Biochem. Cell. Arch. Vol. 24, No. 1, pp. 529-540, 2024 DOI: https://doi.org/10.51470/bca.2024.24.1.

529 ISSN 0972-5075

DocID: https://connectjournals.com/03896.2024.24.529 eISSN 0976-1772

TARGETING GLUTAMATERGIC TRANSMISSION IN

NEUROPSYCHIATRIC DISORDERS: CURRENT OPPORTUNITIES AND
CHALLENGES
Dakme Papi1, Poulami Patra2, Sapna Salar3, Sunil Kumar Rabha4 and Harsh Rastogi5
1
School of Pharmacy, Arunachal University of Studies, Namsai - 792 103, India.
2
Department of Pharmaceutical Technology, Brainware University, Barasat, Kolkata - 700125, India.
3
BBDIT College of Pharmacy, Ghaziabad - 201 206, India.
4
School of Pharmaceutical Sciences, University of Science and Technology Meghalaya (USTM), India.
5
Department of Pharmaceutics, Dr. KN Modi Institute of Pharmaceutical Education and Research, Modinagar - 201 204, India.
*Corresponding author e-mail : poulamipatra665@gmail.com
(Received 25 January 2024, Revised 22 March 2024, Accepted 29 March 2024)

ABSTRACT : This review article examines the current landscape of targeting glutamatergic transmission in neuropsychiatric
disorders, exploring opportunities and confronting challenges. Glutamate, the principal excitatory neurotransmitter in the
brain, plays a crucial role in synaptic plasticity and neural communication, implicating its dysfunction in various neuropsychiatric
conditions. We delve into the fundamentals of glutamatergic transmission, detailing its neurotransmitter status, receptor
subtypes, and mechanisms of reuptake and metabolism. Dysregulated glutamatergic signaling contributes to the pathophysiology
of disorders like major depressive disorder, schizophrenia, bipolar disorder, obsessive-compulsive disorder, anxiety disorders
and autism spectrum disorder. Pharmacological interventions, including NMDA and AMPA receptor modulators and non-
pharmacological techniques such as neurostimulation and cognitive-behavioral therapies are explored. Additionally, novel
approaches like glutamate transporter enhancers and epigenetic modulation of glutamate receptors are discussed. Despite
promising prospects, challenges such as pharmacokinetic limitations and adverse effects necessitate personalized medicine
approaches. Integration with existing treatments and exploring combination therapies offer potential avenues for optimizing
efficacy. Overall, targeting glutamatergic transmission holds considerable promise in reshaping therapeutic strategies for
neuropsychiatric disorders, offering hope for improved patient outcomes.
Key words : Glutamatergic transmission, neuropsychiatric disorders, pharmacological interventions, personalized medicine,
combination therapies.

How to cite : Dakme Papi, Poulami Patra, Sapna Salar, Sunil Kumar Rabha and Harsh Rastogi (2024) Targeting glutamatergic
transmission in neuropsychiatric disorders: Current opportunities and challenges. Biochem. Cell. Arch. 24, 529-540. DOI:
https://doi.org/10.51470/bca.2024.24.1.529

INTRODUCTION binds to receptors on postsynaptic neurons and initiates a

Glutamatergic transmission, the process by which
the neurotransmitter glutamate mediates signaling
between neurons, plays a pivotal role in the complex
workings of the brain (Lewerenz and Maher, 2015).
Glutamatergic transmission refers to the
communication between neurons facilitated by the
neurotransmitter glutamate. Glutamate is the most
abundant excitatory neurotransmitter in the central
nervous system (CNS) and is involved in a wide range
of physiological processes, including synaptic plasticity,
learning and memory. Glutamatergic transmission occurs
when glutamate is released from presynaptic neurons,
cascade of signaling events, ultimately leading to neuronal
excitation (Moghaddam, 1993). Emerging evidence
suggests that dysregulation of glutamatergic transmission
contributes to the pathophysiology of various
neuropsychiatric disorders, including but not limited to
depression, anxiety disorders, schizophrenia, bipolar
disorder and substance use disorders (Ohgi et al, 2015).
Abnormalities in glutamate levels, receptor expression,
and signaling have been implicated in the manifestation
and progression of these conditions. For instance,
alterations in glutamate neurotransmission have been
linked to structural and functional changes in brain regions
involved in mood regulation, cognition and reward
530 Dakme Papi et al
processing (Gilad et al, 1990). Understanding the role of
glutamatergic dysfunction in neuropsychiatric disorders
is crucial for developing targeted therapeutic strategies
aimed at restoring normal glutamate signaling and
alleviating symptoms. This review article provides a
comprehensive examination of the current state of
knowledge regarding the targeting of glutamatergic
transmission in neuropsychiatric disorders (Li et al, 2017).
It begins by elucidating the fundamental mechanisms
underlying glutamate neurotransmission, including the
classification of glutamate receptors and the regulation
of glutamate reuptake and metabolism. The article then
delves into the implications of dysregulated glutamatergic
transmission in the pathogenesis of various
neuropsychiatric disorders, highlighting the potential for
glutamate-based interventions to modulate disease
processes. Furthermore, the review discusses the diverse
therapeutic approaches aimed at targeting glutamatergic
transmission, including pharmacological interventions such
as N-methyl-D-aspartate (NMDA) receptor modulators,
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) receptor modulators and metabotropic glutamate
receptor (mGluR) modulators (Reiner and Levitz, 2018).
Additionally, non-pharmacological interventions, such as
neurostimulation techniques and cognitive-behavioral
therapies, are explored for their ability to modulate
glutamate pathways and mitigate symptoms of
neuropsychiatric disorders (Furukawa et al, 2005).
Moreover, the article examines the clinical applications
and efficacy of glutamate-targeted therapies,
summarizing findings from clinical trials and highlighting
the challenges and limitations associated with current
treatments. Finally, the review outlines future directions
and areas for further research, emphasizing the need for
personalized medicine approaches, the exploration of
novel therapeutic targets, and the integration of glutamate-
targeted therapies with existing treatment modalities.
Glutamatergic transmission: Basics and significance
Understanding the fundamentals of glutamatergic
transmission is essential for comprehending its
significance in neuropsychiatric disorders.
A. Role of glutamate as a neurotransmitter
Glutamate is the primary excitatory neurotransmitter
in the central nervous system (CNS), playing a crucial
role in synaptic transmission and neuronal communication
(Davitz et al, 2017). As a neurotransmitter, glutamate is
involved in various physiological processes, including
synaptic plasticity, learning, memory and motor function.
Glutamate exerts its effects by binding to and activating
glutamate receptors located on the postsynaptic
membrane of neurons. Through these receptor
interactions, glutamate mediates excitatory
neurotransmission, leading to depolarization of the
postsynaptic neuron and initiation of action potentials
(Harris et al, 2017).
B. Glutamate receptors and their subtypes
Glutamate receptors are classified into two main
categories: ionotropic glutamate receptors (iGluRs) and
metabotropic glutamate receptors (mGluRs) (Snyder and
Wilman, 2010). iGluRs are ligand-gated ion channels that
mediate fast excitatory neurotransmission, while mGluRs
are G-protein-coupled receptors that modulate neuronal
excitability and synaptic transmission via intracellular
signaling pathways (aan het Rot et al, 2010).
