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Abstract

Anxiety, stress, and trauma-related disorders are a major public health concern in the United States. Drugs that target the gamma-aminobutyric acid or serotonergic system, such as benzodiazepines and selective serotonin reuptake inhibitors, respectively, are the most widely prescribed treatments for these disorders. However, the role of glutamate in anxiety disorders is becoming more recognized with the belief that drugs that modulate glutamatergic function through either ionotropic or metabotropic glutamate receptors have the potential to improve the current treatment of these severe and disabling illnesses. Animal models of fear and anxiety have provided a method to study the role of glutamate in anxiety. This research has demonstrated that drugs that alter glutamate transmission have potential anxiolytic action for many different paradigms including fear-potentiated startle, punished responding, and the elevated plus maze. Human clinical drug trials have demonstrated the efficacy of glutamatergic drugs for the treatment of obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, and social phobia. Recent data from magnetic resonance imaging studies provide an additional link between the glutamate system and anxiety. Collectively, the data suggest that future studies on the mechanism of and clinical efficacy of glutamatergic agents in anxiety disorders are appropriately warranted.
The Role of Glutamate
in Anxiety and Related Disorders
By Bernadette M. Cortese, PhD, and K. Luan Phan, MD
Dr. Cortese is postdoctoral scholar in the Department of Psychiatry at the Pennsylvania State University College of Medicine, Milton S.
Hershey Medical Center in Hershey. Dr. Phan is assistant professor of psychiatry in the Department of Psychiatry in the Biological Sciences
Division and the Pritzker School of Medicine at the University of Chicago in Illinois.
Disclosure: Dr. Cortese does not have an affiliation with or financial interest in any organization that might pose a conflict of interest.
Dr. Phan has received research grant support from American Psychiatric Institute for Research and Education, the Brain Research
Foundation, the National Institute on Drug Abuse, and the National Institute of Mental Health.
This article was submitted on June 27, 2005, and accepted on August 25, 2005.
Acknowledgment: The authors would like to thank Thomas Uhde, MD, for his comments on earlier versions of this manuscript.
Please direct all correspondence to:
K. Luan Phan, MD, University of Chicago,
Department
of Psychiatry, 5841 South Maryland Avenue,
MC3077 (L-466C), Chicago, IL 60637-1470; E-mail: luan@uchicago.edu.
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Review Article
ABSTRACT
Anxiety, stress, and trauma-related disorders are a
major public health concern in the United States. Drugs
that target the γ-aminobutyric acid or serotonergic system,
such as benzodiazepines and selective serotonin reuptake
inhibitors, respectively, are the most widely prescribed
treatments for these disorders. However, the role of glu-
tamate in anxiety disorders is becoming more recognized
with the belief that drugs that modulate glutamatergic
function through either ionotropic or metabotropic gluta-
mate receptors have the potential to improve the current
treatment of these severe and disabling illnesses. Animal
models of fear and anxiety have provided a method to
study the role of glutamate in anxiety. This research has
demonstrated that drugs that alter glutamate transmis-
sion have potential anxiolytic action for many different
paradigms including fear-potentiated startle, punished
responding, and the elevated plus maze. Human clinical
drug trials have demonstrated the efficacy of glutama-
tergic drugs for the treatment of obsessive-compulsive
disorder, posttraumatic stress disorder, generalized anxi-
ety disorder, and social phobia. Recent data from mag-
netic resonance imaging studies provide an additional link
between the glutamate system and anxiety. Collectively,
the data suggest that future studies on the mechanism of
and clinical efficacy of glutamatergic agents in anxiety
disorders are appropriately warranted.
CNS Spectr. 2005;10(10):820-830
Needs Assessment
Recent preclinical and clinical evidence has implicated the
glutamate system in animal models of anxious behavior and in
human anxiety disorders, including clinical trials showing efficacy
of glutamatergic agents in anxiety disorders. This review provides
a framework for synthesizing the current findings for clinicians,
researchers, and patients who stand to benefit from greater clarity as
to their scientific and therapeutic significance.
Learning Objectives
At the end of this activity, the participant should be able to:
Recognize the different mechanisms of action of various
pharmacologic agents can have on the glutamate neu-
rotransmitter system.
Describe the effects of glutamatergic agents on differ-
ent animal models of anxiety.
Identify which pharmacologic agents with effects on
the glutamate system have been shown to decrease the
clinical symptoms of anxiety.
Understand the potential that basic and translational
neuroscience studies on the glutamate system hold for
testing theories on the pathophysiology and develop-
ing novel pharmacotherapy of anxiety disorders.
Target Audience Neurologists and psychiatrists
Accreditation Statement
Mount Sinai School of Medicine is accredited by the
Accreditation Council for Continuing Medical Education to pro-
vide Continuing Medical Education for physicians.
Mount Sinai School of Medicine designates this educational
activity for a maximum of 3.0 Category 1 credit(s) toward the AMA
Physicians Recognition Award. Each physician should claim only
those credits that he/she actually spent in the educational activity.
Credits will be calculated by the MSSM OCME and provided for
the journal upon completion of agenda.
It is the policy of Mount Sinai School of Medicine to ensure
fair balance, independence, objectivity and scientific rigor in all its
sponsored activities. All faculty participating in sponsored activities
are expected to disclose to the audience any real or apparent discus-
sion of unlabeled or investigational use of any commercial product
or device not yet approved in the United States.
This activity has been peer-reviewed and approved by
Eric Hollander, MD, professor of psychiatry, Mount Sinai School of
Medicine. Review Date: August 22, 2005.
To Receive Credit for This Activity
Read this article, and the two CME-designated accompanying
articles, reflect on the information presented, and then complete
the CME quiz found on pages 840 and 841. To obtain credits, you
should score 70% or better. Termination date: October 31, 2007.
The estimated time to complete this activity is 3 hours.
CME
CME
3
CME
INTRODUCTION
Anxiety, stress, and trauma-related disorders are
a major public health concern in the United States,
with an estimated yearly burden of >$63 billion
dollars in direct (eg, psychiatric and non-psychiatric
care, hospitalization, emergency care and prescrip-
tion drugs) and indirect (eg, reduced productiv-
ity and occupational absenteeism) costs.
1
Anxiety
is commonly experienced and typically adaptive.
However, for >15 million adults/year, this anxiety
is excessive and dysfunctional, manifesting as an
anxiety disorder; together, anxiety disorders are the
most prevalent mental health problem in the US.
2
Furthermore, these individuals are more likely to be
diagnosed with other medical conditions including
irritable bowel syndrome and hypertension and are
at an increased risk for other anxiety disorders and
mood disorders, such as depression.
3
Anxiety disorders, including generalized anxiety
disorder (GAD), specific and social phobias, posttrau-
matic stress disorder (PTSD), obsessive-compulsive dis-
order (OCD), and panic disorder, are typically treated
with medications that target the γ-aminobuytric acid
(GABA) or serotonergic system. Benzodiazepines
and selective serotonin reuptake inhibitors, are the
most widely prescribed treatments for these disor-
ders.
