UMLS:C0036341 - FACTA Search

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interactions between subtypes of dopamine, glutamate and adenosine receptors seem to play an important integrative role in the function of striatal gamma-aminobutyric acid (GABA)ergic efferent neurons. Recent behavioral and biochemical studies suggest the existence of specific interactions between adenosine A2A receptors (A(2A)R), dopamine D2 receptors (D2R) and the group I metabotropic mGlu5 receptors (mGlu5R) in the dorsal striatum. The dual-probe approach in vivo microdialysis technique in freely moving rats was used to study the role of mGlu5R/A2AR/D2R interactions in the modulation of the ventral striopallidal GABA pathway. Perfusion of a selective mGlu5R agonist (CHPG) in the nucleus accumbens facilitated GABA release in the ipsilateral ventral pallidum. This effect was strongly potentiated by co-perfusion with the A2AR agonist CGS 21680. Co-perfusion with the D2R agonist quinpirole counteracted the increase in pallidal GABA levels induced by CGS 21680 and by CGS 21680 plus CHPG. These results demonstrate that mGlu5R/A2AR/D2R interactions play an important modulatory role in the function of the ventral striopallidal GABA pathway, which might have implications for the treatment of schizophrenia and drug addiction.
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PMID:Metabotropic glutamate mGlu5 receptor-mediated modulation of the ventral striopallidal GABA pathway in rats. Interactions with adenosine A(2A) and dopamine D(2) receptors. 1198 50

Use-dependent N-methyl-d-aspartate receptor (NMDAR) antagonists produce behaviors in human volunteers that resemble schizophrenia and exacerbate those behaviors in schizophrenic patients, suggesting that hypofunction of NMDAR-mediated neuronal circuitry may be involved in the etiology of clinical schizophrenia. Activation of the metabotropic glutamate receptor subtype 5 (mGluR5) enhances NMDAR-mediated currents in vitro. Thus, activation of mGluR5 could potentiate hypofunctional NMDARs in neuronal circuitry relevant to schizophrenia. To further elucidate the role of mGluR5, the present study examined the effects of mGluR5 antagonist administration, with and without coadministration of the use-dependent NMDAR antagonist phencyclidine (PCP), on locomotor activity and prepulse inhibition (PPI) of the acoustic startle response in rodents. We further examined PPI in mGluR5 knockout mice. Finally, we examined PPI after administration of the mGluR5 agonist 2-chloro-5-hydroxyphenylglycine (CHPG) alone and in combination with amphetamine. The data indicate that the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine has no effect on locomotor activity or PPI by itself but does potentiate both PCP-induced locomotor activity and disruption of PPI. We further found that mGluR5 knockout mice display consistent deficits in PPI relative to their wild-type controls. Finally, the data indicate that CHPG has no effect on PPI by itself, but ameliorates amphetamine-induced disruption of PPI. Collectively, these data suggest that mGlu5 receptors play a modulatory role on rodent PPI and locomotor behaviors and are consistent with the hypothesis that mGlu5 agonist/potentiators may represent a novel approach for antipsychotic drug development.
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PMID:Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents. 1266 Mar 7

Schizophrenia is a debilitating chronic psychiatric illness affecting 1% of the population. The cardinal features of schizophrenia are positive symptoms (thought disorder, hallucinations, catatonic behavior), negative symptoms (social withdrawal, anhedonia, apathy) and cognitive impairment. Although progress in elucidating the aetiology of schizophrenia has been slow, new insights on the neurochemical and neurophysiological mechanisms underlying the pathophysiology of this illness are beginning to emerge. The glutamate/N-methyl-D-aspartate (NMDA) hypofunction hypothesis of schizophrenia is supported by observations that administration of NMDA glutamate receptor antagonists such as phencyclidine (PCP) or ketamine induces psychosis in humans; moreover, decreased levels of glutamate and changes in several markers of glutamatergic function occur in schizophrenic brain. Administration of PCP or ketamine to rodents elicits an increase in locomotion and stereotypy accompanied by an increase in glutamate efflux in several brain regions. Systemic administration of group II metabotropic glutamate (mGlu) receptor agonists suppresses PCP-induced behavioral effects and the increase in glutamate efflux. Activation of group II mGlu receptors (mGlu2 and mGlu3) decreases glutamate release from presynaptic nerve terminals, suggesting that group II mGlu receptor agonists may be beneficial in the treatment of schizophrenia. In addition, pharmacological manipulations that enhance NMDA function may be efficacious antipsychotics. Selective activation of mGlu5 receptors significantly potentiates NMDA-induced responses, supporting this novel approach for the treatment of schizophrenia. The glutamate hypothesis of schizophrenia predicts that agents that restore the balance in glutamatergic neurotransmission will ameliorate the symptomatology associated with this illness. Development of potent, efficacious, systemically active drugs will help to address the antipsychotic potential of these novel therapeutics. This review will discuss recent progress in elucidating the pharmacology and function of group II mGlu and mGlu5 receptors in the context of current hypotheses on the pathophysiology of schizophrenia and the need for new and better antipsychotics.
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PMID:Metabotropic glutamate receptors: potential drug targets for the treatment of schizophrenia. 1276 19