Ionotropic glutamate receptors (iGluRs)
a. N-methyl-D-aspartate (NMDA) receptors:
NMDA receptors are ionotropic glutamate receptors that
play a critical role in synaptic plasticity, learning, and
memory. Activation of NMDA receptors requires both
glutamate binding and postsynaptic membrane
depolarization, making them unique among glutamate
receptors. Dysregulation of NMDA receptor function has
been implicated in various neuropsychiatric disorders,
including schizophrenia, depression, and Alzheimer’s
disease (Abraham, 2008).
b. α-amino-3-hydroxy-5-methyl-4-isoxazolepro-
pionic acid (AMPA) receptors : AMPA receptors are
another type of ionotropic glutamate receptor that
mediates fast excitatory neurotransmission. They are
involved in synaptic transmission and synaptic plasticity,
particularly in processes such as long-term potentiation
(LTP) and long-term depression (LTD). AMPA receptor
dysfunction has been associated with neurodegenerative
diseases and psychiatric disorders (Alam et al, 1997).
Metabotropic glutamate receptors (mGluRs)
a. Group I mGluRs (mGluR1 and mGluR5):
Group I mGluRs are predominantly postsynaptic receptors
that modulate neuronal excitability and synaptic
transmission through activation of phospholipase C (PLC)
signaling pathways. Dysregulation of group I mGluRs has
been implicated in neuropsychiatric disorders such as
anxiety, depression and drug addiction (Albrecht et al,
2010).
b. Group II and III mGluRs (mGluR2, mGluR3,
mGluR4, mGluR6, mGluR7 and mGluR8) : Group II
and III mGluRs are primarily presynaptic receptors that
regulate neurotransmitter release and synaptic
transmission. They play a crucial role in modulating
glutamate and GABA release, thereby influencing
 Targeting glutamatergic transmission in neuropsychiatric disorders 531
neuronal excitability and synaptic plasticity (Alt et al,
2004).
C. Glutamate reuptake and metabolism
In addition to synaptic release and receptor activation,
glutamate levels in the synaptic cleft are tightly regulated
by mechanisms of reuptake and metabolism. Glutamate
reuptake is primarily mediated by excitatory amino acid
transporters (EAATs), which are located on both
presynaptic and postsynaptic neurons as well as
neighboring glial cells (astrocytes). EAATs actively
transport glutamate from the synaptic cleft into cells,
thereby terminating synaptic transmission and preventing
excitotoxicity (Andersson et al, 2001). Once taken up,
glutamate is metabolized through enzymatic processes,
including conversion to glutamine by the enzyme glutamine
synthetase within astrocytes. Glutamine can then be
transported back to neurons, where it is converted back Fig. 1 : Synaptic Neurotransmission Pathways: Glutamatergic
to glutamate, completing the glutamate-glutamine cycle Excitation.
(Aschrafi et al, 2005).
as therapeutic targets (Banko et al, 2006).
D. Implications of dysregulated glutamatergic
transmission in neuropsychiatric disorders Targeting Glutamatergic transmission: Therapeutic
approaches
Dysregulation of glutamatergic transmission has been
implicated in the pathophysiology of various In recent years, there has been growing interest in
neuropsychiatric disorders, including schizophrenia, major targeting glutamatergic transmission as a therapeutic
depressive disorder, bipolar disorder, anxiety disorders, strategy for neuropsychiatric disorders.
and substance use disorders (Baker et al, 2003). A. Pharmacological interventions
Abnormalities in glutamate neurotransmission, including 1. NMDA receptor modulators: N-methyl-D-
alterations in glutamate levels, receptor expression, and aspartate (NMDA) receptors are ionotropic glutamate
signaling pathways, have been observed in these receptors that play a critical role in synaptic plasticity,
conditions. For example, hypofunction of NMDA learning, and memory. Dysregulation of NMDA receptor
receptors has been proposed as a key mechanism function has been implicated in the pathophysiology of
underlying schizophrenia, while alterations in AMPA neuropsychiatric disorders, including schizophrenia and
receptor expression have been associated with depression depression. Pharmacological modulation of NMDA
and anxiety. Furthermore, disruptions in the balance receptors represents a promising therapeutic approach
between excitatory and inhibitory neurotransmission, as for these conditions (Beart and O’Shea, 2007).
well as aberrant glutamate release and clearance
a. NMDA receptor antagonists : NMDA receptor
mechanisms, contribute to the manifestation of symptoms
antagonists, such as ketamine and memantine, have been
observed in neuropsychiatric disorders (Balla et al, 2001).
extensively studied for their antidepressant and
Glutamate receptors, including ionotropic and antipsychotic effects. Ketamine, in particular, has shown
metabotropic types, play pivotal roles in synaptic rapid and robust antidepressant effects in treatment-
transmission and neuronal excitability (Banasr et al, resistant depression, leading to its approval by the US
2010). Ionotropic receptors, such as AMPA, Kainate, and Food and Drug Administration (FDA) for this indication.
NMDA receptors, mediate fast and slow synaptic However, the use of NMDA receptor antagonists is
transmission, modulating neuronal network activity and associated with potential side effects, including
synaptic plasticity. Metabotropic glutamate receptors, dissociation, psychotomimetic effects, and abuse liability
grouped into three categories (I, II and III), exert diverse (Bendel et al, 2005).
effects on neurotransmitter release and neuronal
b. NMDA receptor agonists : In contrast to
excitability through G protein-coupled signaling pathways.
NMDA receptor antagonists, NMDA receptor agonists
Dysfunction in these receptor systems is implicated in
aim to enhance NMDA receptor function. Compounds
neuropsychiatric disorders, highlighting their significance
such as D-cycloserine and glycine, which act as partial
532 Dakme Papi et al
agonists at the glycine modulatory site of the NMDA
receptor, have been investigated for their potential
therapeutic effects in various neuropsychiatric disorders.
However, the clinical utility of NMDA receptor agonists
remains to be fully elucidated and further research is
needed to determine their efficacy and safety profile
(Berman et al, 2000).
2. AMPA receptor modulators : α-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
receptors are another type of ionotropic glutamate
receptor involved in fast excitatory neurotransmission and
synaptic plasticity. Modulation of AMPA receptor function
represents a potential therapeutic strategy for
neuropsychiatric disorders characterized by aberrant
glutamatergic transmission (Bernard et al, 2010).
a. AMPA receptor positive allosteric
modulators (PAMs) : AMPA receptor PAMs, such as
CX516 and CX546, enhance AMPA receptor function
by binding to allosteric sites on the receptor complex.
These compounds have shown promise as cognitive
enhancers and potential treatments for cognitive deficits
associated with neuropsychiatric disorders, including
schizophrenia and Alzheimer’s disease. However, clinical
development of AMPA receptor PAMs has been hindered
by challenges such as limited selectivity and off-target
effects (Bertaso et al, 2008).
b. AMPA receptor negative allosteric
modulators (NAMs) : AMPA receptor NAMs, such
as perampanel, inhibit AMPA receptor function by binding
to allosteric sites and reducing channel opening probability.