4
Some forms of anxiety are relatively resistant
to treatment with these agents,
5,6
and both benzodi-
azepines and selective serotonin reuptake inhibitors
can be associated with side effects, such as sedation,
memory impairment, potential for substance abuse and
withdrawal syndromes, sexual dysfunction, and weight
gain. Noncompliance with these pharmacologic
agents remains a problem, leading to increased risk for
relapse.
7
Therefore, it has become increasingly appar-
ent that alternative treatment strategies are needed.
8
A novel avenue of neuroscience research
involves the glutamate system, the major excit-
atory neurotransmitter in the mammalian brain.
Given that many stress- and anxiety-related disor-
ders are posited to stem from excessively responsive
or hyperexcitable brain circuits, investigations of
the role of glutamate in anxiety disorders and of
drugs that modulate glutamatergic function have
the potential to improve our understanding and
treatment of these severe and disabling illnesses.
GLUTAMATE PHARMACOLOGY
Glutamate is ubiquitous within the central ner-
vous system and has been shown to play important
roles in many brain processes, including neurode-
velopment (eg, differentiation, migration and sur-
vival),
9
learning (eg, long-term potentiation and
depression),
10
acute neurodegeneration (eg, cerebral
ischemia, traumatic brain injury),
11
chronic neuro-
degeneration (eg, Huntington’s disease, Alzheimer’s
disease),
12
and, more recently, the stress response and
anxiety disorders.
13
Exposure to severe stress has been
associated with glutamate excitotoxicity, which, in
turn, can cause neuronal damage and/or death.
Glutamate exerts its actions through ligand-gated
ion channel (ionotropic) receptors, including the N-
methyl-d-aspartate (NMDA), kainate, and α-amino-
3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA) subtypes, and G protein-coupled metabo-
tropic receptors (mGluR1-8).
14
The ionotropic gluta-
mate receptors are distributed widely throughout the
brain, although density is high in cortical and limbic
regions.
15
The metabotropic receptors have a similar
wide distribution, with a moderate to high expression
in the hippocampus, prefrontal cortex, and amygdala
regions associated with anxiety.
16
The mGluRs are
further classified into three groups: group I recep-
tors (mGluR1 and mGluR5) localized predominately
on postsynaptic neurons are positively coupled to
phospholipase C; group II receptors (mGluR2 and
mGluR3), localized on pre- and post-synaptic neu-
rons, and group III receptors (mGluR4, mGluR6,
mGluR7, and mGluR8) are coupled in an inhibitory
manner to adenylyl cyclase.
17
Limbic and associated
paralimbic brain structures (amygdala, hippocampus,
anterior cingulate cortex [ACC], orbitofrontal cor-
tex, medial prefrontal cortex, insular cortex), regions
extensively implicated in the mediation of fear, and
anxiety in animals and humans
18-21
have been iden-
tified as being richly innervated by glutamatergic
pyramidal cells.
22
Utilizing an immunohisochemistry
tracing technique for localization of glutamate neu-
rons, McDonald
22
reported that 85% to 95% of the
neurons in the basolateral nucleus of the amygdala
were both glutamate positive and projected to the
prefrontal cortex and ventral striatum. Furthermore,
glutamatergic pyramidal cells of the prefrontal cortex
project back to numerous limbic regions, including
the hippocampus and amygdala.
23
Glutamate also exerts its actions in the brain
by affecting the release of other neurotransmitters
including monoamines and GABA. In vivo micro-
dialysis experiments in awake, freely moving rats
24,25
have demonstrated that both mild stress (ie, han-
dling) and intra-striatal infusion of AMPA/kain-
ate agonists facilitate the presynaptic synthesis and
release of dopamine in prefrontal cortex, while infu-
sion of an NMDA agonist resulted in a trend toward
a decrease in prefrontal cortical dopamine release.
24
GABA inhibitory interneurons have been impli-
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cated to have a role in this latter effect.
24
Similar to
dopamine, both in vitro and in vivo studies have
demonstrated modulation of serotonin release by glu-
tamate.
26,27
In addition, current treatments for anxiety
disorders, including topiramate, lamotrigine, and phe-
nytoin, have been shown to modulate monoamine
release in the prefrontal cortex
28
and hippocampus
29
and enhance GABA in entorhinal cortex.
30
Results
from these studies suggest the anxiolytic effects of
glutamatergic drugs may be mediated in part by mod-
ulation of other neurotransmitter systems.
GLUTAMATE AND STRESS
Release of adrenal steroid hormones called glu-
cocorticoids is a normal response to stress. However,
chronic stress and release of glucocorticoids is asso-
ciated with illness and specific neurotoxic events,
including the excess release of glutamate in the
hippocampus.
31
For example, chronic exposure to
immobilization stress in rats is reported to increase
glutamate release and uptake in the hippocampus and
prefrontal cortex.
32-34
Stress caused by forced swim-
ming has also been shown to increase glutamate in
the hippocampus and prefrontal cortex.
35
Chronic
stress may also alter glutamate gene expression, given
that repeated immobilization in rats has been associ-
ated with increased hippocampal AMPA receptor
messenger ribonucleic acid levels.
36
The stress-related effects of glucocorticoids and
subsequent excitotoxicity of glutamate in the hip-
pocampus, make this brain region particularly sus-
ceptible to atrophy.
37
Animal studies have reported
decreased dendritic branching, neuronal death, and
decreased neuronal regeneration of hippocampal
pyramidal cells in response to chronic immobiliza-
tion stress.
38,39
In contrast to the degenerative effects
demonstrated in the hippocampus, chronic immo-
bilization stress produces hypertrophic effects in the
amygdala, including enhanced dendritic arborization
(ie, increase in dendritic length and branch points)
of the pyramidal and stellate neurons of the basolat-
eral complex of the amygdala
39
and bed nucleus of
stria terminalis neurons of the extended amygdala.
40
The paradoxical stress-induced anatomical changes
found in the hippocampus and amygdala appears
consistent with their differential roles in the neural
circuitry of stress. Specifically, the role of the hip-
pocampus in the hypothalamic-pituitary-adrenal axis
is inhibitory and in contrast to the excitatory regula-
tion by the amygdala.
41
Behavioral studies
42,43
have demonstrated this
contradiction in that stress impairs hippocam-
pal-dependent (ie, spatial) learning, but facilitates
amygdala-dependent aversive learning. For example,
chronic stress exposure has been shown to impair per-
formance on a variety of hippocampal- and glutamate-
dependent spatial learning tasks, including the radial
arm maze
44
and Morris water maze.
45
On the other
hand, excess glutamate release has been shown to
facilitate other forms of learning, such as fear-related
learning (ie, fear conditioning). For instance, restraint
stress has been shown to increase freezing in a contex-
tual, fear-conditioning paradigm.
46
Fear conditioning
is a hippocampal- and amygdala-dependent type of
learning in which emotional significance (ie, fear)
develops and attaches to a neutral stimulus, for exam-
ple, contextual cues, through the consistent pairing
of the neutral stimulus with an aversive stimulus.
18
Pharmacologic studies have revealed the importance
of both hippocampal
47
and amygdala
48
NMDA-type
glutamate receptors in the acquisition and expression
of contextual fear in rats. In addition to contextual
fear conditioning, conditioned-fear paradigms, such as
potentiated startle, have been instrumental in demon-
strating the role of glutamate and glutamatergic recep-
tors in the amygdala, in particular, in fear learning.
