Schizophrenia is a debilitating illness, rating as one of the leading causes of lost years of quality of life. The illness imposes a disproportionate burden on patients and their families, healthcare systems and society. Pharmacological management is the cornerstone of treatment of schizophrenia, and antipsychotics, both first generation of antipsychotics and second generation of antipsychotics, are efficacious in reducing levels of psychopathology in acute episodes of schizophrenia. Clearly a need for innovative treatment strategies in schizophrenia that will ensure increased effectiveness against negative symptoms and cognitive dysfunction dysfunction. Therefore, in majority of cases polypharmacy is one of the effective approaches. This review focused on polypharmacy in the treatment of schizophrenia and in particular negative symptoms.

Introduction: The glutamergic receptors affect the synchronization of spike and wave discharges in different animal models of absence seizure. We studied the distribution of a NMDA subtype receptor in CA1 area of the hippocampus.Materials and Methods: Expression of NMDA subreceptor R2, the predominant excitatory neurotransmitter receptor in the brain, was investigated in rats suffering from absence-like seizures.Results: Rats with absence-like seizures exhibited decreased number of these NMDA subreceptors in the hippocampal formation.Conclusion: Changes of expression of these receptors in the hippocampus may be involved in cognition deficits in absence epilepsy.

Introduction: Spreading depression (SD) is an intrinsic bioelectrical activity in central nervous system which play important role in pathophysiology of some disorders such as migraine with aura, epilepsy, transient global amnesia, and spinal cord diseases.Materials and Methods: The juvenile rats were anesthetized and recording electrodes and cannula were implanted over the brain. Repetitive cortical SD events were induced by KCl injection through the cannula. Four weeks after the KCl or Ringer injection, all rats, including control, sham and SD groups, were decapitated and the brains removed. The distribution of NR2B subunit of NMDA receptors and the GluR1 subunit of AMPA receptors were assessed by immunohistochemical staining.Results: Expression of NR2B receptors in the CA1 region significantly increased in the SD group compared with the sham and control group (P<0.05). Also expression of GluR1 receptors in the CA1 and CA3 regions significantly increased in the SD group (P<0.01).Conclusion: Our result showed that SD enhanced expression of the NR2B subunit of NMDA receptors and the GluR1 subunit of AMPA receptors in various regions of the juvenile rat brain.

ObjectivePhysical activity increases brain activity through mechanisms, not yet known. Several research suggest that exercise could have modified neurotransmission of the brain. In addition, recent researches show that glutamate play important role in the morphine dependent rats. On the basis of these results, we studied the effect of treadmill running on variation of glutamate concentration from hypocampal dentate gyrus in the intact and morphine dependent rats.Materials and MethodsTwenty-eight healthy male rats, weighting about 250 g, were assigned to one of four groups as follows: control, morphine, physical activity, morphine with physical activity. Intraperitoneal injection of dissolved morphine with increasing doses of 10 mg/kg, 20 mg/kg and 40 mg/kg, for first, second and third three days, respectively, were applied to make rats morphine dependence. Compulsive running on rat treadmill were performed in a ten-day period (2hr a day, at a speed of 12m/min and an incline of 15 degrees) for the two groups of physical activity and morphine with physical activity. Microdialysis was perfoffi1edseparately and individually for each group (one rat per day). At microdialysis stage, rat was correctly weighted and the anesthetic agent of chloral hydrate 10% at a dose of 450 mg/kg was received through intraperitoneal injection. Then the anesthetized rat was placed in rat specified stereotaxis apparatus, the skull was opened and cleaned, so that the Bregma and Lambda points were identified, and the dimensions of the hypocampal dentate gyrus (DG) were obtained from the atlas of rats brain stereotaxis and hole was made by dentists drill in the location and the micodialysis probe was placed in the measured location in a very accurate manner. Then a CSF (NaCl, KCI, MgCl2, Na2HPO4, NaH2PO4, CaCl2 and Glucose) was entered into probe by microinjection pump with speed of 2 ml/min and the output of the probe was collected in numbered vials. The first hour of output was discharged and afterwards the output of the probe was collected every 20 minutes and immediately kept at -70°C. Finally, glutamate concentration was measured by HPLC method using florescence detector and the results were statistically analyzed.ResultsThe results indicated that in any of three 20-min time periods of sampling after the first hours discharge, the amount of glutamate released into the Dentate gyrus of the fourth group rats (morphine with physical activity) is elevated significantly compared to other groups (p<0.05). In comparison of the control group with the groups of morphine and physical activity, no significant difference was found in any of sampling times (p>0.05).ConclusionTo justify these results, perhaps we can say that morphine would make consistent changes in transmission of glutamatergic synapses and in this way increase its extracellular amount. On the contrary physical activity would decrease its extracellular amount through the elevation of glutamate transmitters (GLTs). Injection of morphine and physical activity thereafter (morphine with physical activity group) interestingly, because of unknown reasons, probably with a synergism effect between two factors (physical activity and morphine) cause a great increase in extracellular glutamate at the dentate gyrus.

