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Abnormalities in dopamine function might be related to psychiatric disorders such as schizophrenia. Even at the same concentration, dopamine exerts opposite effects on information processing in the prefrontal cortex depending on independent dopamine release modes known as tonic and phasic releases. This duality of dopamine prevents a blanket interpretation of the implications of dopamine abnormalities for diseases on the basis of absolute dopamine levels. Moreover, the mechanisms underlying the mode‐specific dopamine abnormalities are not clearly understood. Here, I show that the two modes of dopamine release in the prefrontal cortex of a schizophrenia‐like model are disrupted by different mechanisms. In the schizophrenia‐like model established by perinatal exposure to inflammatory cytokine, epidermal growth factor, tonic release was enhanced and phasic release was decreased in the prefrontal cortex. I examined the activity of dopamine neurons in the ventral tegmental area (VTA), which sends dopamine projections to the prefrontal cortex, under anaesthesia. The activation of VTA dopamine neurons during excitatory stimulation (local application of glutamate or N‐methyl‐d‐aspartic acid [NMDA]), which is associated with phasic activity, was blunt in this model. Dopaminergic neuronal activity in the resting state related to tonic release was increased by disinhibition of the dopamine neurons due to the impairment of 5HT2 (5HT2A) receptor‐regulated GABAergic inputs. Moreover, chronic administration of risperidone ameliorated this disinhibition of dopaminergic neurons. These results provide an idea about the mechanism of dopamine disturbance in schizophrenia and may be informative in explaining the effects of atypical antipsychotics as distinct from those of typical drugs. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe mental disorder characterized by positive, negative, and cognitive symptoms. Cognitive symptoms are a kind of symptoms with high incidence and great impact on patients. There is no effective treatment in clinical practice. N-methyl-d-aspartic acid (NMDA) receptor hypofunction may be an important cause of cognitive symptoms. MK-801 (also named Dizocilpine), a noncompetitive antagonist of NMDA receptor, is often used to construct a model of NMDA receptor dysfunction. In terms of treatment, environmental enrichment (EE) as an environmental intervention can effectively improve the symptoms of cognitive impairment in rodents. In this paper, we first briefly introduce the background of cognitive symptoms and EE in schizophrenia, and then investigate the manifestations of MK-801 induced cognitive impairment, the improvement of EE on these cognitive impairments based on the MK-801 induced schizophrenia rodent models, and the possible mechanism of EE in improving cognitive symptoms. This article reviews the literature in recent years, which provides an important reference for MK-801 to construct a cognitive symptom model of schizophrenia and the mechanism of EE in improving cognitive symptoms of schizophrenia. [ABSTRACT FROM AUTHOR]

Kainate receptors (KARs) are glutamate receptors that participate in the postsynaptic transmission of information and in the control of neuronal excitability, as well as presynaptically modulating the release of the neurotransmitters GABA and glutamate. These modulatory effects, general follow a biphasic pattern, with low KA concentrations provoking an increase in GABA and glutamate release, and higher concentrations mediating a decrease in the release of these neurotransmitters. In addition, KARs are involved in different forms of long‐ and short‐term plasticity. Importantly, altered activity of these receptors has been implicated in different central nervous system diseases and disturbances. Here, we describe the pre‐ and postsynaptic actions of KARs, and the possible role of these receptors in disease, a field that has seen significant progress in recent years. [ABSTRACT FROM AUTHOR]

Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical–subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic abnormalities are not targeted by the presently available therapies. D-amino acids, acting as N-methyl-D-aspartate receptor (NMDAR) modulators, have emerged in the last few years as a potential augmentation strategy in those cases of schizophrenia that do not respond well to antipsychotics, a condition defined as treatment-resistant schizophrenia (TRS), affecting almost 30–40% of patients, and characterized by serious cognitive deficits and functional impairment. In the present systematic review, we address with a direct and reverse translational perspective the efficacy of D-amino acids, including D-serine, D-aspartate, and D-alanine, in poor responders. The impact of these molecules on the synaptic architecture is also considered in the light of dendritic spine changes reported in schizophrenia and antipsychotics' effect on postsynaptic density proteins. Moreover, we describe compounds targeting D-amino acid oxidase and D-aspartate oxidase enzymes. Finally, other drugs acting at NMDAR and proxy of D-amino acids function, such as D-cycloserine, sarcosine, and glycine, are considered in the light of the clinical burden of TRS, together with other emerging molecules. [ABSTRACT FROM AUTHOR]

Cognitive deficits and impaired sensory processing are hallmarks of several neurodevelopmental and neuropsychiatric disorders. N‐methyl‐d‐aspartate receptor (NMDAR) hypofunction contributes to these deficits by disrupting the excitation‐to‐inhibition balance in neuronal networks. Although preclinical data suggest that the activation of gamma‐Aminobutyric acid B receptors (GABABR) may restore excitation‐to‐inhibition balance and rescues some behavioral deficits, GABABR agonists have failed to meet their clinical study endpoints, suggesting more complex interactions at play. Here, we studied the effects of Baclofen (a GABABR agonist) and MK‐801 (a non‐competitive NMDAR antagonist) on the neurophysiology of limbic‐auditory circuits in freely‐moving rats. The pharmacological effects were assessed using resting‐state EEG, auditory‐evoked oscillation, and mismatch negativity paradigms. MK‐801 elevated resting‐state oscillatory power, mainly in the gamma and higher frequency ranges, and impaired auditory‐evoked responses. Baclofen partially normalized resting‐state oscillations but failed to rescue auditory‐evoked oscillatory abnormalities. Coherence analysis indicated that NMDAR hypofunction alters the functional coupling of limbic and thalamocortical circuits in several frequency bands. Baclofen normalized only a fraction of MK‐801‐induced abnormalities (e.g., theta coherence between frontal cortex and amygdala) while reducing delta‐theta and augmenting gamma coherence in thalamocortical circuits. Finally, we report that Baclofen intensified the MK‐801‐induced deficits in auditory mismatch responses. In summary, while Baclofen partially normalizes MK‐801‐induced gamma abnormalities, it either fails to rescue or exacerbates deficits in other phenotypes like functional coupling and auditory processing. We hope that the presented complex interactions between pharmacologically induced NMDAR hypofunction and GABABR agonism inspire a new understanding of the therapeutic potential around GABAergic modulation. [ABSTRACT FROM AUTHOR]

MiRNAs are small, non‐coding RNAs that can silence the expression of various target genes by binding their mRNAs and thus regulate a wide range of crucial bodily functions. However, the miRNA expression profile of schizophrenia after antipsychotic mediation is largely unknown. Non‐competitive N‐methyl‐D‐aspartic acid (NMDA) receptor antagonists such as MK‐801 have provided useful animal models to investigate the effects of schizophrenia‐like symptoms in rodent animals. Herein, the hippocampal miRNA expression profiles of Sprague‐Dawley rats pretreated with MK‐801 were examined after antipsychotic clozapine (CLO) treatment. Total hippocampal RNAs from three groups were subjected to next‐generation sequencing (NGS), and bioinformatics analyses, including differential expression and enrichment analyses, were performed. Eight miRNAs were differentially expressed between the MK‐801 and vehicle (VEH) control groups. Interestingly, 14 miRNAs were significantly differentially expressed between the CLO + MK‐801 and MK‐801 groups, among which rno‐miR‐184 was the most upregulated. Further analyses suggested that these miRNAs modulate target genes that are involved in endocytosis regulation, ubiquitin‐mediated proteolysis, and actin cytoskeleton regulation and thus might play important roles in the pathogenesis of schizophrenia. Our results suggest that differentially expressed miRNAs play important roles in the complex pathophysiology of schizophrenia and subsequently impact brain functions. [ABSTRACT FROM AUTHOR]