49
Glutamatergic mechanisms are also hypothesized to
have a role in certain behavioral manifestations com-
mon to PTSD, including dissociation and perceptual
alterations.
50
More specifically, glutamatergic control
of both hippocampal-dependent associative learning
and amygdala-dependent emotional processing during
and after a stressful event may be significant factors in
these information processing distortions. Direct evi-
dence for this includes reports
51
that NMDA recep-
tor antagonism by ketamine can produce dissociative
symptoms and perceptual alterations (ie, depersonal-
ization, derealization, altered auditory, and visual acu-
ity) akin to those observed with PTSD.
ANIMAL MODELS OF
GLUTAMATE AND ANXIETY
Animal models of fear and anxiety have provided a
method to study the neuroanatomy and neurochemis-
try of anxiety disorders.
52
Some of these animal mod-
els include punishment-induced (eg, Geller-Seifter)
and ethological conflict paradigms (eg, elevated
plus maze), aversive tests (eg, exposure to predator),
conditioned-fear tests (eg, fear-potentiated startle),
and pathophysiological models, including stress and
trauma paradigms, such as chronic immobility and
sleep deprivation. The elevated plus maze, con-
structed of two elevated closed arms and two elevated
open arms, measures the conflict between an ani-
mal’s natural tendency to explore and innate fear of
heights and open spaces (ie, open arm avoidance).
53
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The Geller-Seifter test is a conflict procedure that
measures an animal’s acceptance of punishment (eg,
foot shock) in order to obtain food reward.
54
The
fear-potentiated startle paradigm of conditioned fear
measures the increase in the amplitude of the acous-
tic startle reflex in the presence of a light stimulus
that was previously paired with shock.
55
In a recent study, Uhde and colleagues
56
utilized
a sleep deprivation technique, a method shown to
worsen symptoms of generalized anxiety disorder and
induce panic attacks in humans with panic disorder,
to study the effects of stress on brain chemistry in
the rat. Compared with rats with normal sleep/wake
cycles, 6 hours of sleep deprivation in rats produced
significantly greater levels of glutamate and aspartate
in the medial prefrontal cortex, as measured by high
resolution magic-angle spinning proton magnetic
resonance spectroscopy (
1
H-MRS), a quantitative,
ex vivo MR technique used to measure region-spe-
cific neurochemicals. In non-human primates, in vivo
magnetic resonance spectroscopic imaging has also
revealed significantly increased unresolved glutamate-
glutamine-γ-aminobutyric acid (Glx) in response to
stress.
57
Specifically, mother-infant macaque dyads
were reared on a variable schedule for difficulty of
food procurement, a method shown to have lasting
stress-related behavioral and hormonal effects. At
10 years of age, the macaques that were exposed to
this stressor during infancy had increased Glx/cre-
atine ratios in the ACC compared with matched nor-
mal control subjects. Although the Glx resonance
is a combined measure of glutamate, glutamine, and
GABA, the literature consistently describes variations
in Glx as changes in glutamate alone. This is based
on several lines of evidence,
58-61
including reports that
MRS-measured GABA levels are much lower than
glutamate levels in human brain
58-60
and that gluta-
mate is the most predominant individual component
of the Glx resonance.
61
Nevertheless changes in Glx,
measured at lower field strength (eg, 1.5 Tesla), war-
rant cautious interpretation.
Other anxiety-related behavioral paradigms have
also been used to test drugs with potential anxiolytic
action, including medications that alter glutamate
transmission. The glutamate system has received
much attention as a target for treatments of anxiety
disorders due to both the preclinical animal studies
and human drug trials that have provided good evi-
dence of the efficacy of glutamatergic drugs in the
treatment of anxiety (Table). The fear-potentiated
startle paradigm has been instrumental in this respect.
Although fear conditioning and fear-potentiated
startle paradigms have validated animal models of
PTSD and revealed the involvement of other neu-
rotransmitter systems,
62
there seems to be a specific
role for glutamate. For example, administration of glu-
tamate antagonists to rats has been used to effectively
suppress trauma-enhanced acoustic startle response. In
one study,
63
microinjections of DL-2-amino-5-phos-
phonopentanoic acid (AP5), a competitive NMDA
receptor antagonist, into the caudal pontine reticular
nucleus effectively suppressed fear-potentiated startle
in rats. Others
49
have reported that NMDA glutamate
receptors within the amygdala are particularly impor-
tant to both the learning of fear-potentiated startle
and the extinction of conditioned fear. The NMDA
antagonist AP5 infused directly into the amygdala
dose-dependently blocked the acquisition and expres-
sion of fear-potentiated startle.
64,65
Consistent with
this, D-cycloserine, the NMDA receptor partial ago-
nist acting at the glycine regulatory site, dose-depend-
ently enhanced extinction of the startle response.
66
Other studies
67-69
have also revealed the enhanced
extinction effects associated with D-cycloserine,
including reports on the facilitatory effects of D-cyclo-
serine on extinction of cue-conditioned freezing, a
species-specific defense response.
67-69
In all, these
data suggest a role for the NMDA system in both the
acquisition and extinction of conditioned fear.
Medications that target non-NMDA glutamate
receptors have also been shown to be an important
component of fear behavior. Injections of the AMPA/
kainate receptor agonists kainic acid into the dor-
sal region of the periaqueductal gray, a brain region
critical to the expression of acoustic fear-potentiated
startle, blocked this startle response, while injections
with the AMPA/kainate antagonist 5R,10S)-(+)5-
methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-
5,10-imine enhanced this fear response.
70
Topiramate,
an Food and Drug Administration-approved anticon-
vulsant with several mechanisms of action, including
inhibition of the non-NMDA glutamate receptors
AMPA/kainate,
71
has been shown to significantly
reduce stress-induced increase in acoustic startle
in rats.
72
Topiramate also acts in part to potentiate
GABA by binding to the GABA
A
receptor,
73
an
effect that could also explain its anxiolytic properties.
In addition, the animal data also implicated the
metabotropic glutamate receptors as a potential site
for anxiolytic action.
16
These receptors have shown
to also be involved in fear conditioning and expres-
sion.
