Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies indicate that agonists of the group II metabotropic glutamate receptors (mGluRs), mGluR2 and mGluR3, may provide a novel approach for the treatment of anxiety disorders and schizophrenia. However, the relative contributions of the mGluR2 and mGluR3 subtypes to the effects of the group II mGluR agonists remain unclear. In the present study, we describe an alternate synthesis and further pharmacological characterization of a recently reported positive allosteric modulator of mGluR2 termed biphenyl-indanone A (BINA). In recombinant systems, BINA produced a robust and selective potentiation of the response of mGluR2 to glutamate with no effect on the glutamate response of other mGluR subtypes. In hippocampal brain slices, BINA (1 microM) significantly potentiated the mGluR2/3 agonist-induced inhibition of excitatory synaptic transmission at the medial perforant path-dentate gyrus synapse. BINA was also efficacious in several models predictive of antipsychotic- and anxiolytic-like activity in mice. The behavioral effects of BINA were blocked by the mGluR2/3 antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), suggesting that the in vivo effects of BINA are mediated by increased activation of mGluR2. Collectively, these results indicate that BINA is a selective mGluR2 positive allosteric modulator and provide further support for the growing evidence that selective allosteric potentiators of mGluR2 mimic many of the in vivo actions of mGluR2/3 agonists that may predict therapeutic utility of these compounds.
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PMID:Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice. 1660 16

One of the functions of group II metabotropic glutamate receptors (mGluR2/3) is to modulate glutamate release. Thus, targeting mGluR2/3s might be a novel treatment for several psychiatric disorders associated with inappropriate glutamatergic neurotransmission, such as schizophrenia. In an effort to evaluate the antipsychotic properties of LY379268, a potent and selective mGluR2/3 agonist, we examined its effect on ketamine-evoked hyperlocomotion and sensorimotor gating deficit (PPI) in rats, an animal model of schizophrenia. We also measured the ex vivo tissue level of glutamate (Glu), dopamine (DA) and serotonin (5-HT) as well as the DA metabolites DOPAC and the major 5-HT metabolite HIAA to determine the neurochemical effects of ketamine (12 mg/kg) and LY379268 (1 mg/kg) in the dentate gyrus (DG). While LY379268 (1-3 mg/kg) reduced ketamine-evoked hyperlocomotion (12 mg/kg), it could not restore ketamine-evoked PPI deficits (4-12 mg/kg). In the DG we found that ketamine decreased Glu and DA levels, as well as HIAA/5-HT turnover, and that LY379268 could prevent ketamine effects on Glu level but not on monoamine transmission. These results may indicate that the inability of LY379268 to reverse PPI deficits is attributable to its lack of effect on ketamine-induced changes in monoamine transmission, but that LY379268 can prevent ketamine-evoked changes in glutamate, which is sufficient to block hyperlocomotion. In addition to the partial effectiveness of LY379268 in the ketamine model of schizophrenia, we observed a dual effect of LY379268 on anxious states, whereby a low dose of this compound (1 mg/kg) produced anxiolytic effects, while a higher dose (3 mg/kg) appeared to be anxiogenic. Additional work is needed to address a possible role of LY379268 in schizophrenia and anxiety treatment.
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PMID:Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat. 1685 51

Schizophrenia is characterized by attentional deficits possibly associated with glutamate dysfunction. The role of postsynaptic metabotropic glutamate 5 receptors (mGluR5) or presynaptic inhibitory mGluR2/3 on attention is currently unknown. We investigated the effects of the mGluR5 antagonist MPEP (2-methyl-6[phenylethynyl]-pyridine) and the mGluR2/3 antagonist LY341495 on attention in the 5-choice serial reaction time task (5CSRTT), as well as on food intake to evaluate their effects on food motivation. The effects of pre-feeding and the muscle relaxant curare were examined to characterize the effects of alterations in the motivation or ability to perform the task, respectively. MPEP had no effect on accuracy but overall decreased performance in the 5CSRTT, including decreased speed of responding and decreased premature responses. LY341495 had no significant effect on rats' performance in the 5CSRTT. LY341495 decreased food intake in the home cage to a greater extent than MPEP. Curare decreased the speed of correct responding, reflecting motor impairment. Free feeding decreased overall performance, number of trials completed and number of head entries into the feeder, reflecting decreased motivation to perform the task. Thus, blockade of mGluR5, but not mGluR2/3, decreased overall responding without affecting accuracy in the 5CSRTT.
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PMID:The effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on rats' performance in the 5-choice serial reaction time task. 1712 59