Dizocilpine (MK-801), a non-competitive N-methyl-D-aspartic acid receptor (NMDA-R) antagonist, can induce schizophrenia-like symptoms in healthy individuals, implicating NMDA-R hypofunction in disease pathogenesis. Brain-derived neurotrophic factor (BDNF) is also implicated in schizophrenia, and expression is regulated by NMDA-R activity, suggesting a functional link. We previously found that BDNF signaling was upregulated by MK-801 in cultured hippocampal astrocytes, but the underlying mechanism is not clear. To address this issue, the levels of BDNF expression and secretion were evaluated in hippocampal astrocytes incubated with MK-801 by ELISA and qPCR, with and without NMDA co-incubation or pretreatment of either the ERK1/2 inhibitor, PD98059 or the PI3K inhibitor, LY294002. The apoptosis, viability, and proliferation of the astrocytes were also examined. In the current study, we demonstrate that MK-801 treatment (20 μM for 5 days) enhances the proliferation of rat cultured hippocampal astrocytes. Expression of BDNF mRNA was enhanced after 24 h in MK-801, but returned to near baseline over the next 24 h in the continued presence of MK-801. However, two successive 24-h treatments enhanced BDNF expression. These application regimens had no effect on apoptosis or proliferation rate. Co-addition of NMDA significantly inhibited MK-801-induced upregulation of BDNF. Similarly, MK-801-induced BDNF upregulation was blocked by pretreatment with inhibitors of PI3K and ERK1/2, but not by inhibitors of p38 and JNK. These findings suggested that astrocytes may contribute to the acute neurological and behavioral response to MK-801 treatment via a transient increase in BDNF expression involving NMDA-R–PI3K–ERK signaling. [ABSTRACT FROM AUTHOR]

Background: Dysfunction of the N -methyl- D -aspartate glutamate receptor is involved in the putative pathology of schizophrenia. There is growing interest in the potential of N -methyl- D -aspartate receptor modulators to improve the symptoms of schizophrenia, but the evidence for the use of glutamatergic agents for augmenting schizophrenia remains inconclusive. Aims: We conducted a meta-analysis to test the efficacy and safety of N -methyl- D -aspartate receptor modulator supplements in patients with schizophrenia. Methods: Following a systemic search in MEDLINE, Embase, Cochrane and Scopus, 40 double-blinded, randomised, placebo-controlled trials involving 4937 patients with schizophrenia were included in this meta-analysis. The change in the severity of symptoms among patients with schizophrenia was defined as the primary outcome, whereas the safety profiles of the intervention, including the discontinuation rate and adverse events, were defined as secondary outcomes. Results: When added to antipsychotic treatments, N -methyl- D -aspartate receptor modulators improved multiple schizophrenia symptoms, particularly negative symptoms, and had satisfactory side effects and safety profile. Among the seven glutamatergic agents analysed, glycine, D-serine and sarcosine had better treatment profiles than other agents, and NMDA receptor co-agonists, as a group, provided a reduction in schizophrenia symptoms compared to antipsychotic treatments without supplementation. Augmentation with N -methyl- D -aspartate receptor modulators was only effective among patients treated with antipsychotics other than clozapine. Conclusions: The results indicate that N -methyl- D -aspartate receptor modulators, particularly with glycine, D-serine and sarcosine, are more beneficial than the placebo in treating schizophrenia, and the effects extended to both positive and negative symptoms, when augmented with antipsychotics other than clozapine. [ABSTRACT FROM AUTHOR]

• Repeated PCP administration induces emotional and cognitive impairments. • Repeated PCP administration is associated with increase of GLAST and S100 in the PFC. • Decreased extracellular glutamate levels induced by overexpression of GLAST. • Behavioral abnormalities are not observed in PCP-administered GLAST+/− mice. • GLAST dysfunction plays important roles in the development of behavioral abnormalities. Alterations of the glutamatergic system components, including N -methyl- d -aspartate (NMDA) receptors are relevant to the pathophysiology of schizophrenia. Repeated phencyclidine (PCP) administration induces several schizophrenia-like psychobehavioral abnormalities and decreases extracellular glutamate levels, which are associated with increased levels of glial glutamate and aspartate transporter (GLAST) in the prefrontal cortex (PFC) of mice. In the present study, we investigated the functional roles of GLAST in the emotional and cognitive abnormalities in mice following repeated PCP administration by using GLAST heterozygous (+/−) mice, since GLAST mutant mice are a useful tool for elucidating the contribution of glutamate dysfunction to the pathophysiology of schizophrenia. PCP-administered GLAST wild-type (+/+) mice showed enhancement of immobility in a forced swimming test, impairments of visual recognition memory in a novel object recognition test, decrease in high potassium (K +)-induced extracellular glutamate release, and overexpression of GLAST and S100 proteins in the PFC, compared to saline-administered GLAST+/+ mice. Such behavioral and neurochemical abnormalities were not observed in PCP-administered GLAST+/− mice. In conclusion, these results clearly suggest that genetic GLAST dysfunction and glial activation play important roles in the development of emotional and cognitive abnormalities in PCP-administered GLAST+/+ mice. [ABSTRACT FROM AUTHOR]

MK-801, also known as dizocilpine, is a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that induces schizophrenia-like symptoms. Our previous study showed that brain-derived neurotrophic factor (BDNF) signaling was upregulated in cultured hippocampal astrocytes in response to MK-801. However, dysfunctional NMDA receptors are mainly expressed in neurons. The effects of MK-801 on neuron-derived BDNF expression and of risperidone on MK-801-induced cognitive impairment and changes in BDNF expression are unclear. To address this issue, we examined BDNF expression in the hippocampus of rats that received repeated injections of MK-801 (0.5 mg/kg body weight for 6 days) and in primary cultured hippocampal neurons incubated with 20 μM MK-801 for 24 h. BDNF expression and cognitive function were also evaluated in rats receiving intraperitoneal injections of risperidone (1 mg/kg body weight) once daily for 7 days and in hippocampal neurons incubated with 10 μM risperidone following MK801 treatment. MK-801 treatment decreased BDNF expression in the rat hippocampus as well as the expression and secretion of BDNF in hippocampal neurons in vitro. However, risperidone reversed the effects of MK801 on BDNF level and improved cognitive function in rats treated with MK801. These findings suggest that risperidone may alleviate cognitive impairment caused by MK801 via upregulation of BNDF signaling in the hippocampus. [ABSTRACT FROM AUTHOR]