74
For example, rats given an injection of 2-
methyl-6-(phenylthynyl)-pyridine, a highly potent
group I metabotropic receptor antagonist (mGluR5),
before fear conditioning, dose-dependently blocked
the acquisition of fear and the expression of fear
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TABLE. A SUMMARY OF THE ANIMAL AND HUMAN PHARMACOLOGIC EVIDENCE FOR THE ROLE
OF GLUTAMATE IN ANXIETY
Preclinical Studies
Author(s) (Year) Agent Mechanism Effect
Fendt et al (1996)
63
AP5 NMDA receptor antagonist Fear-potentiated startle
Campeau et al (1992)
64
AP5 NMDA receptor antagonist Fear-potentiated startle
Walker et al (2002)
66
DCS NMDA partial agonist Fear-potentiated startle
(extinction)
Ho et al (2005)
75
DCS NMDA partial agonist EPM (time in open arms)
Karcz-Kubicha et al (1997)
76
DCS NMDA partial agonist EPM (time in open arms)
Anthony and
Nevins (1993)
65
DCS NMDA partial agonist Fear-potentiated startle
Ledgerwood et al (2004)
69
DCS NMDA partial agonist Cue-conditioned freezing
(reinstatement)
Ledgerwood et al (2003)
68
DCS NMDA partial agonist Cue-conditioned freezing
(extinction)
Parnas et al (2005)
67
DCS NMDA partial agonist Cue-conditioned freezing
(extinction)
Klodzinska and
Chojnacka-Wojcik
(2000)
77
DCS NMDA partial agonist Punished drinking
Xie et al (1995)
78
MK-801 NMDA receptor antagonist Punished drinking
Fendt (2000)
70
Kainic acid AMPA/kainate receptor agonist Fear-potentiated startle
Fendt (2000)
70
NBQX AMPA/kainate receptor antagonist Fear-potentiated startle
Kotlinksa and Liljequist
(1998)
79
LY326325 AMPA/kainate receptor antagonist Punished drinking
EPM (time in open arms)
Khan and Liberzon (2004)
72
Topiramate AMPA/kainate receptor agonist Stress-induced startle
Schulz et al (2001)
80
MPEP mGluR5 antagonist Fear-potentiated startle
Ballard et al (2005)
81
MPEP mGluR5 antagonist Punished responding
Linden et al (2004)
82
LY354740 mGluR2/3 agonist EPM (time in open arms)
Shekhar and Keim (2000)
83
LY354740 mGluR2/3 agonist Lactate-induced panic
Helton et al (1998)
84
LY354740 mGluR2/3 agonist Fear-potentiated startle
Walker et al (2002)
49
LY354740 mGluR2/3 agonist Fear-potentiated startle
Johnson et al (2005)
85
3-pyridyl-
methyl-
sufonamides
mGlurR2R receptor
agonist-potentiators
Fear-potentiated startle
Stress-induced hyperthermia
Steckler et al (2005)
86
JNJ16259685 mGluR1 antagonist Punished drinking
Mirza et al (2005)
87
Lamotrigine Sodium channel blocker Conditioned emotional
response
Mirza et al (2005)
87
Riluzole Glutamate release inhibitor Conditioned emotional
response
(continued on page 825)
(ie, fear-potentiated startle), without causing seda-
tive or analgetic effects.
88
Similarly, acute systemic
and oral administration of the group II mGluR 2/3
agonist LY354740 produced a significant reduction
in fear-potentiated startle, without any central ner-
vous system impairments.
84,89
A recent study
84
suggests
that mGluR2 potentiators, which act by increasing
the affinity and apparent potency of glutamate ago-
nists, also demonstrate efficacy in the fear-potentiated
startle paradigm and other rodent models of anxiety,
including stress-induced hyperthermia.
The punished responding paradigms and the
elevated plus maze anxiety models have also been
helpful in describing the role of glutamate in
anxiety. For example, in a conditioned emotional
response task (ie, lever pressing for food in the
presence of a light that was previously paired with
shock), drugs that inhibit glutamate release, such
as lamotrigine and riluzole, demonstrate anxiolytic
properties with increased conditioned emotional
response rates during the presentation of the light.
87
Treatment with 2-methyl-6-(phenylthynyl)-pyr-
idine also dose-dependently increased punished
responding in several conflict paradigms with rats
but did not significantly affect working memory or
spatial learning at these anxiolytic doses.
81
With respect to punished drinking, the studies
are mixed as to whether the compound dizocilpine,
a noncompetitive NMDA antagonist, has anxiolytic
properties.
Xie and colleagues
78
suggested that these
discrepant findings may be due to the variable pre-
treatment intervals used in the previous studies, since
a variety of pretreatment times were assessed and an
optimal time range for administration was reported to
significantly increase punished responding.
78
Similar
to the anxiolytic effects on conditioned startle and
freezing behaviors, administration of D-cycloserine
in rats produced a significant increase in both pun-
ished drinking and time spent in the open arms of the
elevated plus maze.
76,77
However, this latter effect was
recently shown to be reversed (ie, an anxiogenic effect
was measured by a decrease in time spent in the open
arms) with the administration of much lower doses
of the partial NMDA agonist D-cycloserine.
75
Acute
and chronic administration of the mGluR1 antago-
nist JNJ16259685 and administration of the AMPA/
kainate receptor antagonist LY326325 also produces
a dose-dependent significant increase in punished
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TABLE. A SUMMARY OF THE ANIMAL AND HUMAN PHARMACOLOGIC EVIDENCE FOR THE ROLE
OF GLUTAMATE IN ANXIETY
Clinical Studies
Author(s) (Year) Agent Mechanism Effect
Grillon et al (2003)
89
LY354740 mGluR2/3 agonist Fear-potentiated startle
Levine et al (2001)
90
LY354740 mGluR2/3 agonist CO
2
challenge panic
Kellner et al (2005)
91
LY544344 mGluR2/3 agonist CCK-4 challenge panic
Bremner et al (2004)
92
Phenytoin Inhibits glutamate transmission Symptoms of PTSD
Heresco-Levy et al (2002)
93
DCS NMDA partial agonist Symptoms of PTSD
Ressler et al (2004)
94
DCS NMDA partial agonist Symptoms of specific phobia
Berlant and van Kammen
(2002)
95
Topiramate AMPA/kainate receptor agonist Symptoms of PTSD
Berlant (2004)
96
Topiramate AMPA/kainate receptor agonist Symptoms of PTSD
van Ameringen et al
(2004)
97
Topiramate AMPA/kainate receptor agonist Symptoms of social phobia
Coric et al (2005)
98
Riluzole Glutamate release inhibitor Symptoms of OCD
Mathew et al
(In press)
99
Riluzole Glutamate release inhibitor Symptoms of GAD
AP5=DL-2-amino-5-phosphonopentanoic acid; NMDA=N-methyl-D-aspartate; =decreased; =in creased; DCS=D-cycloserine; EPM=elevated
plus maze; MK-801=dizocilpine; AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; NBQX=(5R,10S)-(+)5-methyl-10,11-dihydro-5H-
dibenzo[a,d]cyclohepten-5,10-imine; MPEP=2-methyl-6-(phenylethynyl)-pyridine; mGluR=metabotropic glutamate receptor; CO
2
=carbon dioxide;
CCK-4=cholecystokinin tetrapeptide; PTSD=posttraumatic stress disorder; OCD=obsessive-compulsive disorder; GAD=general anxiety disorder.
Cortese BM, Phan KL. CNS Spectr. Vol 10, No 10. 2005
(continued from page 824)
drinking.
79,86
This study
79
reported that treatment
with LY326325 produced a significant increase in the
time spent in the open arms of the elevated plus maze.
Anxiolytic effects of LY354740 were also found for the
elevated plus maze,
82
an effect prevented by pretreat-
ment with an mGluR selective antagonist and not
present in mGluR2 or mGluR3 receptor knockout
mice.
100
The mGluR agonists have also been found to
have anxiolytic properties in other animal models of
anxiety. One study
83
demonstrated a similar efficacy
of both LY354740 and alprazolam, a benzodiazepine
proven to be a clinically effective anti-panic drug, in
preventing lactate-induced panic-like attacks in rats.
