Purpose Of Review: The ketamine model has dominated drug discovery in schizophrenia over the past decade, supported by genetic and postmortem evidence implicating glutamatergic transmission. This review assesses recent successes and disappointments of glutamatergic agents and identifies promising new directions.
Recent Findings: Strategies focused on enhancing activity of the N-methyl D-aspartate (NMDA) receptor via direct agonists at the glycine site or by inhibition of glycine reuptake have produced modest and often inconsistent evidence of efficacy, as have approaches to reduce excessive glutamate release by lamotrigine or by mGluR2/3 agonists. Strategies targeting α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors have also met with only limited success. Newer approaches include selective allosteric modulation of NMDA receptor subunits and of mGluR5 receptors. In addition, intracellular pathways downstream of NMDA receptors may also provide new treatment targets, as exemplified by phosphodiesterase (PDE) inhibitors.
Summary: Targeting glutamatergic transmission remains one of the most promising strategies in schizophrenia, particularly early in the course of illness, but therapeutic approaches may require greater specificity for receptor subtype type, illness phase, and individual biology in order to enhance efficacy and overcome problems with reproducibility of clinical results.
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http://dx.doi.org/10.1097/YCO.0000000000000152 | DOI Listing |
Fluorescent reporters for glutamate release and postsynaptic Ca signaling are essential tools for quantifying synapse functional heterogeneity across neurons and circuits. However, leveraging these probes for neuroscience requires scalable experimental frameworks. Here, we devised a high-throughput approach to efficiently collect and analyze hundreds of optical recordings of glutaamate release activity at presynaptic boutons in cultured rat hippocampal neurons.
View Article and Find Full Text PDFUnlabelled: Pain therapies that alleviate both pain and sleep disturbances may be the most effective for pain relief, as both chronic pain and sleep loss render the opioidergic system, targeted by opioids, less sensitive and effective for analgesia. Therefore, we first studied the link between sleep disturbances and the activation of nociceptors in two acute pain models. Activation of nociceptors in both acute inflammatory (AIP) and opto-pain models led to sleep loss, decreased sleep spindle density, and increased sleep fragmentation that lasted 3 to 6 hours.
View Article and Find Full Text PDFNeuropharmacology
January 2025
Dept. of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy. Electronic address:
The central nervous system is a well-known steroidogenic tissue producing, among others, cholesterol metabolites such as neuroactive steroids, oxysterols and steroid hormones. It is well known that these endogenous molecules affect several receptor classes, including ionotropic GABAergic and NMDA glutamatergic receptors in neurons. It has been shown that also ionotropic purinergic (P2X) receptors are cholesterol metabolites' targets.
View Article and Find Full Text PDFNeurochem Res
January 2025
Huazhong University of Science and Technology, Tongji Medical College, Wuhan, Hubei, 430000, China.
Epilepsy (EP) is a neurological disorder characterized by abnormal, sudden neuronal discharges. Seizures increase extracellular glutamate levels, causing excitotoxic damage. Glutamate transporter type 1 (GLT-1) and its human homologue excitatory amino acid transporter-2 (EAAT2) clear 95% of extracellular glutamate.
View Article and Find Full Text PDFCureus
December 2024
Internal Medicine, Guthrie Lourdes Hospital, Binghamton, USA.
In narcolepsy with cataplexy, sodium oxybate and the recently FDA-approved drug pitolisant are preferred medications. Armodafinil, a longer-acting, non-amphetamine stimulant, is often used in patients who have narcolepsy without cataplexy. It enhances alertness by increasing presynaptic dopamine transmission presynaptically, amplifying serotonin in the cerebral cortex, activating glutamatergic circuits, which may contribute to its vigilance-enhancing properties, and stimulating orexin activity.
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