Perampanel has been approved for the treatment of
epilepsy and has also shown potential as a treatment for
neuropsychiatric disorders, including depression and
anxiety. However, the use of AMPA receptor NAMs
may be limited by side effects such as dizziness, sedation,
and cognitive impairment (Bezzi et al, 2004).
3. Metabotropic glutamate receptor (mGluR)
modulators : Metabotropic glutamate receptors
(mGluRs) are G-protein-coupled receptors that modulate
neuronal excitability and synaptic transmission via
intracellular signaling pathways. Pharmacological
modulation of mGluR function represents a novel
approach for targeting glutamatergic transmission in
neuropsychiatric disorders (Bird and Lawrence, 2009).
a. Group I mGluR agonists : Group I mGluR
agonists, such as DHPG and LY379268, selectively
activate mGluR1 and mGluR5 receptors, respectively,
leading to modulation of synaptic transmission and
plasticity. These compounds have shown potential as
treatments for neuropsychiatric disorders characterized
by altered glutamatergic signaling, including schizophrenia
and addiction. However, the clinical development of
mGluR agonists has been hampered by challenges such
as poor blood-brain barrier penetration and limited
selectivity (Bolduc et al, 2008).
b. Group II and III mGluR agonists : Group II
and III mGluR agonists, such as LY354740 and LY379268,
modulate glutamate release and neurotransmission,
thereby exerting neuroprotective and antipsychotic
effects. These compounds have been investigated for
their potential therapeutic benefits in schizophrenia,
bipolar disorder and anxiety disorders. However, clinical
trials have yielded mixed results and further research is
needed to elucidate the efficacy and safety profile of
mGluR agonists in neuropsychiatric disorders (Boudin et
al, 2000).
B. Non-pharmacological interventions
1. Neurostimulation techniques : Non-
pharmacological approaches to modulating glutamatergic
transmission include neurostimulation techniques such as
transcranial magnetic stimulation (TMS) and
electroconvulsive therapy (ECT). These techniques aim
to modulate neuronal activity and synaptic plasticity in
specific brain regions implicated in neuropsychiatric
disorders (Bushong et al, 2002).
a. Transcranial magnetic stimulation (TMS) :
TMS involves the delivery of repetitive magnetic pulses
to targeted brain regions, leading to depolarization of
neurons and modulation of cortical excitability. High-
frequency TMS has been investigated as a potential
treatment for depression, with evidence suggesting
beneficial effects on mood regulation and glutamatergic
neurotransmission. However, the precise mechanisms
underlying the antidepressant effects of TMS remain
incompletely understood, and further research is needed
to optimize treatment protocols and identify predictors of
treatment response (Carroll, 2008).
b. Electroconvulsive therapy (ECT) : ECT is a
more invasive neurostimulation technique that involves
the induction of controlled seizures through the
administration of electrical currents to the brain. ECT
has been used for decades as a treatment for severe
depression and other psychiatric disorders, with evidence
suggesting its efficacy in modulating glutamatergic
transmission and synaptic plasticity. However, ECT is
associated with significant side effects, including memory
impairment and cognitive dysfunction, limiting its
widespread use (Chatterton et al, 2002).
2. Cognitive-behavioral therapies targeting
glutamate pathways : Cognitive-behavioral therapies
 Targeting glutamatergic transmission in neuropsychiatric disorders 533
(CBT) represent another non-pharmacological approach been effective in treating anxiety disorders, post-traumatic
to modulating glutamate pathways in neuropsychiatric stress disorder (PTSD) and obsessive-compulsive
disorders. These therapies aim to modify maladaptive disorder (OCD), with evidence suggesting its ability to
cognitive and behavioral patterns associated with modulate glutamatergic neurotransmission in fear circuitry
psychiatric symptoms, thereby promoting adaptive coping regions of the brain. Table 1 includes a selection of
strategies and improving overall functioning (Chen and glutamatergic compounds commonly used in the treatment
Lipton, 2006). of major psychiatric disorders (Choudary et al, 2005).
a. Cognitive restructuring : Cognitive restructuring C. Novel approaches and emerging therapies
techniques involve identifying and challenging negative 1. Glutamate transporter enhancers : Glutamate
or distorted thought patterns that contribute to psychiatric transporters play a critical role in regulating extracellular
symptoms. By promoting more balanced and adaptive glutamate levels and maintaining synaptic homeostasis.
thinking, cognitive restructuring can help individuals with Dysfunction of glutamate transporters has been
neuropsychiatric disorders develop coping strategies and implicated in various neuropsychiatric disorders, including
reduce symptoms such as anxiety and depression. schizophrenia, bipolar disorder and Alzheimer’s disease.
Emerging evidence suggests that cognitive restructuring Novel therapeutic approaches aimed at enhancing
may also modulate glutamatergic neurotransmission in glutamate transporter function represent a promising
brain regions implicated in emotion regulation and avenue for modulating glutamatergic transmission and
cognitive control (Chen et al, 1998). mitigating psychiatric symptoms (Bertaso et al, 2008).
b. Exposure therapy : Exposure therapy is a a. Glutamate transporter subtype-specific
behavioral intervention that involves gradually exposing enhancers : Recent advancements in the understanding
individuals to feared or anxiety-provoking stimuli in a of glutamate transporter biology have led to the
controlled and systematic manner. By confronting and development of subtype-specific enhancers targeting
habituating to these stimuli, individuals can reduce anxiety specific transporter subtypes, such as excitatory amino
and fear responses and learn to tolerate distressing acid transporter 2 (EAAT2) and excitatory amino acid
situations (Conn and Pin, 1997). Exposure therapy has
Table 1 : Glutamatergic compounds in the treatment of major Psychiatric disorders.
Glutamate Compound Mechanism Target Disease References
Receptor
NMDA Ketamine NMDA receptor antagonist Major Depressive Disorder Erecinska and Silver (1990)
NMDA Esketamine NMDA receptor antagonist Major Depressive Disorder El Far et al (2000)
AMPA Riluzole Glutamate release inhibitor Major Depressive Disorder Erecinska and Silver (1990)
AMPA Memantine NMDA receptor antagonist Major Depressive Disorder Fogal et al (2007)
NMDA Glycine Glycine modulatory site agonist Schizophrenia Spectrum Disorders Ohgi et al (2015)
NMDA D-serine Glycine modulatory site agonist Schizophrenia Spectrum Disorders Li et al (2017)
mGluR LY2140023 mGluR2/3 agonist Schizophrenia Spectrum Disorders Reiner and Levitz (2018)
mGluR LY404039 mGluR2/3 agonist Schizophrenia Spectrum Disorders Furukawa et al (2005)
mGluR AZD2066 mGluR2/3 agonist Schizophrenia Spectrum Disorders Davitz et al (2017)
NMDA Memantine NMDA receptor antagonist Bipolar Disorder Harris et al (2017)
NMDA Ketamine NMDA receptor antagonist Bipolar Disorder Snyder and Wilman (2010)
AMPA Riluzole Glutamate release inhibitor Bipolar Disorder Ohgi et al (2015)
AMPA Memantine NMDA receptor antagonist Bipolar Disorder Lewerenz and Maher (2015)
NMDA Ketamine NMDA receptor antagonist Obsessive-Compulsive Disorder Gilad et al (1990)
NMDA Memantine NMDA receptor antagonist Obsessive-Compulsive Disorder Lewerenz and Maher (2015)
NMDA Glycine Glycine modulatory site agonist Anxiety Disorders Moghaddam (1993)
NMDA D-serine Glycine modulatory site agonist Anxiety Disorders Gilad et al (1990)
AMPA Riluzole Glutamate release inhibitor Anxiety Disorders Erecinska and Silver (1990)
AMPA Memantine NMDA receptor antagonist Anxiety Disorders Moghaddam (1993)
NMDA Ketamine NMDA receptor antagonist Autism Spectrum Disorder Debant et al (1996)
NMDA Memantine NMDA receptor antagonist Autism Spectrum Disorder Ehlers et al (1996)
AMPA Riluzole Glutamate release inhibitor Autism Spectrum Disorder El Far et al (2000)
AMPA Memantine NMDA receptor antagonist Autism Spectrum Disorder Andersson et al (2001)
534 Dakme Papi et al
transporter 3 (EAAT3) (Cook, 2010). These compounds
aim to increase glutamate uptake and clearance from
the synaptic cleft, thereby reducing glutamate-mediated
excitotoxicity and promoting synaptic plasticity. Preclinical
studies have shown promising results with glutamate
transporter enhancers in animal models of
neuropsychiatric disorders, highlighting their potential as
novel therapeutic agents (aan het Rot et al, 2010).