Several lines of evidence implicate NMDA receptor dysfunction in the cognitive deficits of schizophrenia, suggesting that pharmacological manipulation of the NMDA receptor may be a feasible therapeutic strategy for treatment of these symptoms. Although direct manipulation of regulatory sites on the NMDA receptor is the most obvious approach for pharmacological intervention, targeting the G-protein coupled metabotropic glutamate (mGlu) receptors may be a more practical strategy for long-term regulation of abnormal glutamate neurotransmission. Heterogeneous distribution, both at structural and synaptic levels, of at least eight subtypes of mGlu receptors suggests that selective pharmacological manipulation of these receptors may modulate glutamatergic neurotransmission in a regionally and functionally distinct manner. Two promising targets for improving cognitive functions are mGlu5 or mGluR2/3 receptors, which can modulate the NMDA receptor-mediated signal transduction by pre- or postsynaptic mechanisms. Preclinical studies indicate that activation of these subtypes of mGlu receptors may be an effective strategy for reversing cognitive deficits resulting form reduced NMDA receptor mediated neurotransmission.
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PMID:Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. 1520 77

Schizophrenia is a complex neuropsychiatric disorder characterized by cognitive deficits, and positive and negative symptoms. All antipsychotics currently used in clinical practice are dopamine D2 receptor antagonists. The idea that adenosine A2A receptor agonists might be of interest for the treatment of schizophrenia derived from studies showing the existence of antagonistic intramembrane interaction between A2A and D2 receptors. Based on results obtained in animal models, a putative antipsychotic-like profile of A2A agonists was put forward. However, A2A agonists were shown to have detrimental effects in animal models of learning and memory. Moreover, these compounds produce many peripheral side-effects which limits their use in clinical trials. On the other hand, The results concerning the influence of A2A receptor antagonists in animal models used in schizophrenia studies such as locomotor activity and prepulse inhibition are fairly controversial. Some cognitive enhancing properties of A2A receptor antagonists have also been found in rats. Recent results showing the existence of heteromeric A2A/D3 and A2A/mGlu5 receptor complexes seem to open up new perspectives on the search for novel therapies of schizophrenia.
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PMID:Potential role of adenosine A2A receptors in the treatment of schizophrenia. 1850 1

Until recently, all known antipsychotic drugs were thought to block the dopamine D2 receptor. New evidence that agonists of the metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate psychotic and affective symptoms of schizophrenia suggests that compounds with different molecular targets may act on a common cellular target to treat schizophrenia. We hypothesized that normalizing the activity of neurons in the orbitofrontal cortex (OFC), a region that is increasingly implicated in the pathophysiology of schizophrenia, presents such a target. We disrupted OFC activity in behaving rats with a use-dependent NMDA antagonist to model the NMDA hypofunction state that may occur in schizophrenia. This systemic treatment increased the activity of most pyramidal cells while inhibiting the activity of putative inhibitory GABA interneurons and increasing behavioral stereotypy. A similar pattern of OFC firing disruption was observed after amphetamine, which models a dopamine hyperactivity state in schizophrenia and which produces a pattern of firing disruption different from those of NMDA antagonists in other prefrontal cortex regions. Antipsychotic drugs haloperidol and clozapine, which target monoamine receptors, as well as an mGlu2/3 agonist and an mGlu5 receptor modulator proposed to have antipsychotic efficacy, reversed the impact of NMDA hypofunction on OFC cells and on behavior. A similar pattern of normalization of OFC activity was observed when treatments were given after amphetamine. Thus, proven or putative antipsychotic drugs with different mechanisms of action similarly reduced the impact of NMDA hypofunction and dopamine hyperfunction on OFC neurons, suggesting that these neurons are a candidate target for the therapeutic effects of antipsychotic medications.
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PMID:Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs. 1900 93

Mental disorders, such as depression, anxiety and schizophrenia, has become a large medical and social problem recently. Studies performed in animal tests and early clinical investigations brought a new insight in the pharmacotherapy of these disorders. Latest investigations are focused mainly on the glutamatergic system, a main excitatory amino acid neurotransmitter in the brain. Evidence indicates that metabotropic glutamate receptors ligands have excellent antidepressant, anxiolytic and antipsychotic effects. Metabotopic glutamate receptors (mGlu) divaded into three groups (group I, II and III) are localized on nerve terminals, postsynaptic sites and glial cells and thus they can influence and modulate the action of glutamate on different levels in the synapse. Recent advances in the identification of selective and specific compounds (both ortho- and allosteric ligands), and the generation of transgenic animals enabled to have new insight into the pathophysiology and therapy of mood disorders. At present, the most potent seem to be negative allosteric modulators of the first group (mGlu1 and mGlu5), and positive allosteric modulators of the second (mGlu2 and mGlu3) and third (mGlu4/7/8) group of mGlu receptors.
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PMID:Metabotropic glutamate receptors in the tripartite synapse as a target for new psychotropic drugs. 1942 11