83
THE HUMAN PSYCHOPHARMACOLOGY
AND CLINICAL STUDIES OF
GLUTAMATE AND ANXIETY
Although relatively few in number, human genetic,
physiological, and behavioral studies also present pre-
liminary evidence for the involvement of glutamate
in fear and anxiety (Table). Arnold and colleagues,
101
reported a significant association between a glutamate
system gene and OCD by measuring the relationship
between variants of the glutamate NMDA receptor
subtype 2B (GRIN2B) and familial incidence and
severity of OCD. Specific findings from this study
included a significant positive association between
5072T/G, a single nucleotide polymorphism located
in the 3’ untranslated region of GRIN2B, and both
OCD diagnosis and lifetime symptom severity. The
authors concluded that GRIN2B could be associated
with increased risk for OCD, a finding in support
of glutamate system changes in the pathophysiol-
ogy of anxiety. In a more recent study,
102
glutamate
levels in cerebrospinal fluid (CSF) of psychotropic
drug-naïve OCD patients were measured and found
to be significantly higher when compared with the
CSF glutamate levels of normal control subjects.
102
A significant relationship between OCD symptom
severity and CSF glutamate levels was not reported.
This could be due to the fact that increased glu-
tamate in CSF has not been confirmed to directly
reflect increased glutamate in the brain. However, it
could indicate a number of brain processes, including
abnormal activity of the glutamate/glutamine cycle.
Nevertheless, the result of increased glutamate in
CSF adds to the growing evidence in support of the
role of glutamate in OCD and anxiety in general.
The fear-potentiated startle paradigm has also been
utilized in humans as a model of conditioned fear.
Similar to the animal studies, LY354740 has been
assessed as a potential anxiolytic with the fear-poten-
tiated startle paradigm in humans. Grillon and col-
leagues
89
reported both a reduction in fear-potentiated
startle to shock anticipation and a lower self-reported
level of state anxiety after treatment with LY354740
in healthy volunteers. LY354740 has also been shown
to be efficacious in an experimentally induced anxi-
ety model of panic attacks that utilized 35% carbon
dioxide inhalation in patients suffering from panic
disorder.
90
Furthermore LY544344, the peptidyl pro-
drug of LY354740 developed for better absorption and
bioavailability, produced a significant decrease in cho-
lecystokinin tetrapeptide-induced subjective anxiety
ratings and panic symptoms in healthy humans who
also demonstrated reduced cholecystokinin tetrapep-
tide-elicited adrenocorticotropin release.
91
Clinical drug trials
92-99
provide convincing evi-
dence for a role of the glutamate system in several
of the anxiety disorders. Specifically, there are vari-
ous reports on clinical drug trials for the treatment
of anxiety disorders using compounds that have
direct actions on glutamate receptors. Phenytoin,
an anticonvulsant with several mechanisms of
action that include both decreasing glutamate and
increase GABA neurotransmission,
103
has recently
been used to treat early abuse-, combat-, and car-
accident-related PTSD.
92
In this small open-label
trial, 3 months of phenytoin treatment resulted in a
significant decrease in PTSD symptoms, including
intrusions, avoidance, and arousal. In another group
of patients with chronic PTSD,
93
treatment with D-
cycloserine resulted in a significant improvement
in anxiety-associated symptoms. Preclinical stud-
ies investigating the effects of D-cycloserine on the
extinction of conditioned-fear responses
104
have led
some to suggest a therapeutic role for D-cycloserine
in the extinction of fear and anxiety associated with
phobia, PTSD, OCD, and panic disorder in humans.
This is especially true given that current behavioral
treatments for fear and anxiety, including behavioral
exposure therapy, is based on extinction.
94
In a recent
randomized, double-blind, placebo-controlled study,
94
patients with acrophobia (ie, fear of heights) were
given combination therapy of behavioral exposure to
heights within a virtual reality glass elevator and oral
administration of either D-cycloserine or placebo.
The D-cycloserine-treated patients compared with
the placebo controls demonstrated significantly larger
reductions in acrophobia symptoms, both in the
virtual environment and in real-world experiences.
These effects were maintained for a 3-month period,
demonstrating both the robust and lasting effect of D-
cycloserine on the extinction of fear in humans.
94
Non-NMDA glutamate receptors also have a
role in anxiety in humans. Similar to the preclinical
826
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Review Article
studies with topiramate, human open-label studies
of topiramate as a monotherapy or adjunctive treat-
ment in adults with chronic PTSD
95,96
report signif-
icant decreases in nightmares and flashbacks, and
a reduction in PTSD Checklist-Civilian Version
score. Topiramate has also been assessed as a treat-
ment for social phobia in a study by van Ameringen
and colleagues
97
who reported a significant drop in
the Liebowitz Social Anxiety Scale score in adult
Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition
105
-diagnosed social phobics (general-
ized type) after 16 weeks of open-label drug therapy.
Again, it is important to note that like phenytoin,
topiramate modulates both excitatory (ie, gluta-
mate) and inhibitory (ie, GABA) neurotransmis-
sion, mechanisms that could both contribute to the
anxiolytic effects demonstrated by these drugs.
Mathew and colleagues
99
reported the preliminary
results of an 8-week, open-label study for treatment
effectiveness of the anti-glutamatergic agent riluzole
100 mg/day in 18 medically healthy, adult patients
with Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition
105
-diagnosed GAD. After 8
weeks, the response rate in trial completers (n=15)
was 80%, while the remission rate (Hamilton Anxiety
Scale score <7) was 53%. Although larger, placebo-
controlled studies are needed, the authors propose
that riluzole may be an effective and well-tolerated
anxiolytic medication with a relatively quick onset of
therapeutic efficacy for the treatment of GAD
. Coric
and colleagues
98
recently demonstrated that augmen-
tation of existing pharmacotherapy with riluzole was
well tolerated and efficacious in treatment-resistant
OCD. In an open-label trial, the authors reported
that of the 13 patients studied, seven had a >35%
reduction in Yale-Brown Obsessive-Compulsive
Scale scores, and five were classified as treatment
responders. These two studies prompt randomized
placebo-controlled clinical trials of riluzole, a gluta-
mate release inhibitor, in anxiety disorders.
HUMAN BRAIN IMAGING STUDIES
OF GLUTAMATE AND ANXIETY
Magnetic resonance imaging (MRI) has been
used to demonstrate the close, albeit indirect, rela-
tionship between glutamate and anxiety. Volumetric
(ie, structural) MRI and functional magnetic reso-
nance imaging (fMRI) studies show that glutamate-
rich brain regions that have been implicated in the
expression of fear and anxiety, such as the hippo-
campus, amygdala, and anterior cingulate cortex, are
either structurally altered or functionally hyperac-
tive in patients diagnosed with anxiety disorders. For
example, studies
106,107
have reported reduced ante-
rior cingulate gray matter volume in trauma survi-
vors who developed PTSD. Hippocampal volume
is also reduced in Vietnam veterans diagnosed with
combat-related PTSD
108
and women diagnosed with
PTSD associated with childhood abuse.