b. Glutamate transporter gene therapy : Gene
therapy approaches targeting glutamate transporter genes
represent another innovative strategy for enhancing
glutamate uptake and clearance in the brain (Abraham,
2008). By delivering viral vectors encoding glutamate
transporter genes to specific brain regions, researchers
can augment glutamate transporter expression and
function, thereby restoring synaptic homeostasis and
ameliorating psychiatric symptoms. Although, still in the
early stages of development, glutamate transporter gene
therapy holds considerable promise as a targeted and
potentially long-lasting treatment for neuropsychiatric
disorders (Dolen et al, 2007).
2. Epigenetic modulation of glutamate
receptors : Epigenetic mechanisms, such as DNA
methylation and histone modification, play a crucial role
in regulating gene expression and synaptic plasticity in
the brain. Dysregulation of epigenetic processes has been
implicated in the pathophysiology of neuropsychiatric
disorders, including depression, schizophrenia, and
addiction (Bushong et al, 2002). Targeting epigenetic
mechanisms associated with glutamate receptors
represents a novel approach for modulating glutamatergic
transmission and treating psychiatric symptoms (Chen et
al, 1998).
a. Histone deacetylase (HDAC) inhibitors :
HDAC inhibitors are a class of compounds that block
the activity of histone deacetylases, enzymes responsible
for removing acetyl groups from histone proteins. By
increasing histone acetylation levels, HDAC inhibitors can
promote a more permissive chromatin state, leading to
enhanced gene transcription and synaptic plasticity (Chen
et al, 1998). Preclinical studies have demonstrated the
efficacy of HDAC inhibitors in modulating glutamate
receptor expression and function, as well as in reversing
behavioral deficits associated with neuropsychiatric
disorders. Clinical trials are underway to evaluate the
safety and efficacy of HDAC inhibitors as novel
treatments for depression, schizophrenia and other
psychiatric conditions (Moghaddam, 1993).
b. DNA methyltransferase (DNMT) inhibitors :
DNMT inhibitors are compounds that block the activity
of DNA methyltransferase enzymes, which catalyze the
addition of methyl groups to DNA molecules, thereby
silencing gene expression (Dingledine et al, 1999). By
inhibiting DNA methylation, DNMT inhibitors can
derepress genes involved in synaptic plasticity and
neurotransmission, including glutamate receptors.
Preclinical studies have shown that DNMT inhibitors can
reverse aberrant DNA methylation patterns associated
with neuropsychiatric disorders and restore normal
glutamatergic signaling. Clinical trials are ongoing to
evaluate the therapeutic potential of DNMT inhibitors in
treating depression, bipolar disorder and other psychiatric
conditions (El Far et al, 2000).
Clinical applications of Targeting Glutamatergic
Transmission in neuropsychiatric disorders
Targeting glutamatergic transmission has emerged
as a promising therapeutic approach for a wide range of
neuropsychiatric disorders. Each disorder presents unique
challenges, complexities and understanding how
glutamatergic dysfunction contributes to their
pathophysiology can inform targeted treatment strategies
(Bushong et al, 2002).
1. Treatment of Major Depressive Disorder
(MDD) : Major depressive disorder (MDD) is a
prevalent and debilitating psychiatric condition
characterized by persistent feelings of sadness,
hopelessness, and loss of interest or pleasure in activities
(Dolen and Bear, 2008). Traditional antidepressant
medications primarily target monoaminergic
neurotransmitter systems, such as serotonin and
norepinephrine, but a significant proportion of patients
do not achieve remission with these treatments.
Glutamatergic dysfunction has been implicated in the
pathophysiology of MDD, providing a rationale for
exploring glutamate-based interventions as novel
treatments (Beart and O’Shea, 2007).
a. Ketamine and Esketamine : Ketamine, an N-
methyl-D-aspartate (NMDA) receptor antagonist, has
garnered considerable attention for its rapid and robust
antidepressant effects, particularly in treatment-resistant
depression (Sahu et al, 2024). Multiple clinical trials have
demonstrated that a single intravenous infusion of
ketamine can produce rapid and sustained improvements
in depressive symptoms, with some patients experiencing
relief within hours of administration (Diazgranados et al,
2010). Esketamine, the S-enantiomer of ketamine, has
been developed as an intranasal formulation and received
FDA approval for treatment-resistant depression. The
mechanisms underlying the antidepressant effects of
ketamine are complex and may involve synaptic plasticity,
increased synaptic connectivity and modulation of
glutamatergic neurotransmission (Davitz et al, 2017).
 Targeting glutamatergic transmission in neuropsychiatric disorders
b. Glutamate Modulators : In addition to ketamine,
other glutamate modulators have shown promise as
potential treatments for MDD. For example, riluzole, an
FDA-approved medication for amyotrophic lateral
sclerosis (ALS), acts as a glutamate release inhibitor and
enhances glutamate reuptake. Several small-scale studies
have reported antidepressant effects of riluzole in patients
with treatment-resistant depression (Li et al, 2017). Other
glutamate modulators, such as memantine and D-
cycloserine have also been investigated for their potential
antidepressant properties, although further research is
needed to elucidate their efficacy and safety profile in
MDD (Harris et al, 2017).
2. Schizophrenia Spectrum disorders :
Schizophrenia spectrum disorders are a group of chronic
and severe mental illnesses characterized by disturbances
in thinking, perception, emotions and behavior.
Glutamatergic dysfunction, particularly hypofunction of
NMDA receptors has been implicated in the
pathophysiology of schizophrenia, offering novel targets
for therapeutic intervention (Ohgi et al, 2015).
a. NMDA Receptor Modulators : Given the
central role of NMDA receptor hypofunction in
schizophrenia, pharmacological modulation of NMDA
receptors represents a promising therapeutic approach.
