Glutamate as a therapeutic target in psychiatric disorders

Abstract

Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Approximately 60% of neurons in the brain, including all cortical pyramidal neurons and thalamic relay neurons, utilize glutamate as their primary neurotransmitter. 1 As a result, virtually all thalamocortical, corticocortical and corticofugal neurotransmission in the brain is mediated by glutamate. Glutamate is released from presynaptic terminals in response to neuronal depolarization, and is recycled by excitatory amino acid (EAA) transporters located on both neurons and glia. 2 Within glia, glutamate is converted to glutamine and released into extracellular fluid from which it is reabsorbed into presynaptic terminals and converted back to glutamate via action of neuronal glutaminase. Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate. 3 As such, functional imaging modalities, such as PET and fMRI, indexing activity primarily of brain glutamatergic systems. 4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling. 7 As with glutamate and GABA transporters, these recycling systems may constitute interesti...

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

“…36 This finding appears particularly interesting in light of the compelling evidence that glutamatergic dysfunction can be related to psychiatric disorders (for review see Javitt 50 ). Taking recent evidence into account that CB1 receptors are, in addition to GABAergic terminals, as well prominently present on glutamatergic synapses 2,3 where they colocalize with VGLUT1 and influence glutamatergic transmission, 3 it was reasonable to hypothesize a potential dysregulation of VGLUT1 expression in CB1 À/À mice.…”

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

“…43 A possible limitation to mGluR as a therapeutic target, however, is the suggestion that group II receptors may desensitize during chronic treatment. 44 …”

Expression of a GRM3 Splice Variant is Increased in the Dorsolateral Prefrontal Cortex of Individuals Carrying a Schizophrenia Risk SNP

“…Group II comprises two receptors, GRM2 and GRM3, which have high sequence homology and are difficult to distinguish with specific ligands and antibodies. Since GRM2/3 activation leads to a net reduction in glutamate neurotransmission (Battaglia et al, 1998;East et al, 1995;Lovinger and McCool, 1995;Yoshino et al, 1996), ligands for these receptors are considered as potential therapeutic agents for a wide range of psychiatric disorders (Javitt, 2004). For example, GRM2/3 agonists reverse cognitive and motor deficits in a rodent NMDA receptor antagonism model for schizophrenia (Moghaddam and Adams, 1998;Olszewski et al, 2004).…”