Background: Evidence supports that the hypofunction of N-methyl-D-aspartate receptor (NMDAR) and downregulation of disrupted-in-schizophrenia 1 (DISC1) contribute to the pathophysiology of schizophrenia. N-Methyl D-aspartate receptor subtype 2B (NR2B)-containing NMDAR are associated with cognitive dysfunction in schizophrenia. GLYX-13 is an NMDAR glycine-site functional partial agonist and cognitive enhancer that does not induce psychotomimetic side effects. However, it remains unclear whether NR2B plays a critical role in the GLYX-13-induced alleviation of schizophrenia-like behaviors in mice. Methods: The effect of GLYX-13 was tested by observing changes in locomotor activity, novel object recognition ability, and prepulse inhibition (PPI) induced by dizocilpine (known as MK-801) in mice. Lentivirus-mediated NR2B knockdown in the hippocampus was assessed to confirm the role of NR2B in GLYX-13 pathophysiology, using Western blots and immunohistochemistry. Results: The systemic administration of GLYX-13 (0.5 and 1 mg/kg, i.p.) ameliorates MK-801 (0.5 mg/kg, i.p.)-induced hyperlocomotion, deficits in memory, and PPI in mice. Additionally, GLYX-13 normalized the MK-801-induced alterations in signaling molecules, including NR2B and DISC1 in the hippocampus. Furthermore, we found that NR2B knockdown produced memory and PPI deficits without any changes in locomotor activity. Notably, DISC1 levels significantly decreased by NR2B knockdown. However, the effective dose of GLYX-13 did not alleviate the memory and PPI dysfunctions or downregulation of DISC1 induced by NR2B knockdown. Conclusion: Our results suggest GLYX-13 as a candidate for schizophrenia treatment, and NR2B and DISC1 in the hippocampus may account for the molecular mechanisms of GLYX-13. [ABSTRACT FROM AUTHOR]

The effects of transcranial direct current stimulation (tDCS) likely depend on cortical N-methyl-D-aspartic acid (NMDA) neurotransmission; however, no previous studies have reported tDCS-mediated modulation of cortical NMDA neurotransmission in humans. The gamma-band auditory steady-state response (ASSR) to a 40 Hz stimulation likely reflects the integrity of cortical NMDA neurotransmission. The present study tested whether the effect of tDCS is reflected in gamma-band ASSRs during a 40 Hz stimulation. Using a double-blind, randomized, crossover study, we performed magnetoencephalography (MEG) and measured the ASSR in 24 healthy participants during 40 Hz of auditory stimulation after prefrontal tDCS (2 mA) or sham (i.e., placebo) treatment. Our results failed to reveal significant differences in any brain between the two conditions after the application of a frequency of approximately 40 Hz. Based on these results, the ASSR is an insufficient method to detect the effect of tDCS on cortical NMDA neurotransmission. Unexpectedly, the results revealed an enhanced beta-band event-related spectral perturbation (ERSP) in the left motor cortex after tDCS compared with that observed after the sham stimuli. Given that beta-band oscillations reflect many functions in motor cortices, the tDCS for the frontal areas had some effect on the left motor cortex while the participants were focusing on not pressing the button with their right index finger. An additional study with an adequate psychological task is necessary to draw a conclusion regarding this unexpected result. [ABSTRACT FROM AUTHOR]

Mutations or deletions of the transcription factor TCF4 are linked to Pitt-Hopkins syndrome (PTHS) and schizophrenia, suggesting that the precise pathogenic mutations dictate cellular, synaptic, and behavioral consequences. Here, we generated two novel mouse models of PTHS, one that mimics the most common pathogenic TCF4 point mutation (human R580W, mouse R579W) and one that deletes three pathogenic arginines, and explored phenotypes of these lines alongside models of pan-cellular or CNS-specific heterozygous Tcf4 disruption. We used mice of both sexes to show that impaired Tcf4 function results in consistent microcephaly, hyperactivity, reduced anxiety, and deficient spatial learning. All four PTHS mouse models demonstrated exaggerated hippocampal long-term potentiation (LTP), consistent with deficits in hippocampus-mediated behaviors. We further examined R579W mutant mice and mice with pancellular Tcf4 heterozygosity and found that they exhibited hippocampal NMDA receptor hyperfunction, which likely drives the enhanced LTP. Together, our data pinpoint convergent neurobiological features in PTHS mouse models and provide a foundation for preclinical studies and a rationale for testing whether NMDAR antagonists might be used to treat PTHS. [ABSTRACT FROM AUTHOR]

Schizophrenia and schizophrenia-like symptoms induced by the dopamine agonists and N-methyl-D aspartate type glutamate receptor antagonists occur only after the adolescent period. Similarly, animal models of schizophrenia by these drugs are also induced after the critical period around postnatal week three. Based upon the development-dependent onsets of these psychotomimetic effects, by using a DNA microarray technique, we identified the WD repeat domain 3 (WDR3) and chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1) genes as novel candidates for schizophrenia-related molecules, whose mRNAs were up-regulated in the adult (postnatal week seven), but not in the infant (postnatal week one) rats by an indirect dopamine agonist, and phencyclidine, an antagonist of the NMDA receptor. WDR3 and other related proteins are the nuclear proteins presumably involved in various cellular activities, such as cell cycle progression, signal transduction, apoptosis, and gene regulation. ALG1 is presumed to be involved in the regulation of the protein N-glycosylation. To further elucidate the molecular pathophysiology of schizophrenia, we have evaluated the genetic association of WDR3 and ALG1 in schizophrenia. We examined 21 single nucleotide polymorphisms [SNPs; W1 (rs1812607)-W16 (rs6656360), A1 (rs8053916)-A10 (rs9673733)] from these genes using the Japanese case-control sample (1,808 schizophrenics and 2,170 matched controls). No significant genetic associations of these SNPs were identified. However, we detected a significant association of W4 (rs319471) in the female schizophrenics (allelic P = 0.003, genotypic P = 0.008). Based on a haplotype analysis, the observed haplotypes consisting of W4 (rs319471)–W5 (rs379058) also displayed a significant association in the female schizophrenics (P = 0.016). Even after correction for multiple testing, these associations remained significant. Our findings suggest that the WDR3 gene may likely be a sensitive factor in female patients with schizophrenia, and that modification of the WDR3 signaling pathway warrants further investigation as to the pathophysiology of schizophrenia. [ABSTRACT FROM AUTHOR]

Alterations in the function of the medial prefrontal cortex (mPFC) and its major thalamic source of innervation, the mediodorsal (MD) thalamus, have been hypothesized to contribute to the symptoms of schizophrenia. The NMDAR antagonist ketamine, used to model schizophrenia, elicits a brain state resembling early stage schizophrenia characterized by cognitive deficits and increases in cortical low gamma (40–70 Hz) power. Here we sought to determine how ketamine differentially affects spiking and gamma local field potential (LFP) activity in the rat mPFC and MD thalamus. Additionally, we investigated the ability of drugs targeting the dopamine D4 receptor (D4R) to modify the effects of ketamine on gamma activity as a measure of potential cognitive therapeutic efficacy. Rats were trained to walk on a treadmill to reduce confounds related to hyperactivity after ketamine administration (10 mg/kg s.c.) while recordings were obtained from electrodes chronically implanted in the mPFC and MD thalamus. Ketamine increased gamma LFP power in mPFC and MD thalamus in a similar frequency range, yet did not increase thalamocortical synchronization. Ketamine also increased firing rates and spike synchronization to gamma oscillations in the mPFC but decreased both measures in MD thalamus. Conversely, walking alone increased both firing rates and spike-gamma LFP correlations in both mPFC and MD thalamus. The D4R antagonist alone (L-745,870) had no effect on gamma LFP power during treadmill walking, although it reversed increases induced by the D4R agonist (A-412997) in both mPFC and MD thalamus. Neither drug altered ketamine-induced changes in gamma power or firing rates in the mPFC. However, in MD thalamus, the D4R agonist increased ketamine-induced gamma power and prevented ketamine’s inhibitory effect on firing rates. Results provide new evidence that ketamine differentially modulates spiking and gamma power in MD thalamus and mPFC, supporting a potential role for both areas in contributing to ketamine-induced schizophrenia-like symptoms. [ABSTRACT FROM AUTHOR]