Several compounds targeting the glycine modulatory site
of the NMDA receptor, such as glycine and D-serine,
have been investigated as adjunctive treatments for
schizophrenia (Chen and Lipton, 2006). These compounds
aim to enhance NMDA receptor function and mitigate
cognitive and negative symptoms associated with the
disorder. Additionally, agents that indirectly modulate
NMDA receptor activity, such as sarcosine and D-
cycloserine, have shown potential as adjunctive
treatments for schizophrenia, although further research
is needed to establish their efficacy and safety (Cook,
2010).
b. mGluR Modulators : Metabotropic glutamate
receptors (mGluRs) represent another potential target for
pharmacological intervention in schizophrenia. Group II
mGluR agonists, such as LY2140023 (also known as
pomaglumetad methionil) have been investigated for their
potential antipsychotic effects (Albrecht et al, 2010).
However, clinical trials of LY2140023 yielded mixed
results, with some studies reporting modest improvements
in symptoms compared to placebo. Other mGluR
modulators, such as LY404039 and AZD2066, have also
been studied in schizophrenia, but their efficacy remains
uncertain (Snyder and Wilman, 2010).
3. Bipolar disorder : Bipolar disorder is a mood
disorder characterized by recurrent episodes of mania or
535
hypomania and depression. Glutamatergic dysfunction has
been implicated in the pathophysiology of bipolar disorder,
particularly during manic episodes, offering potential
targets for pharmacological intervention (Reiner and
Levitz, 2018).
a. NMDA Receptor Modulators : Emerging
evidence suggests that dysregulation of glutamatergic
transmission, particularly NMDA receptor hypofunction,
may contribute to the pathogenesis of bipolar disorder.
As such, NMDA receptor modulators have been explored
as potential treatments for the disorder (Li et al, 2017).
For example, memantine, an NMDA receptor antagonist,
has shown efficacy in reducing manic symptoms in
patients with bipolar disorder. Additionally, ketamine,
which acts as a non-selective NMDA receptor antagonist,
has demonstrated rapid and robust antidepressant effects
in bipolar depression. Further research is needed to
elucidate the mechanisms underlying the therapeutic
effects of NMDA receptor modulators in bipolar disorder
and to optimize treatment strategies (Harris et al, 2017).
b. Glutamate Modulators : In addition to NMDA
receptor modulators, other glutamate modulators have
shown promise as potential treatments for bipolar disorder
(Diazgranados et al, 2010). For example, riluzole, a
glutamate release inhibitor, has been investigated as an
adjunctive treatment for bipolar depression. Preliminary
studies have suggested that riluzole may improve
depressive symptoms and reduce relapse rates in patients
with bipolar disorder. However, larger-scale clinical trials
are needed to confirm these findings and establish the
efficacy of riluzole in bipolar disorder (Lewerenz and
Maher, 2015).
4. Obsessive-Compulsive Disorder (OCD) :
Obsessive-compulsive disorder (OCD) is a chronic and
disabling psychiatric condition characterized by recurrent
obsessions and/or compulsions that cause significant
distress or impairment. While serotonin reuptake inhibitors
(SRIs) are the first-line pharmacological treatment for
OCD, a substantial proportion of patients do not respond
adequately to these medications. Glutamatergic
dysfunction has been implicated in the pathophysiology
of OCD, offering potential targets for novel treatments
(Cook, 2010).
a. Glutamate Modulators : Emerging evidence
suggests that abnormalities in glutamatergic transmission
may contribute to the pathogenesis of OCD. As such,
glutamate modulators have been explored as potential
treatments for the disorder (Snyder and Wilman, 2010).
For example, riluzole, a glutamate release inhibitor, has
been investigated as an adjunctive treatment for OCD.
Preliminary studies have suggested that riluzole may
536 Dakme Papi et al
reduce obsessive-compulsive symptoms and improve
overall functioning in patients with OCD. Additionally,
memantine, an NMDA receptor antagonist, has shown
promise as a treatment for refractory OCD. However,
further research is needed to elucidate the mechanisms
underlying the therapeutic effects of glutamate
modulators in OCD and to optimize treatment strategies
(Bolduc et al, 2008).
b. Neurostimulation techniques : In addition to
pharmacological interventions, neurostimulation
techniques targeting glutamatergic pathways have been
explored as potential treatments for OCD (Singh et al,
2024). For example, deep brain stimulation (DBS) of the
anterior limb of the internal capsule (ALIC), a key node
in the cortico-striato-thalamo-cortical (CSTC) circuit
implicated in OCD has shown promising results in
reducing obsessive-compulsive symptoms and improving
quality of life in refractory OCD patients (Bezzi et al,
2004). Additionally, repetitive transcranial magnetic
stimulation (rTMS) targeting the prefrontal cortex, a brain
region involved in cognitive control and emotion regulation,
has demonstrated efficacy in reducing obsessive-
compulsive symptoms in some patients with OCD
(Albrecht et al, 2010).
5. Anxiety Disorders : Anxiety disorders are a
group of psychiatric conditions characterized by excessive
fear, worry, and avoidance behaviors (Balla et al, 2001).
While selective serotonin reuptake inhibitors (SSRIs) and
serotonin-norepinephrine reuptake inhibitors (SNRIs) are
the first-line pharmacological treatments for anxiety
disorders, a significant proportion of patients do not
achieve remission with these medications. Glutamatergic
dysfunction has been implicated in the pathophysiology
of anxiety disorders, offering potential targets for novel
treatments (Alt et al, 2004).
a. Ketamine and Esketamine : Ketamine, an
NMDA receptor antagonist, has shown rapid and robust
anxiolytic effects in preclinical and clinical studies.
Multiple studies have demonstrated that a single
intravenous infusion of ketamine can produce rapid
reductions in anxiety symptoms, with some patients
experiencing relief within hours of administration (Dev
et al, 2000). Esketamine, the S-enantiomer of ketamine,
has also shown promise as a treatment for anxiety
disorders, particularly treatment-resistant cases. The
mechanisms underlying the anxiolytic effects of ketamine
are complex and may involve modulation of glutamatergic
neurotransmission in brain regions implicated in fear
processing and anxiety regulation (El Far et al, 2000).
b. Glutamate Modulators : In addition to ketamine,
other glutamate modulators have been explored as
potential treatments for anxiety disorders. For example,
riluzole, a glutamate release inhibitor, has shown anxiolytic
effects in preclinical studies and small-scale clinical trials
(Das et al, 1998). Preliminary evidence suggests that
riluzole may reduce anxiety symptoms and improve overall
functioning in patients with anxiety disorders. Additionally,
memantine, an NMDA receptor antagonist, has been
investigated as a treatment for anxiety disorders, although
further research is needed to establish its efficacy and
safety profile (Boudin et al, 2000).
6. Autism Spectrum Disorder (ASD) : Autism
spectrum disorder (ASD) is a neurodevelopmental
disorder characterized by persistent deficits in social
communication and interaction, as well as restricted
interests and repetitive behaviors (Moghaddam, 1993).