Dear Editor-in-ChiefTopiramate (TPM) is a kind of anticonvulsant drug that in 1996 was suggested by Food and Drug Administration (FDA) as curing drug of adults' convulsion. TPM facilitates gamma amino butyric acid (GABA) transference and prevents Glutamates transference, where this process can reduce the cocaine reinforcing effect and can be used in management of cocaine craving (1). There is an assumption that convulsion can be accounted as a running mechanism in addiction.

Introduction: Spreading depression (SD) is a pathophysiological phenomenon, which induced as consequence of ischemia, cerebral hemorrhage and cerebral injury. SD roles in some clinical disorders, including migraine aura, epilepsy, head injury and transient global amnesia, have been documented. SD is a neural hyperactivity, which slowly spread in the brain, passed through neurons or astrocyte, change blood volume, cell metabolism and distribute cell ionic balance. SD is accompanied by a transient hyperactivity, which continues by neuronal depression and hyper excitability.Conclusion: Various investigation on animal and human brains showed enhancement in NMDA, AMPA, GABA as well as serotonin after SD. This review focuses on wide range of investigation on excitatory and inhibitory neurotransmitters after SD.

Objective: Available treatments of depression have limited efficacy and unsatisfactory remission rates. This study aims to review randomized controlled trials (RCTs) investigating effects of glutamate receptor modulators in treating patients with resistant depression. Method: The study protocol was registered in PROSPERO (CRD42021225516). Scopus, ISI Web of Science, Embase, Cochrane Library, Google Scholar, and three trial registries were searched up to September 2020 to find RCTs evaluating glutamate receptor modulators for resistant depression. The difference between intervention and control groups in changing depression scores from baseline to endpoint was considered the primary outcome. Version 2 of the Cochrane risk-of-bias tool for randomized trials was used to assess the quality of the RCTs. No funding was received. Results: Thirty-eight RCTs were included. Based on the included studies, compelling evidence was found for ketamine (with or without electroconvulsive therapy, intravenous or other forms), nitrous oxide, amantadine, and rislenemdaz (MK0657), the results for MK-0657, amantadine, and nitrous oxide were only based on one study for each. Lithium, lanicemine, D-cycloserine, and decoglurant showed mixed results for efficacy, and, riluzole, and 7-chlorokynurenic acid were mostly comparable to placebo. A limited number of studies were available that addressed drugs other than ketamine. Conclusion: The study cannot determine the difference between statistical and clinical significance between the agents and placebo due to high heterogeneity among the RCTs. Nevertheless, ketamine could be used as an efficacious drug in TRD,still, additional studies are needed to delineate the optimum dosage, duration of efficacy, and intervals. Further studies are also recommended on the effectiveness of glutamatergic system modulators other than ketamine on treatment-resistant depression.

Glutamate is extensively and relatively uniformly distributed in the central nervous system (CNS) and its effects mediated by two distinct groups of receptors including Ionotropic and metabotropic glutamate receptors. Concentration of glutamate in the nervous system is much higher than in other tissues. Glutamate receptors play an important role in synaptic transmission, neural plasticity and neural development. Although glutamate has various neural physiological effects, it is a strong neurotoxin and high concentration of glutamate in synaptic milieu and extra cellular space plays a critical role in neurodegenerative diseases like ischemia, acute neural trauma and many other CNS disorders.Selective ligands for glutamate receptors have made considerable advances in the identification of the physiological and pathological roles of these receptors in the nervous system. Furthermore, advances in animal models of neurodegenerative disorders have lead to the application of many glutamatergic compounds in clinical studies. These compounds consist of ionotropic glutamate receptor antagonists that examined in clinical tests for disorders including epilepsy, ischemic stroke, etc. The purpose of this review is to describe ionotropic glutamate receptors and their possible roles in excitotoxicity and nervous system disorders. Then we will discuss briefly about transporters for glutamate and their association in the pathology of CNS disorders. Finally, involvement of ionotropic glutamate receptors in neurological disorders including schizophrenia, Alzheimer's disease and epilepsy will be explained.