Rationale: Altered glutamate NMDA receptor function is implicated in schizophrenia, and gender differences have been demonstrated in this illness. Objectives: This study aimed to investigate the interaction of gonadal hormones with NMDA receptor-mediated locomotor hyperactivity and PPI disruption in mice. Results: The effect of 0.25 mg/kg of MK-801 on locomotor activity was greater in male mice than in female mice. Gonadectomy (by surgical castration) significantly reduced MK-801-induced hyperlocomotion in male mice, but no effect of gonadectomy was seen in female mice or on amphetamine-induced locomotor hyperactivity. The effect of MK-801 on prepulse inhibition of startle (PPI) was similar in intact and castrated male mice and in ovariectomized (OVX) female mice. In contrast, there was no effect of MK-801 on PPI in intact female mice. Forebrain NMDA receptor density, as measured with [H]MK-801 autoradiography, was significantly higher in male than in female mice but was not significantly altered by either castration or OVX. Conclusions: These results suggest that male sex hormones enhance the effect of NMDA receptor blockade on psychosis-like behaviour. This interaction was not seen in female mice and was independent of NMDA receptor density in the forebrain. Male sex hormones may be involved in psychosis by an interaction with NMDA receptor hypofunction. [ABSTRACT FROM AUTHOR]

Rationale: Both prefrontal cortex (PFC) GABA and NMDA transmission regulate attentional processes, yet how they may differentially regulate signal detection or other aspects of attention is unclear. Objectives: We examined PFC GABA and NMDA receptor regulation of attention using a sustained attention task (SAT) permitting identification of distinct forms of impairments. As this task requires implementation of conditional rules, we also investigated how reducing PFC GABA transmission affected performance of visual and auditory conditional discriminations. Methods: Male rats were well-trained on the SAT that required identifying whether a brief visual stimulus (500-50 ms) was present/absent by pressing one of two levers. They then received intra-PFC infusions of the GABA antagonist bicuculline (12.5-50 ng), the NMDA antagonist MK-801 (6 μg), and i.p. injections of MK-801 (0.1-0.3 mg/kg) prior to testing. Separate groups were trained either on a similar task where the visual stimulus was presented for 2.5 s, or a task where presentation of one of two auditory cues required responding on a left or right lever. Results: Both doses of bicuculline impaired vigilance, selectively increasing errors during nonsignal trials. Intra-PFC MK-801 induced subtle impairments at short signal durations. Systemic MK-801 impaired performance and increased response latencies. Visual and auditory conditional discrimination was impaired by 50 ng, but not 12.5 ng of bicuculline. Conclusions: These findings highlight a key role for PFC GABA transmission in reducing sensitivity to distractors during attentional performance. Furthermore, they reveal that disruption of GABA signaling can interfere with the ability to implement conditional rules. [ABSTRACT FROM AUTHOR]

ObjectivesHypofunction of NMDA receptor is implicated in the pathophysiology, particularly cognitive impairment, of schizophrenia. Sarcosine, a glycine transporter I (GlyT-1) inhibitor, and sodium benzoate, ad-amino acid oxidase (DAAO) inhibitor, can both enhance NMDA receptor-mediated neurotransmission. We proposed simultaneously inhibiting DAAO and GlyT-1 may be more effective than inhibition of either in improving the cognitive and global functioning of schizophrenia patients.MethodsThis study compared add-on sarcosine (2 g/day) plus benzoate (1 g/day) vs. sarcosine (2 g/day) for the clinical symptoms, as well as the cognitive and global functioning, of chronic schizophrenia patients in a 12-week, double-blind, randomised, placebo-controlled trial. Participants were measured with the Positive and Negative Syndrome Scale and the Global Assessment of Functioning Scale every 3 weeks. Seven cognitive domains, recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Committee, were measured at weeks 0 and 12.ResultsAdjunctive sarcosine plus benzoate, but not sarcosine alone, improved the cognitive and global functioning of patients with schizophrenia, even when their clinical symptoms had not improved.ConclusionsThis finding suggestsN-methyl-d-aspartate receptor-enhancement therapy can improve the cognitive function of patients with schizophrenia, further indicating this pro-cognitive effect can be primary without improvement in clinical symptoms. [ABSTRACT FROM PUBLISHER]

Background. Although antipsychotics are the mainstay treatment of schizophrenia, they don't adequately address residual positive, negative and depressive symptoms. The aim of the present study is to assess the effect of adjunctive memantine treatment on positive, negative and depressive symptoms of schizophrenia. Methods. This randomized, placebo-controlled study was conducted in Noor Hospital, Isfahan, Iran, 2013-2014; 32 patients in maintenance treatment were included in each group, using block sampling; inclusion criteria were age 18-65 years, normal intellectual ability, being diagnosed with schizophrenia for the past two years, being treated with fixed doses of atypical antipsychotic for at least three months before randomization. Exclusion criteria were pregnancy, breast feeding, having received electro-convulsive therapy in the past two weeks, drug or substance abuse and dependence, psychiatric/ neurological comorbidities, and sensitivity to memantine. Patients in the intervention group were treated with memantine plus atypical antipsychotic; while in the control group, patients received placebo and atypical antipsychotic. Patients were assessed by Positive and Negative Symptom Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) initially and every four weeks to the end of the 12th week. Data were analyzed in SPSS 17.0 using t-test, chi square, analysis of variance (ANOVA), and analysis of covariance (ANCOVA). Results. Positive symptoms (p=0.028), negative symptoms (0.004), general psychopathology (p<0.001), depressive symptoms (p<0.001) and total symptom severity (p<0.001) decreased significantly in patients receiving add-on memantine. Conclusion. This study shows that, add-on memantine would be helpful, in the adjunctive treatment of depressive, positive, negative and general symptoms in patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCZ) is a neurodevelopmental psychiatric disorder, in which cognitive function becomes disrupted at early stages of the disease. Although the mechanisms underlying cognitive impairments remain unclear, N-methyl-D-aspartate receptors (NMDAR) hypofunctioning in the prefrontal cortex (PFC) has been implicated. Moreover, cognitive symptoms in SCZ are usually unresponsive to treatment with current antipsychotics and by onset, disruption of the dopamine system, not NMDAR hypofunctioning, dominates the symptoms. Therefore, treating cognitive deficits at an early stage is a realistic approach. In this study, we tested whether an early treatment targeting mGluR2 would be effective in ameliorating cognitive impairments in the methylazoxymethanol acetate (MAM) model of SCZ. We investigated the effects of an mGluR2 agonist/mGluR3 antagonist, LY395756 (LY39), on the NMDAR expression and function in juveniles, as well as cognitive deficits in adult rats after juvenile treatment. We found that gestational MAM exposure induced a significant decrease in total protein levels of the NMDAR subunit, NR2B, and a significant increase of pNR2BTyr1472 in the juvenile rat PFC. Treatment with LY39 in juvenile MAM-exposed rats effectively recovered the disrupted NMDAR expression. Furthermore, a subchronic LY39 treatment in juvenile MAM-exposed rats also alleviated the learning deficits and cognitive flexibility impairments when tested with a cross-maze based set-shifting task in adults. Therefore, our study demonstrates that targeting dysfunctional NMDARs with an mGluR2 agonist during the early stage of SCZ could be an effective strategy in preventing the development and progression in addition to ameliorating cognitive impairments of SCZ. [ABSTRACT FROM AUTHOR]