While behavioral interventions and educational support
are the mainstays of treatment for ASD, pharmacological
interventions targeting glutamatergic dysfunction may
offer additional benefits for some individuals with the
disorder (Danysz and Parsons, 1998).
a. Glutamate Modulators : Emerging evidence
suggests that abnormalities in glutamatergic transmission
may contribute to the pathogenesis of ASD. As such,
glutamate modulators have been explored as potential
treatments for the disorder (Bhatt et al, 2024). For
example, memantine, an NMDA receptor antagonist, has
shown promise as a treatment for core symptoms of ASD,
such as social communication deficits and repetitive
behaviors (Ehlers et al, 1996). Several small-scale clinical
trials have reported improvements in ASD symptoms with
memantine treatment, although larger-scale studies are
needed to confirm these findings and establish the
efficacy of memantine in ASD. Additionally, riluzole, a
glutamate release inhibitor, has been investigated as a
treatment for ASD, although further research is needed
to elucidate its effects on core symptoms of the disorder
(Conn and Pin, 1997).
b. Neurostimulation Techniques : In addition to
pharmacological interventions, neurostimulation
techniques targeting glutamatergic pathways have been
explored as potential treatments for ASD (Debant et al,
1996). For example, repetitive transcranial magnetic
stimulation (rTMS) targeting the dorsolateral prefrontal
cortex (DLPFC), a brain region implicated in cognitive
control and social cognition, has shown promise in
improving social communication skills and reducing
repetitive behaviors in individuals with ASD. Additionally,
transcranial direct current stimulation (tDCS), which
modulates cortical excitability and synaptic plasticity, has
been investigated as a treatment for ASD, although
further research is needed to establish its efficacy and
 Targeting glutamatergic transmission in neuropsychiatric disorders 537
safety profile (Alam et al, 1997). manage potential side effects early in the treatment
Challenges and Future Directions in Targeting process. Furthermore, the development of biomarkers and
Glutamatergic Transmission predictive algorithms for treatment response and adverse
reactions can facilitate personalized medicine approaches
As promising as targeting glutamatergic transmission
and improve patient outcomes (Chatterton et al, 2002).
may be for the treatment of neuropsychiatric disorders,
several challenges and considerations need to be C. Need for personalized medicine approaches
addressed to maximize the effectiveness and safety of : Given the heterogeneity of neuropsychiatric disorders
these interventions (Das et al, 1998). and individual variability in treatment response, there is a
growing recognition of the need for personalized medicine
A. Pharmacokinetic challenges of glutamate
approaches in psychiatry. Glutamate-targeted therapies
modulators : One of the primary challenges associated
offer the potential for more precise and tailored treatments
with glutamate modulators is their pharmacokinetic
based on patients’ unique neurobiological profiles, genetic
properties, including absorption, distribution, metabolism,
factors and clinical characteristics (Alt et al, 2004). By
and excretion (Boudin et al, 2000). Many glutamate
identifying biomarkers of glutamatergic dysfunction and
modulators have poor bioavailability or limited brain
treatment response, clinicians can stratify patients into
penetration, which can significantly impact their efficacy
subgroups and select the most appropriate interventions
and therapeutic potential. For example, some compounds
for their specific needs. Personalized medicine approaches
may be rapidly metabolized in the liver or undergo
may involve the use of genetic testing, neuroimaging
extensive first-pass metabolism, leading to low systemic
techniques, and clinical assessments to inform treatment
exposure and limited central nervous system (CNS)
decisions and optimize therapeutic outcomes (Furukawa
penetration (Dev et al, 2000). Additionally, the blood-brain
et al, 2005). For example, genetic polymorphisms in
barrier (BBB) presents a formidable obstacle to the
glutamate receptor genes or alterations in glutamate levels
delivery of drugs targeting glutamatergic transmission,
measured by magnetic resonance spectroscopy (MRS)
as it restricts the passage of molecules into the brain.
may serve as biomarkers for predicting treatment
Addressing pharmacokinetic challenges requires the
response to glutamate modulators. Similarly, neuroimaging
development of novel drug delivery systems and
biomarkers such as functional connectivity patterns or
formulations that enhance CNS penetration and
glutamate receptor density could help identify individuals,
bioavailability. Strategies such as prodrug design,
who are most likely to benefit from specific interventions
nanotechnology-based delivery systems, and optimization
(Aschrafi et al, 2005).
of physicochemical properties can improve drug
pharmacokinetics and maximize therapeutic efficacy (El D. Integration of glutamate-targeted therapies
Far et al, 2000). with existing treatments : Another challenge in the
field of glutamate-targeted therapies is the integration of
B. Adverse effects and safety concerns : Another
these interventions with existing treatments for
important consideration in the development of glutamate-
neuropsychiatric disorders (Bendel et al, 2005). Many
targeted therapies is the potential for adverse effects and
patients receive multiple medications or undergo
safety concerns. Glutamate modulators can affect
combination therapies to manage their symptoms, raising
multiple neurotransmitter systems and cellular processes,
concerns about potential drug interactions, additive
leading to a wide range of side effects that may limit
effects, or overlapping mechanisms of action. Integrating
their clinical utility (Andersson et al, 2001). For example,
glutamate-targeted therapies into existing treatment
NMDA receptor antagonists such as ketamine and
algorithms requires careful consideration of
memantine can cause dissociative symptoms,
pharmacodynamic and pharmacokinetic properties, as
hallucinations, and cognitive impairment, particularly at
well as potential synergistic or antagonistic effects with
higher doses. Similarly, drugs targeting glutamate
other medications (Choudary et al, 2005). Collaborative
transporters or metabotropic glutamate receptors may
and multidisciplinary approaches involving psychiatrists,
have off-target effects that contribute to adverse reactions
neuroscientists, pharmacologists, and other healthcare
(Balla et al, 2001). To mitigate adverse effects and safety
professionals are essential for optimizing treatment
concerns, it is essential to optimize drug selectivity and
strategies and ensuring comprehensive care for patients
specificity for their intended targets, while minimizing
with neuropsychiatric disorders. Clinical guidelines and
interactions with other neurotransmitter systems or
consensus recommendations may help standardize
cellular pathways. Additionally, careful monitoring of
treatment protocols and facilitate the safe and effective
patients and dose titration protocols can help identify and
integration of glutamate-targeted therapies into routine
538 Dakme Papi et al
practice (Beart and O’Shea, 2007).
E. Potential for combination therapies and
synergistic effects : Despite the challenges associated
with glutamate-targeted therapies, there is growing
interest in exploring combination therapies and synergistic
effects with other treatment modalities. Combinatorial
approaches involving glutamate modulators,
psychotherapy, neurostimulation techniques and lifestyle
interventions may offer complementary mechanisms of
action and enhance therapeutic outcomes for patients with
complex or treatment-resistant conditions (Fogal et al,
2007). For example, combining glutamate modulators with
traditional antidepressants or mood stabilizers could target
multiple neurotransmitter systems implicated in mood
regulation and synaptic plasticity, potentially enhancing
antidepressant or mood-stabilizing effects. Similarly,
combining glutamate-targeted therapies with cognitive-
behavioral therapy (CBT) or mindfulness-based
interventions may promote adaptive coping strategies and
improve functional outcomes in patients with anxiety
disorders or PTSD (Bolduc et al, 2008). Exploring the
potential for combination therapies and synergistic effects
requires rigorous preclinical and clinical research to
identify optimal treatment combinations, dosing regimens,
and patient populations (Carroll, 2008). Additionally,
mechanistic studies are needed to elucidate the
neurobiological underpinnings of synergistic interactions
between different treatment modalities and to inform
rational drug development strategies (Fogal et al, 2007).
