Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

Rationale  

The glutamatergic theory of schizophrenia proposes a dysfunction of ionotropic N-methyl-d-aspartate receptors (NMDA-R). Several therapeutic strategies address NMDA-R function and the effects of antipsychotic agents on NMDA-R expression have been described. Within the second-generation antipsychotics, the partial dopaminergic and serotonergic agonist aripiprazole (APZ) was able to counteract the behavioral effects of NMDA-R antagonists.     

Behavioral and molecular evidence for psychotropic effects in <Emphasis Type="SmallCaps">l</Emphasis>-theanine

Rationale  

l-Theanine (N-ethyl-l-glutamine) is an amino acid uniquely found in green tea and historically considered to be a relaxing agent. It is a glutamate derivative and has an affinity for glutamatergic receptors. However, its psychotropic effects remain unclear.     

Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome

Rationale  

Studies in the Fmr1 knockout (KO) mouse, a model of fragile X syndrome (FXS), suggest that excessive signaling through group I metabotropic glutamate receptors (mGluRs), comprised of subtypes mGluR1 and mGluR5, may play a role in the pathogenesis of FXS. Currently, no studies have assessed the effect of mGluR1 modulation on Fmr1 KO behavior, and there has not been an extensive behavioral analysis of mGluR5 manipulation in Fmr1 KO mice.     

Effects of low-dose <Emphasis Type="SmallCaps">d</Emphasis>-serine on recognition and working memory in mice

Rationale  

d-Serine is an endogenous co-agonist of the N-methyl-d-aspartate (NMDA) receptor and has been suggested to improve cognitive deficits in schizophrenia.     

d-Serine and a glycine transporter-1 inhibitor enhance social memory in rats

Rationale  

Glutamatergic abnormalities are involved in the etiology of schizophrenia. Clinical evidence demonstrates that positive modulation of “glycine modulatory sites” on N-methyl-d-aspartic acid (NMDA) receptors improve cognitive deficits as well as positive and negative symptoms in schizophrenic patients.     

A comparison of the effects of ketamine and phencyclidine with other antagonists of the NMDA receptor in rodent assays of attention and working memory

Rationale  

N-methyl-d-Aspartate receptor (NMDAR) antagonists such as ketamine induce cognitive symptoms in man similar to those of schizophrenia and therefore might be useful as models of the disease in animals. However, it is unclear which NMDAR antagonist(s) offer the best means to produce cognitive deficits in attention and working memory and to what extent those deficits can be measured selectively in rats.     

Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia

Background: Normalization of excessive glutamate neurotransmission through activation of the metabotropic glutamate receptor 2 (mGluR2) represents a novel and promising approach for the treatment of schizophrenia. This strategy has gained support through the evaluation of dual mGluR2/3 agonists that act directly at the glutamate (orthosteric) binding site. Importantly, clinical validation of the mechanism was achieved in a Phase II study in schizophrenia patients with mGluR2/3 agonist LY404039. Selective positive allosteric modulators (potentiators) of mGluR2 that bind to the transmembrane region of the receptor have shown efficacy in rodent models predictive of antipsychotic activity, but have yet to be evaluated in the clinic. Allosteric mGluR2 potentiators may offer advantages over orthosteric mGluR2/3 agonists as a result of their unique mode of action and ability to achieve superior mGluR2 selectivity. Objective/method: This review focuses on the structures and biological activities of small molecule potentiators of mGluR2 that appeared in the patent literature between 2006 and early 2009. Conclusion: Potent mGluR2 potentiators that span a broad range of structural diversity have been disclosed. Narrow patent filings within select series and drug-like properties of corresponding preferred compounds suggest that development candidates have likely been nominated.     

Group II mGluR agonist LY354740 and NAAG peptidase inhibitor effects on prepulse inhibition in PCP and <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine models of schizophrenia

Rationale  

Group II metabotropic glutamate receptor (mGluR) agonists represent a novel approach to the treatment of schizophrenia. Inasmuch as the peptide neurotransmitter N-acetylaspartylglutamate (NAAG) activates these receptors, NAAG peptidase inhibitors conceptually represent a parallel path toward development of new antipsychotic drugs. While group II agonists are effective in several animal models of schizophrenia, they are reported to lack efficacy in moderating the effects of phencyclidine (PCP) on prepulse inhibition of acoustic startle in animal models of sensory processing deficits found in this disorder.     

Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development

Rationale

Fragile X syndrome (FXS) is considered the leading inherited cause of intellectual disability and autism. In FXS, the fragile X mental retardation 1 (FMR1) gene is silenced and the fragile X mental retardation protein (FMRP) is not expressed, resulting in the characteristic features of the syndrome. Despite recent advances in understanding the pathophysiology of FXS, there is still no cure for this condition; current treatment is symptomatic. Preclinical research is essential in the development of potential therapeutic agents.

Objectives

This review provides an overview of the preclinical evidence supporting metabotropic glutamate receptor 5 (mGluR5) antagonists as therapeutic agents for FXS.

Results

According to the mGluR theory of FXS, the absence of FMRP leads to enhanced glutamatergic signaling via mGluR5, which leads to increased protein synthesis and defects in synaptic plasticity including enhanced long-term depression. As such, efforts to develop agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. Animal models, particularly the Fmr1 knockout mouse model, have become invaluable in exploring therapeutic approaches on an electrophysiological, behavioral, biochemical, and neuroanatomical level. Two direct approaches are currently being investigated for FXS treatment: reactivating the FMR1 gene and compensating for the lack of FMRP. The latter approach has yielded promising results, with mGluR5 antagonists showing efficacy in clinical trials.

Conclusions

Targeting mGluR5 is a valid approach for the development of therapeutic agents that target the underlying pathophysiology of FXS. Several compounds are currently in development, with encouraging results.     

The role of NMDA receptors in the signal attenuation rat model of obsessive–compulsive disorder

Rationale  

In recent years, an increasing body of evidence points to the involvement of the glutamatergic system and specifically the glutamatergic ionotropic N-methyl-d-aspartate (NMDA) receptor in the pathophysiology of obsessive–compulsive disorder (OCD).     

Inhibition of cerebral type 1 cannabinoid receptors is associated with impaired auditory mismatch negativity generation in the ketamine model of schizophrenia

Rationale  

Preclinical and clinical research suggests that the endogenous cannabinoid system is involved in cognitive impairments related to schizophrenia. In particular, the deficient generation of mismatch negativity (MMN) indicating auditory sensory memory is a characteristic finding in schizophrenic patients. Experimental studies implicate deficient N-methyl-d-aspartate (NMDA) receptor functioning in such abnormalities.     

Ketamine-induced deficit of auditory gating in the hippocampus of rats is alleviated by medial septal inactivation and antipsychotic drugs

Rationale  

Gating of sensory responses is impaired in schizophrenic patients and animal models of schizophrenia. Ketamine, an N-methyl-d-aspartate receptor antagonist, is known to induce schizophrenic-like symptoms including sensory gating deficits in humans.     

Rapid development of tolerance to sub-anaesthetic dose of ketamine: an oculomotor study in macaque monkeys

Background  

Ketamine, a non-competitive N-methyl-d-aspartic acid antagonist, has been widely used for anaesthetic purposes. At sub-anaesthetic dosage, it induces a dissociative state similar to schizophrenia. The discovery of this effect on dissociative state has led to its use as a pharmacological model of schizophrenia and has also been responsible for its illegal use as a recreational drug. Whereas the former has provided invaluable information, the latter has demonstrated that repeated administration of ketamine induces tolerance. Surprisingly, a review of the relevant literature shows that tolerance to sub-anaesthetic doses of ketamine is largely unreported in neuropharmacological studies.     

Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects

Rationale Some of the behavioral consequences of deficits in N-methyl-d-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry.Objective This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects.Methods Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.7 h prior to ketamine administration (bolus of 0.26 mg/kg over 1 min, infusion of 0.65 mg/kg per hour for 100 min). Thus on each test day each subject received a single dose of LY354740 (or its matched placebo) and both saline and ketamine infusions.Results Ketamine impaired attention, working memory, and delayed recall. It also produced positive and negative symptoms, perceptual changes, and dysphoric mood. LY354740 did not have a significant effect on working memory on the placebo day; however, it produced a significant dose-related improvement in working memory during ketamine infusion.Conclusions These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.     

The mGluR2/3 agonist LY379268 reverses post-weaning social isolation-induced recognition memory deficits in the rat

Rationale  

Current antipsychotics are ineffective at treating the negative and cognitive symptoms of schizophrenia, so there is a substantial need to develop more effective therapeutics for this debilitating disorder. The type II metabotropic glutamate receptor (mGluR2/3) is a novel, potential therapeutic target requiring evaluation in appropriate preclinical models of schizophrenia.     

Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABA<Subscript>A</Subscript> and mGlu receptor subtypes

Rationale  

Repeated activation of corticotropin-releasing factor (CRF) receptors is associated with increased anxiety and enhanced stress responsivity, which may be mediated via limbic GABAergic and glutamatergic transmission.     

The effects of PRX-07034, a novel 5-HT<Subscript>6</Subscript> antagonist,on cognitive flexibility and working memory in rats

Rationale  

Accumulating evidence indicates that schizophrenia and autism spectrum disorder patients are marked by cognitive deficits in working memory and strategy switching. There is accumulating evidence that 5-hydroxytryptamine (5-HT)₆ receptors may serve as a useful target to improve cognitive functioning.     

Association between PLA2G12A polymorphism and patients with schizophrenia in a southern Chinese Han population

Background

Elevated phospholipase A2 (PLA2) activity is reported to be involved in the development of schizophrenia. Further study revealed an association between PLA2 groups XIIA (PLA2G12A) polymorphism and patients with schizophrenia in a northeast Chinese Han population.

Objective

This study will further examine whether PLA2G12A rs3087494 polymorphism is associated with patients with schizophrenia in a southern Chinese Han population.

Methods

This polymorphism was genotyped in 438 patients with schizophrenia (diagnosed according to Diagnostic and Statistical Manual of Mental Disorders‐IV) and 876 healthy controls using a case–control design. Demographic and clinical data were collected in all subjects.

Results

The allele and genotype frequencies of PLA2G12A rs3087494 polymorphism significantly differed between groups (both, p < .001). These differences still were significant by adjusting for sex and age. However, there was no difference in age at onset among 3 genotype groups in patients with schizophrenia by adjusting for the variables (F = 0.22, p = .80). Stepwise multivariate regression analysis showed that this polymorphism was not associated with age at onset in patients with schizophrenia (β = .008, t = .07, p = .94).

Conclusions

Our results indicated that even though PLA2G12A rs3087494 polymorphism did not influence age at onset in patients with schizophrenia, it may play an important role in the susceptibility to schizophrenia in a southern Chinese Han population.     

RGS4 overexpression in the rat dorsal striatum modulates mGluR5- and amphetamine-mediated behavior and signaling

Rationale

Regulator of G-protein signaling 4 (RGS4) is a brain-enriched negative modulator of G-protein-coupled receptor signaling. Decreased availability of RGS4 in the frontal cortex and striatum has been described in animal models of schizophrenia and drug addiction. However, cellular and behavioral consequences of dysregulated RGS4-dependent receptor signaling in the brain remain poorly understood.

Objective

This study aims to investigate whether RGS4, through inhibiting the function of mGluR5 receptors in the dorsal striatum (dSTR), regulates cellular and behavioral responses to acute amphetamine.

Methods

After herpes simplex virus-RGS4 was infused into the dSTR, RGS4 overexpression as well as binding of recombinant RGS4 to mGluR5 was assessed. The effect of RGS4 overexpression on behavioral activity induced by the intrastriatal mGluR5 agonist, DHPG, or amphetamine was recorded. Activation of extracellular signal-regulated kinase (ERK) and Akt (protein kinase B) was measured in the dSTR tissue at the end of each behavioral experiment.

Results

RGS4 overexpressed in the dSTR coimmunoprecipitated with mGluR5 receptors and suppressed both behavioral activity and phospho-ERK levels induced by DHPG. RGS4 overexpression or the mGluR5 antagonist, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP), attenuated amphetamine-induced phospho-ERK (but not phospho-Akt) levels. RGS4 suppressed amphetamine-induced vertical activity and augmented horizontal activity over 90?min. Similarly, MTEP augmented amphetamine-induced horizontal activity, but did not affect vertical activity.

Conclusions

The present data demonstrate that RGS4 in the dSTR attenuates amphetamine-induced ERK signaling and decreases the behavioral efficacy of acute amphetamine likely by limiting mGluR5 function.     

Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and sertindole

Rationale  

A pivotal role for glutamate in the pathophysiology and treatment of schizophrenia has been suggested. Few reports have investigated the impact of antipsychotics on postsynaptic density (PSD) molecules involved in glutamatergic transmission and synaptic remodeling. Homer is a key PSD molecule putatively implicated in schizophrenia.