A growing body of psychiatric research has emerged, focusing on the role of endocannabinoid system in psychiatric disorders. For example, the endocannabinoid system, via cannabinoid CB (CB1 and CB2) receptors, is able to control the function of many receptors, such as N-methyl- d-aspartate (NMDA) receptors connected strictly with psychosis or other schizophrenia-associated symptoms. The aim of the present research was to investigate the impact of the CB1 receptor ligands on the symptoms typical for schizophrenia. We provoked psychosis-like effects in mice by an acute administration of NMDA receptor antagonist, MK-801 (0.1-0.6 mg/kg). An acute administration of MK-801 induced psychotic symptoms, manifested in the increase in locomotor activity (hyperactivity), measured in actimeters, as well as the memory impairment, assessed in the passive avoidance task. We revealed that an acute injection of CB1 receptor agonist, oleamide (5-20 mg/kg), had no influence on the short- and long-term memory-related disturbances, as well as on the hyperlocomotion in mice, provoking by an acute MK-801. In turn, an amnestic effects or hyperactivity induced by an acute MK-801 was attenuated by an acute administration of AM 251 (0.25-3 mg/kg), a CB1 receptor antagonist. The present findings confirm that endocannabinoid system is able to modify a variety of schizophrenia-like responses, including the cognitive disturbances and hyperlocomotion in mice. Antipsychotic-like effects induced by CB1 receptor antagonist, obtained in our research, confirm the potential effect of CB1 receptor blockade and could have important therapeutic implications on clinical settings, in the future. [ABSTRACT FROM AUTHOR]

Schizophrenia is a severe and complex mental disorder with high heritability. There is evidence that mutations in the gene of Nmethyl- d -aspartate-type glutamate receptors (NMDAR) are associated with schizophrenia. GRIN2B encodes a subunit of NMDARs, and has been identified as a candidate gene for many psychiatric disorders, especially schizophrenia. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in GRIN2B were associated with schizophrenia. Four SNPs (rs890, rs1806191, rs219872, rs172677) were genotyped in 752 schizophrenic patients and 846 healthy controls of the Chinese Han population. Our results indicate differences in allele and genotype frequencies of rs890 between case and control. These results were assessed by adapting different genetic models (codominant, dominant, recessive, overdominant, log-additive models). After controlling for confounding factors including sex and age, rs890 remained associated with schizophrenia. In addition, rs890 and rs1806191 were found to form a haplotype associated with schizophrenia. In summary, our results indicate that the GRIN2B SNP rs890 might be associated with schizophrenia in the Chinese Han population. [ABSTRACT FROM AUTHOR]

Aim Finding a relationship between schizophrenia symptoms severity and initial level of BDNF and its changes during augmentation of antipsychotic treatment with sarcosine. Method 57 individuals with schizophrenia with predominantly negative symptoms completed a 6-month RCT prospective study. The patients received 2 g of sarcosine (n=27) or placebo (n=30) daily. At the beginning, after 6 weeks and 6 months BDNF levels were measured. Severity of symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS). Results BDNF serum levels were stable after 6 weeks and 6 months in both groups. We noted improvement in negative symptoms, general psychopathology and total PANSS score in sarcosine group comparing to placebo, however there was no correlations between serum BDNF concentrations and PANSS scores in all assessments. Initial serum BDNF concentrations cannot be used as a predictor of the improvement resulting from adding sarcosine. Conclusions Our results indicate that either BDNF is not involved in the NMDA-dependent mechanism of sarcosine action or global changes in BDNF concentrations induced by amino-acid cannot be detected in blood assessments. [ABSTRACT FROM AUTHOR]

Aim: Find changes in matrix metallopeptidase-9 (MMP-9) levels during augmentation of antipsychotic treatment with sarcosine and a relationship between schizophrenia symptoms severity and initial level of MMP-9. Method: Fifty-eight patients with diagnosis of schizophrenia with predominant negative symptoms participated in a six-month prospective RCT (randomized controlled trial). The patients received two grams of sarcosine (n = 28) or placebo (n = 30) daily. At the beginning, after six weeks and after six months MMP-9 levels were measured. Severity of symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS). Results: MMP-9 serum levels were stable after six weeks and six months in both groups. We noted improvement in negative symptoms, general psychopathology and total PANSS score in sarcosine group compared to placebo; however, there was no correlations between serum MMP-9 concentrations and PANSS scores in all assessments. Initial serum MMP-9 concentrations cannot be used as an improvement predictor acquired during sarcosine augmentation. Conclusions: Our results indicate that either MMP-9 is not involved in the N-methyl-D-aspartate (NMDA)-dependent mechanism of sarcosine action in terms of clinical parameters or sarcosine induced changes in peripheral MMP-9 concentrations cannot be detected in blood assessments. [ABSTRACT FROM AUTHOR]

Visual learning and memory are one of the key cognitive domains disturbed in schizophrenia. Glutamate NMDA receptors play a crucial role in spatial learning and memory and NMDA receptor antagonists, such as phencyclidine (PCP), impair spatial learning and memory. Pigmented rat strains have superior vision than albino rat strains and are therefore commonly used in visually-demanding cognitive tests. However, all previous water maze experiments using acutely administered PCP to induce schizophrenia-like cognitive deficits have been conducted with albino Wistar rats. This study was designed to assess whether pigmented Lister Hooded (LH) rats would be more suitable in modeling acute PCP-induced deficits in Morris water maze (MWM) task than Wistar rats. We also evaluated whether the efficacy of atypical antipsychotics in reversing PCP-induced spatial navigation deficits was dependent on the rat strain. First, we compared the PCP dose-response in the range of 1.3–2.0 mg/kg (s.c.) at causing deficits in MWM performance. Then, the efficacies of sertindole 1.6 mg/kg (s.c.) and risperidone 0.04 mg/kg (s.c.) in reversing PCP-induced spatial navigation deficits were investigated. Drug-naïve LH rats showed a better spatial memory than Wistar rats. Furthermore, PCP induced deficits in spatial navigation at lower doses in LH than in Wistar rats. In addition, PCP-induced deficits were partly reversed by sertindole in LH but not in Wistar rats. Our results suggest that the deficits in spatial learning and memory that resemble memory deficits found in schizophrenia patients are better modeled by PCP in LH rats than Wistar rats. [ABSTRACT FROM AUTHOR]

Rationale: An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored. Objectives: We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl- d-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia. Methods: Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions. Results: In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine. Conclusions: We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3. [ABSTRACT FROM AUTHOR]

This Special Issue focuses on the auditory-evoked mismatch negativity (MMN), an electrophysiological index of change, and its reduction in schizophrenia. The following brief review is an attempt to complement the behavioral and clinical contributions to the Special Issue by providing basic information on synaptic interactions and processing in auditory cortex. A key observation in previous studies is that the MMN involves activation of cortical N -methyl- d -aspartate (NMDA) receptors. Yet, NMDA receptor activation is regulated by a number of synaptic events, which also may contribute to the MMN reduction in schizophrenia. Accordingly, this review will focus on synaptic interactions, notably inhibitory regulation of NMDA receptor-mediated activity, in auditory cortex. [ABSTRACT FROM AUTHOR]

Reductions in the size of the mismatch negativity (MMN), an event-related potential component elicited in response to unexpected stimuli, are arguably the most robust neurophysiological findings in schizophrenia. Several studies have now demonstrated that ‘true’ human-like deviance detection mismatch responses (MMRs) can be generated in the rodent brain and therefore that animal models can be used to examine the neurobiology of schizophrenia-like MMR impairments and investigate the efficacy of new treatments in addressing underlying neurobiological mechanisms. Two broad categories of animal models have been examined for schizophrenia-like MMRs: models involving N -methyl- D -aspartate receptor hypofunction, and models involving an insult or exposure during development. While these models have been shown to exhibit reductions in MMRs, it is still unclear whether or not these reductions involve changes to neural adaptation to repetitive stimuli or whether they reflect impairments in the response to unexpected deviations in regular patterns. [ABSTRACT FROM AUTHOR]

The article presents a review of the current status of research into cognitive symptoms of schizophrenia and their management. Topics discussed include the proposal to view schizophrenia as a cognitive illness, newer targets of drug action including the N-methyl-D-aspartate receptor (NMDA) glutamate receptor, and the benefits of cognitive remediation therapies.

