced nociceptive responses.
Animals ; Edema ; Melitten ; Nociception ; Rats ; Receptors, Metabotropic Glutamate

It is imperative to analyse brain injuries directly in real time, so as to find effective therapeutic compounds to protect brain injuries by stress. We established a system which could elucidate the real time Ca2+ dynamics in an organotypic cultured hippocampal slice by the insults of artificial stress hormone, dexamethasone. The real time Ca2+ dynamics could continuously be detected in cornus ammonis 3 (CA3) of the organotypic hippocampus for 8 hours under confocal microscopy. When dexamethasone concentration was increased, the Ca2+ was also increased in a dose dependent manner at 1~100 microM concentrations. Moreover, when the organotypic cultured hippocampal slice was treated with a glutamate receptor antagonist together with dexamethasone, the real time Ca2+ dynamics were decreased. Furthermore, we confirmed by PI uptake study that glutamate receptor antagonist reduced the hippocampal tissue damage caused by dexamethasone treatment. Therefore, our new calcium ion dynamics system in organotypic cultured hippocampal slice after dexamethasone treatment could provide real time analysis method for investigation of brain injuries by stress.
Brain Injuries ; Calcium* ; Cornus ; Dexamethasone* ; Hippocampus ; Microscopy, Confocal ; Receptors, Glutamate

Long-Term Potentiation ; Neuronal Plasticity ; Receptors, Metabotropic Glutamate ; Synaptic Transmission

Flavonoids have been shown to affect calcium signaling in neurons. However, there are no reports on the effect of apigenin on glutamate-induced calcium signaling in neurons. We investigated whether apigenin affects glutamate-induced increase of free intracellular Ca2+concentration ([Ca2+]i) in cultured rat hippocampal neurons, using fura-2-based digital calcium imaging and microfluorimetry. The hippocampal neurons were used between 10 and 13 days in culture from embryonic day 18 rats. Pretreatment of the cells with apigenin (1micrometerto 100micrometer for 5 min inhibited glutamate (100 micrometer 1 min) induced [Ca2+]i increase, concentration-dependently. Pretreatment with apigenin (30micrometer for 5 min significantly decreased the [Ca2+]i responses induced by two ionotropic glutamate receptor agonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA, 10 micrometer 1 min) and N-methyl-D-aspartate (NMDA, 100 micrometer 1 min), and significantly inhibited the AMPA-induced peak currents. Treatment with apigenin also significantly inhibited the [Ca2+]i response induced by 50 mM KCl solution, decreased the [Ca2+]i responses induced by the metabotropic glutamate receptor agonist, (S)-3,5-dihydroxyphenylglycine (DHPG, 100micrometer 90 s), and inhibited the caffeine (10 mM, 2 min)-induced [Ca2+]i responses. Furthermore, treatment with apigenin (30micrometer significantly inhibited the amplitude and frequency of 0.1 mM [Mg2+o-induced [Ca2+]i spikes. These data together suggest that apigenin inhibits glutamate-induced calcium signaling in cultured rat hippocampal neurons.
Animals ; Apigenin ; Caffeine ; Calcium ; Calcium Signaling ; Glutamic Acid ; N-Methylaspartate ; Neurons ; Rats ; Receptors, Glutamate ; Receptors, Metabotropic Glutamate

No abstract available.
Animals ; Brain* ; Excitatory Amino Acids* ; N-Methylaspartate* ; Rats* ; Receptors, Glutamate* ; Receptors, N-Methyl-D-Aspartate*

BACKGROUND: Ionotropic glutamate receptors of the N-methyl-D-aspartate receptor (NMDAR) type are expressed on keratinocytes and play a role in the proliferation, differentiation, and cornification of keratinocytes. However, the expression profile of NMDAR and its role in cutaneous malignancy is unclear. OBJECTIVE: We analyzed the expression of NMDAR-1 in cutaneous squamous cell carcinoma (SCC) and investigated the relationship between NMDAR-1 expression and clinicopathological parameters. METHODS: Thirty-two patients with biopsy-proven cutaneous SCC were enrolled in this study. Each patient was analyzed for tumor diameter, location, local recurrence, and metastasis by conducting a chart review. The SCC specimens were histologically divided into differentiated and undifferentiated groups based on Broders' system. NMDAR-1 expression was examined by performing immunohistochemistry, and the relative staining intensity in the SCCs was graded into 5 levels. According to the staining intensity of NMDAR-1, the specimens were categorized into two groups: the higher group and the lower group. RESULTS: Fifteen (88%) of 17 tumors in the higher group were differentiated SCC, whereas 14 (93%) of 15 tumors in the lower group were undifferentiated SCC. In addition, NMDAR-1 expression was inversely correlated with metastasis (p=0.049). Local recurrence was associated with a lower staining intensity, but the results were not statistically significant. CONCLUSION: Our results demonstrate that NMDAR-1 expression in cutaneous SCC is significantly correlated with its differentiation and metastasis. Therefore, it may be a prognostic indicator for cutaneous SCC.
Carcinoma, Squamous Cell ; Humans ; Immunohistochemistry ; Keratinocytes ; N-Methylaspartate ; Neoplasm Metastasis ; Receptors, Ionotropic Glutamate ; Recurrence

OBJECTIVE: Recently, there are many reports that glutamate receptors have close relationships with a pathophysiology of schizophrenia. The purpose of this study was to assess the effects of D-cycloserine, which is glycine site partial agonist in NMDA receptor on psychopathologic symptoms and cognitive functions. METHODS: This study was done for chronic schizophrenic inpatients taking typical antipsychotics for more than 4 months. Exclusion criteria were patients with over 8 points according to Simpson-Angus scale for EPS or those with over 17 points of Hamilton Depression Scale. Patients were randomized to classify into two groups; D-cycloserine group (n=13) and placebo group (n=13). Each group received D-cycloserine 100 mg or placebo separately for 8 weeks. Psychopathology was evaluated with PANSS at baseline, 2nd week, fourth week and eighth week. Cognitive function was evaluated with KWIS at baseline and eighth week. RESULTS: Total 26 patients completed this trial. The average period of morbidity was 10.39+/-3.87 years and the average doses of antipsychotic was 1228.35+/-720.30 mg based on chlorpromazine equivalent. In positive subscale, negative subscale, general psychopathology subscale, total PANSS scale and KWIS, there were no significant differences between D-cycloserine and placebo groups. However, negative subscale scores had decreased from 24.92+/-3.64 (Baseline) to 23.46+/-3.41 (week 8) (p=0.077). CONCLUSION: There were no clear changes in positive symptom, negative symptom, memory, language function, and performance intelligence when D-cycloserine 100 mg was given with antipsychotic medication. However, some patients showed clear improvement in negative symptom, especially blunted affect. Therefore, D-cycloserine combination therapy could be effective for negative symptom. In future, study that can show effectiveness in psychopathology and cognitive function according to drug dosage is needed.
Antipsychotic Agents ; Chlorpromazine ; Cognition* ; Depression ; Glycine ; Humans ; Inpatients ; Intelligence ; Memory ; N-Methylaspartate ; Psychopathology ; Receptors, Glutamate ; Schizophrenia*