Cortical metabotropic glutamate receptors (mGluRs) seem to be involved in habituation of simple stimulus-bound behaviors (e.g., habituation to acoustic startle or odor-elicited orienting response). Habituation deficits may contribute to the cognitive symptoms of schizophrenia. In the present study, male NMRI mice were injected with mGluR2/3 antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY-341495) 30 min before being placed into novel arenas for automatic motor activity recording (2-h sessions). Administration of LY-341495 (1-10 mg/kg s.c.) dose-dependently prevented the habituation of the locomotor activity. Effects of LY-341495 (10 mg/kg) were fully and dose-dependently reversed by i.p. administration of haloperidol (0.03-0.3 mg/kg), clozapine (1-10 mg/kg), risperidone (0.01-0.1 mg/kg), olanzapine (0.3-3 mg/kg), aripiprazole (1-10 mg/kg), and sulpiride (3-30 mg/kg), each of which was given 15 min before the test. Effects of antipsychotic drugs were observed at the dose levels that did not affect spontaneous motor activity. LY-341495-induced delayed hyperactivity was also partially attenuated by lithium (50-200 mg/kg), amisulpride (1-10 mg/kg), and the selective dopamine D3 antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011A; 3-30 mg/kg). Application of diazepam, imipramine, or several agonists and/or antagonists acting at various receptors that are thought to be relevant for antipsychotic treatment [e.g., 5-hydroxytryptamine (5-HT)(2A), 5-HT(3), and 5-HT(6) antagonists; 5-HT(1A) agonist; D4 antagonist; CB1 antagonist; ampakines; and glycine transporter inhibitor) had no appreciable effects. Thus, behavioral deficits induced by mGluR2/3 blockade (such as delayed motor hyperactivity) are selectively reversed by clinically used antipsychotic drugs.
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PMID:Habituation deficits induced by metabotropic glutamate receptors 2/3 receptor blockade in mice: reversal by antipsychotic drugs. 1713 47

Acute administration of NMDA receptor (NMDAR) antagonists such as phencyclidine (PCP) or ketamine induces symptoms that closely resemble those of schizophrenia in humans, a finding that has led to the hypothesis that a decreased NMDAR function may be a predisposing or even causative factor in schizophrenia. However, the precise neuropharmacological mechanisms underlying these effects remain to be fully elucidated. Here, we applied pharmacological MRI (phMRI) to examine the brain circuitry underlying the psychotomimetic action of PCP in the anesthetized rat, and investigated how these functional changes are modulated by drugs that possess distinct pharmacological mechanisms. Acute administration of PCP (0.5 mg/kg i.v.) produced robust and sustained positive relative cerebral blood volume (rCBV) changes in discrete cortico-limbo-thalamic regions. Pretreatment with the selective D2 dopamine antagonist raclopride (0.3 mg/kg i.p.) did not significantly affect the rCBV response to PCP, while the atypical antipsychotic clozapine (5 mg/kg i.p.) produced region-dependent effects, with complete suppression of the rCBV response in the thalamus, and weaker attenuation of the response in cortical and hippocampal structures. The response to PCP was strongly suppressed in all regions by pretreatment with two drugs that can inhibit aberrant glutamatergic activity: the anticonvulsant lamotrigine (10 mg/kg i.p.) and the mGluR2/3 agonist LY354740 (10 mg/kg i.p.). Taken together, our findings corroborate the pivotal role of dysfunctional glutamatergic neurotransmission in the functional response elicited by PCP, while the lack of effect of raclopride argues against a primary role of dopamine D2 receptor activation in this process. Finally, the thalamic effect of clozapine could be key to elucidating the functional basis of its pharmacological action.
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PMID:Differential effects of antipsychotic and glutamatergic agents on the phMRI response to phencyclidine. 1780 12

The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR-mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR-mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.
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PMID:Identification of a serotonin/glutamate receptor complex implicated in psychosis. 1832 19

Glutamate is a major neurotransmitter in the central nervous system, and abnormal glutamate neurotransmission has been implicated in many neurological disorders, including schizophrenia, Alzheimer's disease, Parkinson's disease, addiction, anxiety, depression, epilepsy, and pain. Metabotropic glutamate receptors (mGluRs) activate intracellular signaling cascades in a G protein-dependent manner, which offer the opportunity for developing drugs that regulate glutamate neurotransmission in a functionally selective manner. In the present study, we further characterize the human mGluR2 (hmGluR2) potentiator binding site by showing that the substitution of the three amino acids found to be required for hmGluR2 potentiation, specifically Ser(688), Gly(689), and Asn(735), with the homologous hmGluR3 amino acids, inactivates the positive allosteric modulator activity of several structurally unique mGluR2 potentiators. Based on the characterization of the hmGluR2 potentiator binding site, we developed a novel scintillation proximity assay that was able to discriminate between compounds that were hmGluR2-specific potentiators, and those that were active on both hmGluR2 and hmGluR3. In addition, we substituted Ser(688), Gly(689), and Asn(735) into hmGluR3 and created an active hmGluR2 allosteric modulation site on the hmGluR3 receptor.
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PMID:Transposition of three amino acids transforms the human metabotropic glutamate receptor (mGluR)-3-positive allosteric modulation site to mGluR2, and additional characterization of the mGluR2-positive allosteric modulation site. 1843 Aug 63