CONCLUSION
Targeting glutamatergic transmission represents a
promising and evolving therapeutic approach for a wide
spectrum of neuropsychiatric disorders. Despite facing
challenges such as pharmacokinetic limitations, potential
adverse effects, and the need for personalized medicine
strategies, the field continues to advance with innovative
drug development, refined treatment protocols, and
interdisciplinary collaboration. By understanding the
complex role of glutamate in the pathophysiology of these
disorders and harnessing the potential of glutamate-
targeted interventions, clinicians and researchers can pave
the way for more effective and individualized treatments.
Integration of glutamate modulators with existing
therapies, exploration of combination treatments and
continued investigation into the neurobiological
mechanisms underlying glutamatergic dysfunction will be
crucial for optimizing clinical outcomes and improving the
quality of life for patients with neuropsychiatric conditions.
Moving forward, a comprehensive and patient-centered
approach that considers both the molecular intricacies of
glutamatergic signaling and the unique needs of individuals
will be essential for translating scientific discoveries into
tangible benefits for those affected by neuropsychiatric
disorders.
Conflict of interest : None
REFERENCES
Aan het Rot M, Collins K A, Murrough J W, Perez A M, Reich D L,
Charney D S and Mathew S J (2010) Safety and efficacy of
repeated-dose intravenous ketamine for treatment-resistant
depression. Biological Psychiatry 67(2), 139–145.
Abraham W C (2008) Metaplasticity: tuning synapses and networks
for plasticity. Nat. Rev. Neurosci. 9, 387.
Alam M R, Johnson R C, Darlington D N, Hand T A, Mains R E and
Eipper B A (1997) Kalirin, a cytosolic protein with spectrin-
like and GDP/GTP exchange factor-like domains that interacts
with peptidylglycine alpha-amidating monooxygenase, an
integral membrane peptide-processing enzyme. J. Biol. Chem.
272, 12667–12675.
Albrecht P, Lewerenz J, Dittmer S, Noack R, Maher P and Methner
A (2010) Mechanisms of oxidative glutamate toxicity: the
glutamate/cystine antiporter system xc- as a neuroprotective
drug target. CNS & Neurol. Dis. Drug Targ. 9(3), 373–382.
Alt A, Weiss B, Ogden A M, Knauss J L, Oler J, Ho K and Bleakman
D (2004) Pharmacological characterization of glutamatergic
agonists and antagonists at recombinant human homomeric and
heteromeric kainate receptors in vitro. Neuropharmacol. 46,
793–806.
Andersson O, Stenqvist A, Attersand A and von Euler G (2001)
Nucleotide sequence, genomic organization and chromosomal
localization of genes encoding the human NMDA receptor
subunits NR3A and NR3B. Genomics 78, 178–184.
Aschrafi A, Cunningham B A, Edelman G M and Vanderklish P W
(2005) The fragile X mental retardation protein and group I
metabotropic glutamate receptors regulate levels of mRNA
granules in brain. Proc. Nat. Acad. Sci. United States Am. 102,
2180–2185.
Baker D A, McFarland K, Lake R W, Shen H, Tang X C, Toda S and
Kalivas P W (2003) Neuroadaptations in cystine-glutamate
exchange underlie cocaine relapse. Nat. Neurosci. 6, 743–749.
Balla A, Koneru R, Smiley J, Sershen H and Javitt D C (2001)
Continuous phencyclidine treatment induces schizophrenia-
like hyperreactivity of striatal dopamine release.
Neuropsychopharmacol. 25, 157–164.
Banasr M, Chowdhury G M, Terwilliger R, Newton S S, Duman R
S, Behar K L and Sanacora G (2010) Glial pathology in an
animal model of depression: reversal of stress-induced cellular,
metabolic and behavioral deficits by the glutamate-modulating
drug riluzole. Molecular Psychiatry 15, 501–511.
Banko J L, Hou L, Poulin F, Sonenberg N and Klann E (2006)
Regulation of eukaryotic initiation factor 4E by converging
signaling pathways during metabotropic glutamate receptor-
dependent long-term depression. The J. Neurosci. 26, 2167–
2173.
Beart P M and O’Shea R D (2007) Transporters for L-glutamate: an
update on their molecular pharmacology and pathological
involvement. British J. Pharmacol. 150, 5–17.
Bendel O, Meijer B, Hurd Y and von Euler G (2005) Cloning and
expression of the human NMDA receptor subunit NR3B in
 Targeting glutamatergic transmission in neuropsychiatric disorders
the adult human hippocampus. Neurosci. Lett. 377, 31–36.
Berman R M, Cappiello A, Anand A, Oren D A, Heninger G R,
Charney D S and Krystal J H (2000) Antidepressant effects of
ketamine in depressed patients. Biological Psychiatry 47, 351–
354.
Bernard R, Kerman I A, Thompson R C, Jones E G, Bunney W E,
Barchas J D and Watson S J (2010) Altered expression of
glutamate signaling, growth factor and glia genes in the locus
coeruleus of patients with major depression. Molecular
Psychiatry.
Bertaso F, Zhang C, Scheschonka A, de Bock F, Fontanaud P, Marin
P and Lerner-Natoli M (2008) PICK1 uncoupling from
mGluR7a causes absence-like seizures. Nat. Neurosci. 11, 940–
948.
Bezzi P, Gundersen V, Galbete J L, Seifert G, Steinhauser C, Pilati E
and Volterra A (2004) Astrocytes contain a vesicular
compartment that is competent for regulated exocytosis of
glutamate. Nat. Neurosci. 7, 613–620.
Bhatt P, Kumar V, Malik M K and Kumar T (2024) Citrus Flavonoids:
Recent advances and Future Perspectives on preventing
Cardiovascular diseases. The Flavonoids 131-152.
Bird M K and Lawrence A J (2009) The promiscuous mGlu5
receptor—a range of partners for therapeutic possibilities?
Trends Pharmacol. Sci. 30, 617–623.
Bolduc F V, Bell K, Cox H, Broadie K S and Tully T (2008) Excess
protein synthesis in Drosophila fragile X mutants impairs
long-term memory. Nat. Neurosci. 11, 1143–1145.
Boudin H, Doan A, Xia J, Shigemoto R, Huganir R L, Worley P and
Craig A M (2000) Presynaptic clustering of mGluR7a requires
the PICK1 PDZ domain binding site. Neuron 28, 485–497.
Bushong E A, Martone M E, Jones Y Z and Ellisman M H (2002)
Protoplasmic astrocytes in CA1 stratum radiatum occupy
separate anatomical domains. J. Neurosci. 22, 183–192.
Carroll F I (2008) Antagonists at metabotropic glutamate receptor
subtype 5: structure activity relationships and therapeutic
potential for addiction. Annals New York Acad. Sci. 1141, 221–
232.
Chatterton J E, Awobuluyi M, Premkumar L S, Takahashi H,
Talantova M, Shin Y and Zhang D (2002) Excitatory glycine
receptors containing the NR3 family of NMDA receptor
subunits. Nature 415, 793–798.