The pathophysiology of schizophrenia is associated with disturbed glutamate signalling, particularly via a dysfunction of the N -methyl- d -aspartate (NMDA) receptor. In rodents, behavioural sensitisation to the NMDA receptor antagonist MK-801 is proposed to recapitulate aspects of the NMDA receptor hypofunction hypothesis of schizophrenia. The aim of this study was to determine the modulatory role of MK-801 dose and environmental context on the development and expression of MK-801-induced behavioural sensitisation. Sprague Dawley rats were administered saline or varying doses of MK-801 (i.p.) once daily for 7 days and locomotor activity was recorded. After 5 days of withdrawal, rats were challenged with their respective dose to test for sensitisation. From this experiment a sensitising dose was obtained. In the second experiment the magnitude of sensitisation was compared between rats that were treated in either a home or test environmental context. Rats treated with 0.25 mg/kg MK-801 developed robust sensitisation when challenged after withdrawal. Rats treated with lower (0.1 mg/kg) or higher (0.5 mg/kg) doses of MK-801 did not develop locomotor sensitisation. Sensitisation to 0.25 mg/kg MK-801 developed equally between rats treated in the home or test context. The study shows that male Sprague Dawley rats develop behavioural sensitisation to repeated injections of MK-801. The development of sensitisation is selective to MK-801 dose in an inverted-U dose response fashion. In this paradigm MK-801 induced sensitisation was expressed similarly between groups treated in two distinct environmental contexts. [ABSTRACT FROM AUTHOR]

Rationale: Abnormal oscillatory activity associated with N-methyl- D-aspartate (NMDA) receptor hypofunction is widely considered to contribute to the symptoms of schizophrenia. Objective: This study aims to characterise the changes produced by NMDA receptor antagonists and antipsychotics on accumbal high-frequency oscillations (HFO; 130-180 Hz) in mice. Methods: Local field potentials were recorded from the nucleus accumbens of freely moving mice. Results: Systemic injection of ketamine and MK801 both dose-dependently increased the power of HFO and produced small increases in HFO frequency. The atypical antipsychotic drug, clozapine, produced a robust dose-dependent reduction in the frequency of MK801-enhanced HFO, whilst haloperidol, a typical antipsychotic drug, had little effect. Stimulation of NMDA receptors (directly or through the glycine site) as well as activation of 5-HT receptors, reduced the frequency of MK801-enhanced HFO, but other receptors known to be targets for clozapine, namely 5-HT, 5-HT and histamine H receptors had no effect. Conclusions: NMDA receptor antagonists and antipsychotics produce broadly similar fundamental effects on HFO, as reported previously for rats, but we did observe several notable differences. In mice, HFO at baseline were weak or not detectable unlike rats. Post-injection of NMDA receptor antagonists HFO was also weaker but significantly faster. Additionally, we found that atypical antipsychotic drugs may reduce the frequency of HFO by interacting with NMDA and/or 5-HT receptors. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) plays a critical role in the motoric and glutamate releasing action of N-methyl-D-aspartate (NMDA)-antagonist stimulants. Earlier studies utilized neuronal nitric oxide synthase inhibitors (nNOS) for studying the neurobehavioral effects of non-competitive NMDA-antagonist stimulants such as dizocilpine (MK-801) and phencyclidine (PCP). This study explores the role of the inducible nitric oxide synthase inhibitors (iNOS) aminoguanidine (AG) and (-)-epigallocatechin-3-gallate (EGCG) in NMDA-antagonist induced motoric behavior and prefrontal cortical glutamate efflux. Adult male rats were administered a dose range of AG, EGCG, or vehicle prior to receiving NMDA antagonists MK-801, PCP, or a conventional psychostimulant (cocaine) and tested for motoric behavior in an open arena. Glutamate in the medial prefrontal cortex (mPFC) was measured using in vivo microdialysis after a combination of AG or EGCG prior to MK-801. Acute administration of AG or EGCG dose-dependently attenuated the locomotor and ataxic properties of MK-801 and PCP. Both AG and EGCG were unable to block the motoric effects of cocaine, indicating the acute pharmacologic action of AG and EGCG is specific to NMDA antagonism and not generalizable to all stimulant class drugs. AG and EGCG normalized MK-801-stimulated mPFC glutamate efflux. These data demonstrate that AG and EGCG attenuates NMDA antagonist-stimulated motoric behavior and cortical glutamate efflux. Our results suggest that EGCG-like polyphenol nutraceuticals (contained in "green tea" and chocolate) may be clinically useful in protecting against the adverse behavioral dissociative and cortical glutamate stimulating effects of NMDA antagonists. Medications that interfere with NMDA antagonists such as MK-801 and PCP have been proposed as treatments for schizophrenia. [ABSTRACT FROM AUTHOR]

Rationale: Current treatments for schizophrenia have modest, if any, efficacy on cognitive dysfunction, creating a need for novel therapies. Their development requires predictive animal models. The N-methyl- d-aspartate (NMDA) hypothesis of schizophrenia indicates the use of NMDA antagonists, like subchronic phencyclidine (scPCP) to model cognitive dysfunction in adult animals. Objectives: The objective of this study was to assess the scPCP model by (1) reviewing published findings of scPCP-induced neurochemical changes and effects on cognitive tasks in adult rats and (2) comparing findings from a multi-site study to determine scPCP effects on standard and touchscreen cognitive tasks. Methods: Across four research sites, the effects of scPCP (typically 5 mg/kg twice daily for 7 days, followed by at least 7-day washout) in adult male Lister Hooded rats were studied on novel object recognition (NOR) with 1-h delay, acquisition and reversal learning in Morris water maze and touchscreen-based visual discrimination. Results: Literature findings showed that scPCP impaired attentional set-shifting (ASST) and NOR in several labs and induced a variety of neurochemical changes across different labs. In the multi-site study, scPCP impaired NOR, but not acquisition or reversal learning in touchscreen or water maze. Yet, this treatment regimen induced locomotor hypersensitivity to acute PCP until 13-week post-cessation. Conclusions: The multi-site study confirmed that scPCP impaired NOR and ASST only and demonstrated the reproducibility and usefulness of the touchscreen approach. Our recommendation, prior to testing novel therapeutics in the scPCP model, is to be aware that further work is required to understand the neurochemical changes and specificity of the cognitive deficits. [ABSTRACT FROM AUTHOR]