109
Although
there have been other reports of no difference in
hippocampal volume in patients diagnosed with
PTSD,
110,111
a meta-analysis of nine studies published
between the years of 1995 and 2003
112
revealed sig-
nificantly smaller left and right hippocampal volume
in traumatized adults diagnosed with PTSD com-
pared with healthy and traumatized controls.
Interestingly, the human MRI studies that describe
the effects of stress and trauma on the volume of hip-
pocampus and amygdala are comparable with the
animal studies of hippocampal and amygdalar den-
dritic arborization that were previously described.
Consistent with the stress-induced hypertrophic
effects described in animals, recent reports
113-115
show
MRI-measured increases in the volume of amygdala
in children and adolescents diagnosed with anxiety
disorders, such as GAD and OCD.
113-115
Functional brain imaging techniques, such as posi-
tron emissions tomography (PET) and fMRI, have
revealed altered brain activity in the same neuroana-
tomical regions that have been linked with anxiety
disorders through volumetric MRI. For example, panic
disorder patients show altered PET-assessed brain
metabolism in the hippocampus and ACC,
116
while
combat veterans diagnosed with PTSD demonstrate
differential blood flow patterns in the amygdala.
117
Other studies using fMRI have effectively linked a
deficit in amygdala functioning during a social cue
task in patients diagnosed with social anxiety disor-
der. Stein and colleagues
118
and Birbaumer and col-
leagues
119
have both shown hyper-responsive limbic
areas (ie, amygdala) as a reaction to negatively biased
social cues (eg, harsh/unaccepting faces) in subjects
diagnosed with social anxiety disorder. Again, these
imaging studies do not provide a direct relationship
between glutamate functioning and the pathophysi-
ology of anxiety. They only suggest that glutamate-
rich brain regions are altered and/or dysfunctional in
people diagnosed with anxiety disorders.
1
H-MRS is an in vivo imaging technique that
enables the quantification of specific neurochemi-
cals and some neurotransmitters including glutamate.
While most studies focus on N-acetylaspartate and
anxiety disorders,
120-125
several studies provide particu-
larly strong evidence for regional-specific alterations
in brain levels of glutamate in people diagnosed with
anxiety disorders. Grachev and Apkarian
126
reported
827
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Review Article
an increase in
1
H-MRS-detected glutamate in the
frontal cortex of healthy subjects with high versus
low state-trait anxiety,
126
and changes in glutamate
in humans diagnosed with specific anxiety disorders,
such as social anxiety and OCD.
127,128
One of these
studies
127
compared glutamate in the ACC and occip-
ital cortices of humans diagnosed with generalized
social anxiety disorder to age- and sex-matched con-
trols. Social anxiety disorder patients had a 13.2%
higher Glu/creatine ratio in the ACC than did their
matched comparison subjects, while there were no
differences between the groups in Glu/creatine in the
control voxel in the occipital cortex. Furthermore,
intensity of social anxiety symptoms, as measured
by the Liebowitz Social Anxiety Scale, was corre-
lated with the ratio of Glu/creatine, demonstrating
the functional significance of glutamate in general-
ized social anxiety disorder. Interestingly, in this same
group, Glu/creatine levels in the ACC were corre-
lated with activation of the rostral ACC in response
to harsh, aversive faces.
129
Rosenberg and colleagues
130
also examined the relationship between glutamate
and anxiety by measuring the concentrations of the
Glx (ie, the
1
H-MRS-assessed glutamate, glutamine
and GABA complex) resonance in the frontal cor-
tex of psychotropically naïve pediatric patients diag-
nosed with OCD. This study reported significantly
reduced Glx concentrations in the ACC of the OCD
group compared with healthy controls. A previous
study by the same research group
128
demonstrated
significantly increased glutamatergic concentrations
(ie, Glx) in the caudate of treatment-naïve pediatric
OCD patients compared with controls. Furthermore,
this elevated Glx signal in caudate, along with OCD
symptomology, was reduced to control levels after 12
weeks of pharmacologic treatment. Keshavan and
colleagues
131
hypothesized that a possible tonic-phasic
dysregulation of the glutamate system in prefrontal
neural circuits may explain the apparent conflicting
Glx levels reported in these OCD patients. In other
words, reduced tonic Glx in ACC may lead to pha-
sic Glx overactivity in the caudate and explain the
reported decrease in ACC Glx and increase in cau-
date Glx. In addition, this opposed neurochemical
finding is also consistent with previous neuroana-
tomical studies
132,133
that have reported inverse cor-
relations between ACC and basal ganglia volume in
OCD patients. Although few in number, the MRS
neurochemical studies discussed in this review provide
evidence that anxiety disorders are associated with
alterations in the glutamate system.
CONCLUSION
The glutamate system function of regulating neu-
ronal excitability in limbic/paralimbic brain struc-
tures is important in fear and anxiety responses. An
emerging body of evidence supports the role of gluta-
mate in mediating the physiological and behavioral
sequelae associated with stress and anxiety in animals.
Moreover, compounds that act on glutamate receptors
have been shown to alleviate anxiety symptoms. The
precise mechanism of anxiolytic action in humans has
yet to be elucidated, though brain imaging studies sug-
gest that abnormalities in glutamatergic function and
regulation may underlie the pathophysiology of anxi-
ety disorders. The emerging preclinical and clinical
evidence suggests that future studies on the mecha-
nism of and efficacy of glutamatergic agents in anxiety
disorders are appropriately warranted.
CNS
REFERENCES
1. Greenberg PE, Sisitsky T, Kessler RC, et al. The economic burden of anxiety disorders
in the 1990s. J Clin Psychiatry. 1999;60:427-435.
2. Lepine JP. The epidemiology of anxiety disorders: prevalence and societal costs. J Clin
Psychiatry. 2002;63(suppl 14):4-8.
3. Marciniak M, Lage MJ, Landbloom RP, Dunayevich E, Bowman L. Medical and produc-
tivity costs of anxiety disorders: case control study. Depress Anxiety. 2004;19:112-120.
4. Liberzon I, Phan KL, Khan S, Abelson JL. Role of GABA-A receptors in anxiety:
Evidence from animal models, clinical psychopharmacology, and neuroimaging stud-
ies. Current Neuropharmacology. 2003;1:267-283.
5. Hamner MB, Robert S, Frueh BC. Treatment-resistant posttraumatic stress disorder:
strategies for intervention. CNS Spectr. 2004;9:740-752.
6. van Ameringen M, Mancini C, Pipe B, Bennett M. Optimizing treatment in social
phobia: a review of treatment resistance. CNS Spectr. 2004;9:753-762.
7. Keller MB, Hirschfeld RM, Demyttenaere K, Baldwin DS. Optimizing outcomes in depres-
sion: focus on antidepressant compliance. Int Clin Psychopharmacol. 2002;17:265-271.
8. Gorman JM. New molecular targets for antianxiety interventions. J Clin Psychiatry.
2003;64:28-35.
9. Lujan R, Shigemoto R, Lopez-Bendito G. Glutamate and GABA receptor signalling
in the developing brain. Neuroscience. 2005;130:567-580.