Chen H S and Lipton S A (2006) The chemical biology of clinically
tolerated NMDA receptor antagonists. J. Neurochem. 97,
1611–1626.
Chen H S, Wang Y F, Rayudu P V, Edgecomb P, Neill J C, Segal M M
and Jensen F E (1998) Neuroprotective concentrations of the
N-methyl-D-aspartate open-channel blocker memantine are
effective without cytoplasmic vacuolation following post-
ischemic administration and do not block maze learning or long-
term potentiation. Neuroscience 86, 1121–1132.
Choudary P V, Molnar M, Evans S J, Tomita H, Li J Z, Vawter M P
and Jones E G (2005). Altered cortical glutamatergic and
GABAergic signal transmission with glial involvement in
depression. Proc. Nat. Acad. Sci. United States Am. 102, 15653–
15658.
Conn P J and Pin J P (1997) Pharmacology and functions of
metabotropic glutamate receptors. Ann. Rev. Pharmacol.
Toxicol. 37, 205–237.
539
Cook E H Jr (2010) Reduction of increased repetitive self-grooming
in ASD mouse model by metabotropic 5 glutamate receptor
antagonism; randomized controlled trial of Early Start Denver
Model. Autism Research 3, 40–42.
Danysz W and Parsons C G (1998) Glycine and N-methyl-D-
aspartate receptors: Physiological significance and possible
therapeutic applications. Pharmacol. Rev. 50, 597–664.
Das S, Sasaki Y F, Rothe T, Premkumar L S, Takasu M, Crandall J E
and Nakanishi N (1998) Increased NMDA current and spine
density in mice lacking the NMDA receptor subunit NR3A.
Nature 393, 377–381.
Davitz M S, Wu W E, Soher B J, Babb J S, Kirov I I and Huang J
(2017) Quantifying global-brain metabolite level changes with
whole-head proton MR spectroscopy at 3T. Magnetic
Resonance Imaging 35, 15–9. https://doi.org/10.1016/
j.mri.2016.08.012
Debant A, Serra-Pages C, Seipel K, O’Brien S, Tang M, Park S H and
Streuli M (1996) The multidomain protein Trio binds the LAR
transmembrane tyrosine phosphatase, contains a protein kinase
domain, and has separate rac-specific and rho-specific guanine
nucleotide exchange factor domains. Proc. Nat. Acad. Sci. United
States Am. 93, 5466–5471.
Dev K K, Nakajima Y, Kitano J, Braithwaite S P, Henley J M and
Nakanishi S (2000) PICK1 interacts with and regulates PKC
phosphorylation of mGLUR7. J. Neurosci. 20, 7252–7257.
Diazgranados N, Ibrahim L, Brutsche N E, Newberg A, Kronstein P,
Khalife S and Zarate C A Jr (2010) A randomized add-on trial
of an N-methyl-D-aspartate antagonist in treatment-resistant
bipolar depression. Arch. Gen. Psyc. 67, 793–802.
Dingledine R, Borges K, Bowie D and Traynelis S F (1999) The
glutamate receptor ion channels. Pharmacological Reviews 51,
7–61.
Dolen G and Bear M F (2008) Role for metabotropic glutamate
receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome.
J. Physiol. 586, 1503–1508.
Dolen G, Osterweil E, Rao B S, Smith G B, Auerbach B D, Chattarji
S and Bear M F (2007) Correction of fragile X syndrome in
mice. Neuron 56, 955–962.
Ehlers M D, Zhang S, Bernhadt J P and Huganir R L (1996)
Inactivation of NMDA receptors by direct interaction of
calmodulin with the NR1 subunit. Cell 84, 745–755.
El Far O, Airas J, Wischmeyer E, Nehring R B, Karschin A and Betz
H (2000) Interaction of the C-terminal tail region of the
metabotropic glutamate receptor 7 with the protein kinase C
substrate PICK1. Europ. J. Neurosci. 12, 4215–4221.
Erecinska M and Silver I A (1990) Metabolism and role of glutamate
in mammalian brain. Progress in Neurobiology 35, 245–296.
Fogal B, Li J, Lobner D, McCullough L D and Hewett S J (2007)
System x(c)-activity and astrocytes are necessary for
interleukin-1 beta-mediated hypoxic neuronal injury. J.
Neurosci. 27, 10094–10105.
Furukawa H, Singh S K, Mancusso R and Gouaux E (2005) Subunit
arrangement and function in NMDA receptors. Nature
438(7065), 185–192. https://doi.org/10.1038/nature04089
Gilad G M, Gilad V H, Wyatt R J and Tizabi Y (1990) Region-
selective stress-induced increase of glutamate uptake and release
in rat forebrain. Brain Research 525(2), 335–338. https://doi.org/
10.1016/0006-8993(90)90886-G
540 Dakme Papi et al
Harris A D, Saleh M G and Edden R A (2017). Edited (1)H magnetic
resonance spectroscopy in vivo: Methods and metabolites.
Magnetic Resonance in Medicine 77(4), 1377–89. https://doi.org/
10.1002/mrm.26619
Lewerenz J and Maher P (2015) Chronic glutamate toxicity in
neurodegenerative diseases-what is the evidence? Front.
Neurosci. 9, 469. https://doi.org/10.3389/fnins.2015.00469
Li C T, Lu C F, Lin H C, Huang Y Z, Juan C H and Su T P (2017)
Cortical inhibitory and excitatory function in drug-naive
generalized anxiety disorder. Brain Stimulation 10(3), 604–608.
https://doi.org/10.1016/j.brs.2016.12.007
Moghaddam B (1993) Stress preferentially increases extraneuronal
levels of excitatory amino acids in the prefrontal cortex:
comparison to hippocampus and basal ganglia. J. Neurochem.
60(5), 1650–1657. https://doi.org/10.1111/j.1471-
4159.1993.tb13387.x
Ohgi Y, Futamura T and Hashimoto K (2015) Glutamate signaling in
synaptogenesis and NMDA receptors as potential therapeutic
targets for psychiatric disorders. Curr. Mol. Med. 15(3), 206–
221. https://doi.org/10.2174/1566524015666150330143008
Reiner A and Levitz J (2018) Glutamatergic signaling in the central
nervous system: Ionotropic and metabotropic receptors in
concert. Neuron 98(5), 1080–98. https://doi.org/10.1016/
j.neuron.2018.05.018
Sahu K K, Kaurav M, Bhatt P, Minz S, Pradhan M, Khan J and
Yadav K (2024) Utility of nanomaterials in wound management.
In : Nanotechnological Aspects for Next-Generation Wound
Management (pp. 101-130). Academic Press.
Singh S, Bhatt P, Kumar V and Singh N P (2024) Phytonutrients,
Anthocyanidins, and Anthocyanins: Dietary and Medicinal
Pigments with Possible Health Benefits. In : Advances in
Flavonoids for Human Health and Prevention of Diseases (pp.
23-46). Apple Academic Press.
Snyder J and Wilman A (2010) Field strength dependence of PRESS
timings for simultaneous detection of glutamate and glutamine
from 1.5 to 7T. J. Magn. Reson. 203(1), 66–72. https://doi.org/
10.1016/j.jmr.2009.12.002