Summary Schizophrenia is associated with disruptions in N -methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu 5 ) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu 5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu 5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu 5 coupling to G αq -mediated signaling but not mGlu 5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu 5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy. Video Abstract [ABSTRACT FROM AUTHOR]

Numerous studies have demonstrated that NMDA stimulation of the rat ventral hippocampus induces hyperactivity and disruption of prepulse inhibition (PPI) and some reports have provided insights into the different neural substrates of these two effects. Bilateral or unilateral NMDA stimulation have been applied in these studies, but have never been compared directly. Thus, results of these studies can be related to each other only with reservations. Therefore – given the substantial interest in the behavioral effects of hippocampal overactivity and the neural substrates underlying PPI with respect to schizophrenia – the present experiments compared hyperactivity and PPI disruption following uni- or bilateral NMDA stimulation of the ventral hippocampus. Both bilateral and unilateral infusion of NMDA (0.5 μg/0.5 μl/side) induced hyperactivity in the open field and disrupted PPI. The major difference noted between unilateral and bilateral infusions was that the effects of bilateral infusions were stronger than those of the unilateral infusions. [ABSTRACT FROM AUTHOR]

When subjected to a phasic input, sensory cortical neurons display a remarkable ability to entrain faithfully to the driving stimuli. The entrainment to rhythmic sound stimuli is often referred to as the auditory steady-state response (ASSR) and can be captured using noninvasive techniques, such as scalp-recorded electroencephalography (EEG). An ASSR to a driving frequency of approximately 40 Hz is particularly interesting in that it shows, in relative terms, maximal power, synchrony, and synaptic activity. Moreover, the 40-Hz ASSR has been consistently found to be abnormal in schizophrenia patients across multiple studies. The nature of the reported abnormality has been less consistent; while most studies report a deficit in entrainment, several studies have reported increased signal power, particularly when there are concurrent positive symptoms, such as auditory hallucinations. However, the neuropharmacological basis for the 40-Hz ASSR, as well as its dysfunction in schizophrenia, has been unclear until recently. On the basis of several recent reports, it is argued that the 40-Hz ASSR represents a specific marker for cortical NMDA transmission. If confirmed, the 40-Hz ASSR may be a simple and easy-to-access pharmacodynamic biomarker for testing the integrity of cortical NMDA neurotransmission that is robustly translational across species. [ABSTRACT FROM AUTHOR]

Cognitive impairment, including impaired social cognition, is largely responsible for the deterioration in social life suffered by patients with psychiatric disorders, such as schizophrenia and major depressive disorder (MDD). Brexpiprazole (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one), a novel serotonin–dopamine activity modulator, was developed to offer efficacious and tolerable therapy for different psychiatric disorders, including schizophrenia and adjunctive treatment of MDD. In this study, we investigated whether brexpiprazole could improve social recognition deficits (one of social cognition deficits) in mice, after administration of the N -methyl- d -aspartate (NMDA) receptor antagonist MK-801 (dizocilpine). Dosing with dizocilpine (0.1 mg/kg) induced significant impairment of social recognition in mice. Brexpiprazole (0.01, 0.03, 0.1 mg/kg, p.o.) significantly ameliorated dizocilpine-induced social recognition deficits, without sedation or a reduction of exploratory behavior. In addition, brexpiprazole alone had no effect on social recognition in untreated control mice. By contrast, neither risperidone (0.03 mg/kg, p.o.) nor olanzapine (0.03 mg/kg, p.o.) altered dizocilpine-induced social recognition deficits. Finally, the effect of brexpiprazole on dizocilpine-induced social recognition deficits was antagonized by WAY-100,635, a selective serotonin 5-HT 1A antagonist. These results suggest that brexpiprazole could improve dizocilpine-induced social recognition deficits via 5-HT 1A receptor activation in mice. Therefore, brexpiprazole may confer a beneficial effect on social cognition deficits in patients with psychiatric disorders. [ABSTRACT FROM AUTHOR]

Schizophrenia is a chronic and severe mental disorder characterized by the disintegration of cognitive thought processes and emotional responses. Despite the precise cause of schizophrenia remains unclear, it is hypothesized that a dysregulation of the N-methyl-D-aspartate (NMDA) receptor in the brain is a major contributing factor to its development. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is implicated in learning and memory processes. In the present study, we investigated in vivo the effects of voluntary wheel running on behavioral symptoms associated with NMDA receptor expression, using MK-801-induced schizophrenic mice. Abilify (aripiprazole), a drug used to treat human schizophrenia patients, was used as the positive control. For the assessment of behavioral symptoms affecting locomotion, social interaction and spatial working memory, the open-field, social interaction and Morris water maze tests were conducted. For investigating the biochemical parameters, NMDA receptor expression in the hippocampal CA2-3 regions and prefrontal cortex was detected by NMDA immunofluorescence and BDNF expression in the hippocampus was measured using western blot analysis. MK-801 injection for 14 days induced schizophrenia-like behavioral abnormalities with decreased expression of the NMDA receptor and BDNF in the brains of mice. The results indicated that free access to voluntary wheel running for 2 weeks alleviated schizophrenia-like behavioral abnormalities and increased the expression of NMDA receptor and BDNF, comparable to the effects of aripiprazole treatment. In the present study, the results suggest that NMDA receptor hypofunctioning induced schizophrenia-like behaviors, and that voluntary wheel running was effective in reducing these symptoms by increasing NMDA receptor and BDNF expression, resulting in an improvement of disease related behavioral deficits. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate (NMDA) receptor hypofunction has been implicated in the pathophysiology of schizophrenia. The illness is also characterized by gamma oscillatory disturbances, which can be evaluated with precise frequency specificity employing auditory cortical entrainment paradigms. This computational study investigates how synaptic NMDA hypofunction may give rise to network level oscillatory deficits as indexed by entrainment paradigms. We developed a computational model of a local cortical circuit with pyramidal cells and fast-spiking interneurons (FSI), incorporating NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA), and γ-aminobutyric acid (GABA) synaptic kinetics. We evaluated the effects of varying NMDA conductance on FSIs and pyramidal cells, as well as AMPA to NMDA ratio. We also examined the differential effects across a broad range of entrainment frequencies as a function of NMDA conductance. Varying NMDA conductance onto FSIs revealed an inverted-U relation with network gamma whereas NMDA conductance onto the pyramidal cells had a more monotonic relationship. Varying NMDA vs. AMPA conductance onto FSIs demonstrated the necessity of AMPA in the generation of gamma while NMDA receptors had a modulatory role. Finally, reducing NMDA conductance onto FSI and varying the stimulus input frequency reproduced the specific reductions in gamma range (~40 Hz) as observed in schizophrenia studies. Our computational study showed that reductions in NMDA conductance onto FSIs can reproduce similar disturbances in entrainment to periodic stimuli within the gamma range as reported in schizophrenia studies. These findings provide a mechanistic account of how specific cellular level disturbances can give rise to circuitry level pathophysiologic disturbance in schizophrenia. [ABSTRACT FROM AUTHOR]

