Allosteric Modulators for the Treatment of Schizophrenia: Targeting Glutamatergic Networks

Menniti, Frank S.; Lindsley, Craig W.; Conn, P. Jeffrey; Pandit, J.; Zagouras, Panayiotis; Volkmann, Robert A.

doi:10.2174/1568026611313010005

Cited by 80 publications

(143 citation statements)

References 242 publications

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“…NMDA receptors participate in the development of the CNS (Colonnese et al, 2005;Colonnese and Constantine-Paton, 2006;Kelsch et al, 2012). In addition, overactivation of NMDA receptors can promote seizures and cell death (Choi, 1994;Rothman and Olney, 1995;Obrenovitch et al, 1997;Dirnagl et al, 1999;Yurkewicz et al, 2005), and NMDA receptor hypofunction is a leading hypothesis for schizophrenia (Coyle, 2012;Menniti et al, 2013). Thus, there is considerable interest in factors that control NMDA receptor expression and function.…”

Section: Gaba/glutamate Receptor Mutations In Neurologic Diseasesmentioning

confidence: 99%

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Yuan¹,

Low²,

Moody³

et al. 2015

Mol Pharmacol

182

176

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The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-D-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.

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Section: Gaba/glutamate Receptor Mutations In Neurologic Diseasesmentioning

confidence: 99%

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Yuan¹,

Low²,

Moody³

et al. 2015

Mol Pharmacol

182

176

View full text Add to dashboard Cite

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“…One approach to try to circumvent the toxicity issue has been to develop positive allosteric modulators, also known as AMPAkines. However, their success has been limited, in part due to low bioavailability and toxicity issues for some of the compounds [182,183]. Thus, it remains to be demonstrated if AMPAkines can have a potential as antidepressants.…”

Section: Target Profiles With Preclinical Validation Onlymentioning

confidence: 99%

Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs

Dale

Bang‐Andersen

Sanchéz

2015

Biochemical Pharmacology

201

108

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The monoamine hypothesis has been the prevailing hypothesis of depression over the last several decades. It states that depression is associated with reduced monoamine function. Hence efforts to increase monoamine transmission by inhibiting serotonin (5-HT) and norepinephrine (NE) transporters has been a central theme in depression research since the 1960s. The selective 5-HT reuptake inhibitors (SSRIs) and 5-HT and NE reuptake inhibitors (SNRIs) that have emerged from this line of research are currently first line treatment options for major depressive disorder (MDD). One of the recent trends in antidepressant research has been to refine monoaminergic mechanisms by targeting monoaminergic receptors and additional transporters (e.g. with multimodal drugs and triple re-uptake inhibitors) or by adding atypical antipsychotics to SSRI or SNRI treatment. In addition, several other hypotheses of depression have been brought forward in pre-clinical and clinical research based on biological hallmarks of the disease and efficacy of pharmacological interventions. A central strategy has been to target glutamate receptors (for example, with intravenous infusions of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine). Other strategies have been based on modulation of cholinergic and γ-aminobutyric acid (GABA)ergic transmission, neuronal plasticity, stress/hypothalamic pituitary adrenal(HPA)-axis, the reward system and neuroinflammation. Here we review the pharmacological profiles of compounds that derived from these strategies and have been recently tested in clinical trials with published results. In addition, we discuss putative treatments for depression that are being investigated at the preclinical level and outline future directions for antidepressant research.

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“…Some authors reported a correlation between decreased plasma levels of glycine and its metabolites and negative symptoms [186,187]. However, the glycine "coagonists" have shown modest effect on negative symptoms [12,[188][189][190].…”

Section: Studies Of Associations Between Glutamate/gabaergic Neurotramentioning

confidence: 99%

Neurobiological background of negative symptoms

Galderisi

Merlotti

Mucci

2015

Eur Arch Psychiatry Clin Neurosci

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Studies investigating neurobiological bases of negative symptoms of schizophrenia failed to provide consistent findings, possibly due to the heterogeneity of this psychopathological construct. We tried to review the findings published to date investigating neurobiological abnormalities after reducing the heterogeneity of the negative symptoms construct. The literature in electronic databases as well as citations and major articles are reviewed with respect to the phenomenology, pathology, genetics and neurobiology of schizophrenia. We searched PubMed with the keywords "negative symptoms," "deficit schizophrenia," "persistent negative symptoms," "neurotransmissions," "neuroimaging" and "genetic." Additional articles were identified by manually checking the reference lists of the relevant publications. Publications in English were considered, and unpublished studies, conference abstracts and poster presentations were not included. Structural and functional imaging studies addressed the issue of neurobiological background of negative symptoms from several perspectives (considering them as a unitary construct, focusing on primary and/or persistent negative symptoms and, more recently, clustering them into factors), but produced discrepant findings. The examined studies provided evidence suggesting that even primary and persistent negative symptoms include different psychopathological constructs, probably reflecting the dysfunction of different neurobiological substrates. Furthermore, they suggest that complex alterations in multiple neurotransmitter systems and genetic variants might influence the expression of negative symptoms in schizophrenia. On the whole, the reviewed findings, representing the distillation of a large body of disparate data, suggest that further deconstruction of negative symptomatology into more elementary components is needed to gain insight into underlying neurobiological mechanisms.

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Allosteric Modulators for the Treatment of Schizophrenia: Targeting Glutamatergic Networks

Cited by 80 publications

References 242 publications

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs

Neurobiological background of negative symptoms

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