10. Stanton PK. LTD, LTP, and the sliding threshold for long-term synaptic plasticity.
Hippocampus. 1996;6:35-42.
11. Swan JH, Meldrum BS. Protection by NMDA antagonists against selective cell loss
following transient ischaemia. J Cereb Blood Flow Metab. 1990;10:343-351.
12. Hynd MR, Scott HL, Dodd PR. Glutamate-mediated excitotoxicity and neurodegen-
eration in Alzheimer’s disease. Neurochem Int. 2004;45:583-595.
13. Meldrum BS. Glutamate as a neurotransmitter in the brain: review of physiology and
pathology. J Nutr. 2000;130(4S suppl):1007S-1015S.
14. Kew JN, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and
pharmacology. Psychopharmacology (Berl). 2005;179:4-29.
15. Krystal JH, D’Souza DC, Petrakis IL, et al. NMDA agonists and antagonists as probes
of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders.
Harv Rev Psychiatry. 1999;7:125-143.
16. Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD.
Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat
Rev Drug Discov. 2005;4:131-144.
17. Conn PJ, Pin JP. Pharmacology and functions of metabotropic glutamate receptors.
Annu Rev Pharmacol Toxicol. 1997;37:205-237.
18. LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci. 2000;23:155-184.
19. Davis M. The role of the amygdala in fear-potentiated startle: implications for animal
models of anxiety. Trends Pharmacol Sci. 1992;13:35-41.
20. Adolphs R. Neural systems for recognizing emotion. Curr Opin Neurobiol.
2002;12:169-177.
21. Cannistraro PA, Rauch SL. Neural circuitry of anxiety: evidence from structural and
functional neuroimaging studies. Psychopharmacol Bull. 2003;37:8-25.
22. McDonald AJ. Glutamate and aspartate immunoreactive neurons of the rat basolat-
eral amygdala: colocalization of excitatory amino acids and projections to the limbic
circuit. J Comp Neurol. 1996;365:367-379.
Review Article
828
Volume 10 – Number 10 © MBL Communications Inc. CNS Spectrums – October 2005
23. Mathew SJ, Coplan JD, Schoepp DD, Smith EL, Rosenblum LA, Gorman JM.
Glutamate-hypothalamic-pituitary-adrenal axis interactions: implications for mood and
anxiety disorders. CNS Spectr. 2001;6:555-564.
24. Jedema HP, Moghddam B. Characterization of excitatory amino acid modulation of dopa-
mine release in the prefrontal cortex of conscious rats. J Neurochem. 1996;66:1448-1453.
25. Takahata R, Moghaddam B. Glutamatergic regulation of basal and stimulus-activated
dopamine release in the prefrontal cortex. J Neurochem. 1998;71:1443-1449.
26. Becquet D, Hery M, Francois-Bellan AM, et al. Glutamate, GABA, glycine and taurine
modulate serotonin synthesis and release in rostral and caudal rhombencephalic raphe
cells in primary cultures. Neurochem Int. 1993;23:269-283.
27. Cheramy A, Romo R, Godeheu G, Baruch P, Glowinski J. In vivo presynaptic control
of dopamine release in the cat caudate nucleus–II. Facilitatory or inhibitory influence of
L-glutamate. Neuroscience. 1986;19:1081-1090.
28. Okada M, Yoshida S, Zhu G, Hirose S, Kaneko S. Biphasic actions of topiramate
on monoamine exocytosis associated with both soluble N-ethylmaleimide-sensitive
factor attachment protein receptors and Ca(2+)-induced Ca(2+)-releasing systems.
Neuroscience. 2005;134:233-246.
29. Ahmad S, Fowler LJ, Whitton PS. Lamotrigine, carbamazepine and phenytoin differ-
entially alter extracellular levels of 5-hydroxytryptamine, dopamine and amino acids.
Epilepsy Res. 2005;63:141-149.
30. Cunningham MO, Jones RS. The anticonvulsant, lamotrigine decreases spontaneous
glutamate release but increases spontaneous GABA release in the rat entorhinal cortex
in vitro. Neuropharmacology. 2000;39:2139-2146.
31. Sapolsky RM. Stress and plasticity in the limbic system. Neurochem Res. 2003;28:1735-1742.
32. Fontella FU, Vendite DA, Tabajara AS, et al. Repeated restraint stress alters hippocampal
glutamate uptake and release in the rat. Neurochem Res. 2004;29:1703-1709.
33. Gilad GM, Gilad VH, Wyatt RJ, Tizabi Y. Region-selective stress-induced increase of
glutamate uptake and release in rat forebrain. Brain Res. 1990;525:335-338.
34. Lowy MT, Wittenberg L, Yamamoto BK. Effect of acute stress on hippocampal glutamate
levels and spectrin proteolysis in young and aged rats. J Neurochem. 1995;65:268-274.
35. Moghaddam B. Stress preferentially increases extraneuronal levels of excitatory
amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J
Neurochem. 1993;60:1650-1657.
36. Schwendt M, Jezova D. Gene expression of two glutamate receptor subunits in response
to repeated stress exposure in rat hippocampus. Cell Mol Neurobiol. 2000;20:319-329.
37. McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci. 1999;22:105-122.
38. Magarinos AM, McEwen BS. Stress-induced atrophy of apical dendrites of hippocampal
CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid
receptors. Neuroscience. 1995;69:89-98.
39. Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S. Chronic stress induces con-
trasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J
Neurosci. 2002;22:6810-6818.
40. Vyas A, Bernal S, Chattarji S. Effects of chronic stress on dendritic arborization in the
central and extended amygdala. Brain Res. 2003;965:290-294.
41. Herman JP, Cullinan WE. Neurocircuitry of stress: central control of the hypothalamo-
pituitary-adrenocortical axis. Trends Neurosci. 1997;20:78-84.
42. Shors TJ, Weiss C, Thompson RF. Stress-induced facilitation of classical conditioning.
Science. 1992;257:537-539.
43. Shors TJ, Mathew PR. NMDA receptor antagonism in the lateral/basolateral but not
central nucleus of the amygdala prevents the induction of facilitated learning in response
to stress. Learn Mem. 1998;5:220-230.
44. Luine V, Villegas M, Martinez C, McEwen BS. Repeated stress causes reversible impair-
ments of spatial memory performance. Brain Res. 1994;639:167-170.
45. Isgor C, Kabbaj M, Akil H, Watson SJ. Delayed effects of chronic variable stress during
peripubertal-juvenile period on hippocampal morphology and on cognitive and stress
axis functions in rats. Hippocampus. 2004;14:636-648.
46. Conrad CD, LeDoux JE, Magarinos AM, McEwen BS. Repeated restraint stress facilitates
fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav
Neurosci. 1999;113:902-913.
47. Bast T, Zhang WN, Feldon J. Dorsal hippocampus and classical fear conditioning to
tone and context in rats: effects of local NMDA-receptor blockade and stimulation.
Hippocampus. 2003;13:657-675.
48. Maren S, Aharonov G, Stote DL, Fanselow MS. N-methyl-D-aspartate receptors in the
basolateral amygdala are required for both acquisition and expression of conditional fear
in rats. Behav Neurosci. 1996;110:1365-1374.