Group II metabotropic glutamate receptors (mGluRs) comprise mGluR2 (mGlu2; encoded by GRM2) and mGluR3 (mGlu3; encoded by GRM3) and modulate glutamate neurotransmission and synaptic plasticity. Here we review the expression and function of mGluR3 and its involvement in schizophrenia. mGluR3 is expressed by glia and neurons in many brain regions and has a predominantly presynaptic distribution, consistent with its role as an inhibitory autoreceptor and heteroceptor. mGluR3 splice variants exist in human brain but are of unknown function. Differentiation of mGluR3 from mGluR2 has been problematic because of the lack of selective ligands and antibodies; the available data suggest particular roles for mGluR3 in long-term depression, in glial function and in neuroprotection. Some but not all studies find genetic association of GRM3 polymorphisms with psychosis, with the risk alleles also being associated with schizophrenia-related endophenotypes such as impaired cognition, cortical activation and glutamate markers. The dimeric form of mGluR3 may be reduced in the brain in schizophrenia. Finally, preclinical findings have made mGluR3 a putative therapeutic target, and now direct evidence for antipsychotic efficacy of a group II mGluR agonist has emerged from a randomised clinical trial in schizophrenia. Together these data implicate mGluR3 in aetiological, pathophysiological and pharmacotherapeutic aspects of the disorder.
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PMID:The group II metabotropic glutamate receptor 3 (mGluR3, mGlu3, GRM3): expression, function and involvement in schizophrenia. 1854 26

Glutamate exerts its effects through binding and activation of two classes of specific receptors: ionotropic (iGluRs) and metabotropic (mGluRs). Group I mGluR includes mGluR1 and mGluR5 subtypes, group II includes mGluR2 and mGluR3 subtypes and group III includes the subtypes mGluR 4, 6, 7 and 8. Glutamate and its receptors are found in all key hypothalamic areas critically involved in reproduction and neuroendocrine function. To date, considerable data support an important role for iGluRs in the control of neuroendocrine function; however, the role of mGluRs as regulators of hypothalamic-pituitary function has not been clearly elucidated. mGluRs could be exerting a fine tune on the release of hypothalamic factors that regulate hormone release such as Substance P, GABA, alpha-MSH and CRH. Group II mGluR exert a direct inhibitory effect on anterior pituitary prolactin and GH secretion. Moreover, some group II mGluR agonists, like LY 354,740 and LY 379,268, can modulate PRL secretion from the anterior pituitary through their actions as dopamine receptor agonists. Evidence suggests a role for group III mGluR subtypes in stress-related behavioral disorders. Several reports indicate that selective ligands for mGluR subtypes have potential for the treatment of a wide variety of neurological and psychiatric disorders, including depression, anxiety disorders, schizophrenia, epilepsy and Alzheimer's disease among others. Since converging lines of evidence suggest a role for mGluRs subtypes in neuroendocrine regulation of hormone secretion, mGluRs neuroendocrine actions must be taken in consideration to insure proper treatment of these diseases. Moreover, discovery of selective agonists provides an opportunity to investigate the physiological role of mGluR subtypes and to directly test the neuroendocrine actions of mGluRs. Finally, mGluRs selective agonists may have an impact in the treatment of conditions involving chronic stress, such as depression and anxiety disorders, since they regulate neuroendocrine stress circuits involving the HPA axis and stress-sensitive hormones such as oxytocin and prolactin. This review aims to provide a survey of our current understanding of the effects of mGluR activation on neuroendocrine function.
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PMID:Role of metabotropic glutamate receptors in the control of neuroendocrine function. 1861 55

In the past decade, the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia has received support from several lines of clinical evidence, including genetic, postmortem and human psychosis modeling. Recently, superiority of a mGluR2/3 receptor agonist over placebo was demonstrated in a randomized double-blind clinical trial in patients with schizophrenia. Considering the fact that currently available antipsychotics are all dopamine blockers to varying degrees without direct effects on glutamate transmission, this clinical trial highlights the potential utility of glutamatergic agents. In healthy volunteers, the NMDA channel antagonist ketamine induces transient cognitive dysfunction, perceptual aberrations and changes reminiscent of the negative symptoms of schizophrenia. However, how ketamine produces these effects is unclear. Preclinical data on NMDAR hypofunction offer further insights into the pathogenesis of the disorder as it relates to disorganized behavior, stereotypic movements and cognitive dysfunction in the rodent. This review evaluates the existing clinical and preclinical literature in an effort to shed light on the mechanism of action of ketamine as a probe to model NMDAR hypofunction in healthy volunteers. Included in this perspective are direct and indirect effects of ketamine at the neuronal level and in the intact brain. In addition to ketamine's effects on presynaptic and postsynaptic function, effects on glia and other neurotransmitter systems are discussed. While increased extracellular glutamate levels following NMDA antagonist administration stand out as a well replicated finding, evidence suggests that ketamine's effects are not restricted to pyramidal cells, but extend to GABAergic interneurons and the glia. In the glia, ketamine has significant downstream effects on the glutathione metabolism. Further studies are needed to identify the mechanistic connections between ketamine's effects at the cellular and behavioral levels.
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PMID:The acute effects of NMDA antagonism: from the rodent to the human brain. 1870 87


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