Rationale: Disturbances in information processing and cognitive function are key features of schizophrenia. Nicotinic α7 acetylcholine receptors (α7-nAChR) are involved in sensory gating and cognition, thereby representing a viable therapeutic strategy. Objectives and methods: We investigated the effects of GTS-21, an α7-nAChR partial agonist, on prepulse inhibition (PPI) of acoustic startle in two pharmacologic impairment models in Wistar male rats: NMDA-glutamate receptor antagonism by MK-801 and dopamine receptor agonism by apomorphine. The cognitive effects of GTS-21 were assessed using the object recognition task (ORT) at short (3 h) and long (48 h) delays in Sprague-Dawley male rats. Pharmacological specificity was assessed by methyllycaconitine (MLA) coadministration with GTS-21. Results: In the PPI task, GTS-21 (1-10 mg/kg) alone did not alter the PPI response or startle amplitude. Coadministration of GTS-21 with MK-801 (0.1 mg/kg) or apomorphine (0.5 mg/kg) abolished the pharmacologic-induced PPI impairment as did the antipsychotics clozapine (5.0 mg/kg) and haloperidol (0.3 mg/kg). MK-801 alone increased startle amplitude which was blocked by GTS-21. In the ORT, GTS-21 (0.1-10 mg/kg) reversed the MK-801 (0.08 mg/kg)-induced memory deficit at the 3 h delay and enhanced memory at the 48 h delay, an effect abolished by MLA (0.313-5 mg/kg). Conclusions: The results extend our preclinical pharmacological understanding of GTS-21 to include the ability of GTS-21 to modulate NMDA-glutamate receptor function, in vivo. Given the role of NMDA-glutamate receptor involvement in schizophrenia, α7-nAChR agonists may represent a novel treatment strategy for the pathophysiological deficits of schizophrenia and other psychiatric disorders. [ABSTRACT FROM AUTHOR]

Schizophrenia patients exhibit a decreased ability to detect change in their auditory environment as measured by auditory event-related potentials (ERP) such as mismatch negativity. This deficit has been linked to abnormal NMDA neurotransmission since, among other observations, non-selective channel blockers of NMDA reliably diminish automatic deviance detection in human subjects as well as in animal models. Recent molecular and functional evidence links NR2B receptor subtype to aberrant NMDA transmission in schizophrenia. However, it is unknown if NR2B receptors participate in pre-attentive deviance detection. We recorded ERP from the vertex of freely behaving rats in response to frequency mismatch protocols. We saw a robust increase in N1 response to deviants compared to standard as well as control stimuli indicating true deviance detection. Moreover, the increased negativity was highly sensitive to deviant probability. Next, we tested the effect of a non-selective NMDA channel blocker (ketamine, 30mg/kg) and a highly selective NR2B antagonist, CP-101,606 (10 or 30mg/kg) on deviance detection. Ketamine attenuated deviance mainly by increasing the amplitude of the standard ERP. Amplitude and/or latency of several ERP components were also markedly affected. In contrast, CP-101,606 robustly and dose-dependently inhibited the deviant's N1 amplitude, and as a consequence, completely abolished deviance detection. No other ERPs or components were affected. Thus, we report first evidence that NR2B receptors robustly participate in processes of automatic deviance detection in a rodent model. Lastly, our model demonstrates a path forward to test specific pharmacological hypotheses using translational endpoints relevant to aberrant sensory processing in schizophrenia. [ABSTRACT FROM AUTHOR]

Rationale: Schizophrenia is a debilitating disorder comprising positive, negative and cognitive deficits with a poorly defined neurobiological aetiology; therefore, animal models with greater translational reliability are essential to develop improved therapies. Objectives: This study combines two developmental challenges in rats, neonatal phencyclidine (PCP) injection and subsequent rearing in social isolation from weaning, to attempt to produce more robust behavioural deficits with greater translational relevance to schizophrenia than either challenge alone. Methods: Forty-two male Lister-hooded rat pups received the N-methyl- d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP, 10 mg/kg, s.c.), or vehicle on post-natal day (PND) 7, 9 and 11 and were weaned on PND 23 into group housing (saline-treated n = 11 or PCP-treated n = 10) or isolation (saline n = 10 or PCP n = 11). Six weeks post-weaning, novelty- and PCP-induced (3.2 mg/kg) locomotor activity, novel object discrimination, prepulse inhibition of acoustic startle and contextual memory in a conditioned emotion response (CER) were recorded. Results: Isolation rearing alone significantly elevated baseline locomotor activity and induced visual recognition memory impairment in novel object discrimination. Neonatal PCP treatment did not induce locomotor sensitisation to a subsequent acute PCP injection, but it impaired prepulse inhibition when combined with isolation rearing. CER freezing behaviour was significantly reduced by isolation rearing but an even greater effect occurred when combined with neonatal PCP treatment. Conclusions: Neonatal PCP and isolation rearing both produce behavioural deficits in adult rats, but combined treatment caused a wider range of more severe cognitive impairments, providing a more comprehensive preclinical model to determine the neurobiological aetiology of schizophrenia than either treatment alone. [ABSTRACT FROM AUTHOR]

At the synapse, D-serine is an endogenous co-agonist for the N-methyl-D-aspartate receptor (NMDAR). It plays an important role in synaptic transmission and plasticity and has also been linked to several pathological diseases such as schizophrenia and Huntington's. The quantification of local changes in n-serine concentration is essential to further understanding these processes. We report herein the development of a disk-shaped amperometric enzymatic biosensor for detection of D-serine based on a 25 μm diameter platinum disk microelectrode with an electrodeposited poly-m-phenylenediamine (PPD) layer and an K gracilis D-amino acid oxidase (RgDAAO) layer. The disk-shaped D-serine biosensor is 1-5 orders of magnitude smaller than previously reported probes and exhibits a sensitivity of 276 μA cm-2 mM-1 with an in vitro detection limit of 0.6 μM. We demonstrate its usefulness for in vivo applications by measuring the release of endogenous D-serine in the brain of Xenopus laevis tadpoles. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Despite ample evidence supporting the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia, progress in the development of effective therapeutics based on this hypothesis has been limited. Facilitation of NMDA receptor function by co-agonists (D-serine or glycine) only partially alleviates the symptoms in schizophrenia; other means to facilitate NMDA receptors are required. NMDA receptor sub-types differ in their subunit composition, with varied GluN2 subunits (GluN2A-GluN2D) imparting different physiological, biochemical and pharmacological properties. CIQ is a positive allosteric modulator that is selective for GluN2C/GluN2D-containing NMDA receptors (Mullasseril et al.). EXPERIMENTAL APPROACH The effect of systemic administration of CIQ was tested on impairment in prepulse inhibition (PPI), hyperlocomotion and stereotypy induced by i.p. administration of MK-801 and methamphetamine. The effect of CIQ was also tested on MK-801-induced impairment in working memory in Y-maze spontaneous alternation test. KEY RESULTS We found that systemic administration of CIQ (20 mg⋅kg-1i.p.) in mice reversed MK-801 (0.15 mg⋅kg-1 i.p.)-induced, but not methamphetamine (3 mg⋅kg-1 i.p.)-induced, deficit in PPI. MK-801 increased the startle amplitude to pulse alone, which was not reversed by CIQ. In contrast, methamphetamine reduced the startle amplitude to pulse alone, which was reversed by CIQ. CIQ also partially attenuated MK-801- and methamphetamine-induced hyperlocomotion and stereotyped behaviours. Additionally, CIQ reversed the MK-801-induced working memory deficit in spontaneous alternation in a Y-maze. CONCLUSION AND IMPLICATIONS Together, these results suggest that facilitation of GluN2C/GluN2D-containing receptors may serve as an important therapeutic strategy for treating positive and cognitive symptoms in schizophrenia. [ABSTRACT FROM AUTHOR]