The glutamate hypothesis of schizophrenia suggests that hypofunction of N-methyl-D-aspartate (NMDA) receptors may be critical for schizophrenic symptoms; therefore, pharmacological approaches that enhance NMDA function may be beneficial for the treatment of schizophrenia. Several lines of evidence indicate that NMDA and metabotropic glutamate (mGlu) 5 receptors are closely associated signaling partners and that a selective mGlu5 receptor agonist might provide a viable approach for increasing NMDA receptor function in the treatment of schizophrenia. The orthosteric binding sites across members of the mGlu receptor subtype for a particular endogenous ligand are often highly conserved, making it difficult to achieve high selectivity for the specific mGlu5 receptor. The advanced currents of drug discovery have developed multiple highly selective allosteric modulators of mGlu5 receptors. In the present review, we provide an update of the recent patents and development of positive allosteric modulators of the mGlu5 receptor and explore their therapeutic potential for schizophrenia.
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PMID:Recent patents on positive allosteric modulators of the metabotropic glutamate 5 receptor as a potential treatment for schizophrenia. 1983 91

Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications that effectively treat positive symptoms of schizophrenia (e.g., delusions and hallucinations) and have been approved by regulatory agencies since the 1950s. Blockade of 5-hydroxytryptamine(2A) receptors plays a contributory role in the actions of the second generation of antipsychotic drugs, the so-called atypical antipsychotics. Nevertheless, substantial unmet medical needs remain for the treatment of negative symptoms and cognitive dysfunction. Recognition that dissociative anesthetics block the N-methyl-D-aspartate (NMDA) receptor channel has inspired a search for glutamatergic therapeutic mechanisms because ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerbate the symptoms of patients with schizophrenia. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors at critical sites in local circuits modulate the function of a given brain region or control projections from one region to another (e.g., hippocampal-cortical or thalamocortical projections). The demonstration that a metabotropic glutamate 2/3 (mGlu2/3) receptor agonist prodrug decreased both positive and negative symptoms of schizophrenia raised hopes that glutamatergic mechanisms may provide therapeutic advantages. In addition to discussing the activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), we discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter inhibitors and mGlu5 receptor PAMs. The hope is that by modulating glutamatergic neurotransmission, the dysfunctional circuitry of the schizophrenic brain (both local circuits and long-loop pathways) will be improved.
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PMID:Glutamatergic (N-methyl-D-aspartate receptor) hypofrontality in schizophrenia: too little juice or a miswired brain? 1993 74

Schizophrenia is one of the most important forms of psychiatric illness and may be chronic and highly disabling. It has been suggested that specific neurochemical abnormality is due to dopaminergic overactivity in the brain. Schizophrenia is currently thought to be associated with a hypoglutamatergic state that is mimicked by acute Phencyclidine (PCP), an antagonist of the N-methyl-D-aspartate (NMDA) receptor subtype. Administration of PCP or ketamine in rodents has been used to model aspects of schizophrenia. Taken into consideration the role of glutamatergic system in development of schizophrenia and involvement of striatal dopaminergic receptors in generation of schizophrenia symptoms, it was planned to study functional interaction between NMDA and metabotropic glutamatergic receptors 5 (mGluR5) in schizophrenia-associated behavioral and memory disturbance and the role of mGluRs allosteric modulation in cortico-striatal synaptic plasticity. In our experiments investigation of dose-dependent effects of ketamine revealed that 0.3mg/kg ketamine induces statistical changes most of behavioral and cognitive parameters in rats. Changes in emotional state showed decrease of the number and total duration of groomings in open field experiments as wall as in passive avoidance task. Decrease of motor activity was also detected, while no significant changes were observed in number of defecations. In T-maze test it was shown that spatial memory was damaged. To determine whether mGlu5 and NMDA receptor interact to regulate complex behaviors that are relevant to cognitive disorders such as schizophrenia we focused on assessing whether the selective mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine MPEP mimics or exacerbates the effects of the NMDA receptor antagonist. Ketamine-induced memory disturbance was significantly increased after injection of mGluR5 negative allosteric modulators MPEP. In In vitro experiments the agonist at group I metabotropic glutamate receptors (mGluRI) (RS)-3,5-dihydroxyphenyl-glycine (DHPG,100 microM) evoked a persistent depression of the second component (N2) of the cortico-striatal field potential in rat slices. DHPG-induced plasticity was not NMDA-dependent. mGlu5 negative allosteric modulator MPEP diminishes the inhibition of synaptic responses induced by DHPG and completely blocked the late phase of depression. Our behavioral and in vitro data suggested that between NMDA and mGlu5 receptors there are functional interaction. Thus in some neurological or psychiatric disorders with NMDA dysfunction pharmacological manipulation of mGlu5 receptors could have therapeutic use.
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PMID:The role of the mGluR allosteric modulation in the NMDA-hypofunction model of schizophrenia. 2009 Jan 56

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