49. Walker DL, Davis M. The role of amygdala glutamate receptors in fear learning, fear-
potentiated startle, and extinction. Pharmacol Biochem Behav. 2002;71:379-392.
50. Chambers RA, Bremner JD, Moghaddam B, Southwick SM, Charney DS, Krystal JH.
Glutamate and post-traumatic stress disorder: toward a psychobiology of dissociation.
Semin Clin Neuropsychiatry. 1999;4:274-281.
51. Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive
NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and
neuroendocrine responses. Arch Gen Psychiatry. 1994;51:199-214.
52. Shekhar A, McCann UD, Meaney MJ, et al. Summary of a National Institute of Mental
Health workshop: developing animal models of anxiety disorders. Psychopharmacology
(Berl). 2001;157:327-339.
53. Pellow S, File SE. Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated
plus-maze: a novel test of anxiety in the rat. Pharmacol Biochem Behav. 1986;24:525-529.
54. Geller I. Effect of punishment on lever pressing maintained by food reward or brain
stimulation. Physiol Behav. 1970;5:203-206.
55. Davis M, Astrachan DI. Conditioned fear and startle magnitude: effects of different footshock
or backshock intensities used in training. J Exp Psychol Anim Behav Process. 1978;4:95-103.
56. Uhde, T, Galloway, M, Fang, J, et al. Sleep deprivation and excitatory amino acids.
Neuropsychopharmacology. 2004;29:S213.
57. Mathew SJ, Shungu DC, Mao X, et al. A magnetic resonance spectroscopic imaging study of
adult nonhuman primates exposed to early-life stressors. Biol Psychiatry. 2003;54:727-735.
58. Bartha R, Drost DJ, Menon RS, Williamson PC. Comparison of the quantification preci-
sion of human short echo time (1)H spectroscopy at 1.5 and 4.0 Tesla. Magn Reson Med.
2000;44:185-192.
59. Ke Y, Cohen BM, Bang JY, Yang M, Renshaw PF. Assessment of GABA concentration in
human brain using two-dimensional proton magnetic resonance spectroscopy. Psychiatry
Res. 2000;100:169-178.
60. Kaiser LG, Schuff N, Cashdollar N, Weiner MW. Age-related glutamate and glutamine
concentration changes in normal human brain: 1H MR spectroscopy study at 4 T.
Neurobiol Aging. 2005;26:665-672.
61. Stanley JA, Drost DJ, Williamson PC, Thompson RT. The use of a priori knowledge to
quantify short echo in vivo 1H MR spectra. Magn Reson Med. 1995;34:17-24.
62. Munro LJ, Kokkinidis L. Infusion of quinpirole and muscimol into the ventral tegmental
area inhibits fear-potentiated startle: implications for the role of dopamine in fear expres-
sion. Brain Res. 1997;746:231-238.
63. Fendt M, Koch M, Schnitzler HU. NMDA receptors in the pontine brainstem are neces-
sary for fear potentiation of the startle response. Eur J Pharmacol. 1996;318:1-6.
64. Campeau S, Miserendino MJ, Davis M. Intra-amygdala infusion of the N-methyl-D-
aspartate receptor antagonist AP5 blocks acquisition but not expression of fear-potenti-
ated startle to an auditory conditioned stimulus. Behav Neurosci. 1992;106:569-574.
65. Anthony EW, Nevins ME. Anxiolytic-like effects of N-methyl-D-aspartate-associ-
ated glycine receptor ligands in the rat potentiated startle test. Eur J Pharmacol.
1993;250:317-324.
66. Walker DL, Ressler KJ, Lu KT, Davis M. Facilitation of conditioned fear extinction by
systemic administration or intra-amygdala infusions of D-cycloserine as assessed with
fear-potentiated startle in rats. J Neurosci. 2002;22:2343-2351.
67. Parnas AS, Weber M, Richardson R. Effects of multiple exposures to d-cycloserine on
extinction of conditioned fear in rats. Neurobiol Learn Mem. 2005;83:224-231.
68. Ledgerwood L, Richardson R, Cranney J. Effects of D-cycloserine on extinction of condi-
tioned freezing. Behav Neurosci. 2003;117:341-349.
69. Ledgerwood L, Richardson R, Cranney J. D-cycloserine and the facilitation of extinction
of conditioned fear: consequences for reinstatement. Behav Neurosci. 2004;118:505-513.
70. Fendt M. Expression and conditioned inhibition of fear-potentiated startle after stimula-
tion and blockade of AMPA/Kainate and GABA(A) receptors in the dorsal periaque-
ductal gray. Brain Res. 2000;880:1-10.
71. Rosenfeld WE. Topiramate: a review of preclinical, pharmacokinetic, and clinical data.
Clin Ther. 1997;19:1294-1308.
72. Khan S, Liberzon I. Topiramate attenuates exaggerated acoustic startle in an animal
model of PTSD. Psychopharmacology (Berl). 2004;172:225-229.
73. Czuczwar SJ, Patsalos PN. The new generation of GABA enhancers. Potential in the
treatment of epilepsy. CNS Drugs. 2001;15:339-350.
74. Walker DL, Rattiner LM, Davis M. Group II metabotropic glutamate receptors within
the amygdala regulate fear as assessed with potentiated startle in rats. Behav Neurosci.
2002;116:1075-1083.
75. Ho YJ, Hsu LS, Wang CF, Hsu et al. Behavioral effects of d-cycloserine in rats: The role
of anxiety level. Brain Res. 2005;1043:179-185.
76. Karcz-Kubicha M, Jessa M, Nazar M, et al. Anxiolytic activity of glycine-B antagonists and
partial agonists–no relation to intrinsic activity in the patch clamp. Neuropharmacology.
1997;36:1355-1367.
77. Klodzinska A, Chojnacka-Wojcik E. Anticonflict effect of the glycineB receptor
partial agonist, D-cycloserine, in rats. Pharmacological analysis. Psychopharmacology
(Berl). 2000;152:224-228.
78. Xie ZC, Buckner E, Commissaris RL. Anticonflict effect of MK-801 in rats: time course
and chronic treatment studies. Pharmacol Biochem Behav. 1995;51:635-640.
79. Kotlinska J, Liljequist S. The putative AMPA receptor antagonist, LY326325, produces
anxiolytic-like effects without altering locomotor activity in rats. Pharmacol Biochem Behav.
1998;60:119-124.
80. Schulz B, Fendt M, Gasparini F, Lingenhohl K, Kuhn R, Koch M. The metabotropic
glutamate receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocks
fear conditioning in rats. Neuropharmacology. 2001;41:1-7.
81. Ballard TM, Woolley ML, Prinssen E, Huwyler J, Porter R, Spooren W. The effect of
829
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Review Article
the mGlu5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a
comparison. Psychopharmacology (Berl). 2005;179:218-229.
82. Linden AM, Greene SJ, Bergeron M, Schoepp DD. Anxiolytic activity of the
MGLU2/3 receptor agonist LY354740 on the elevated plus maze is associated with
the suppression of stress-induced c-Fos in the hippocampus and increases in c-Fos
induction in several other stress-sensitive brain regions. Neuropsychopharmacology.
2004;29:502-513.
83. Shekhar A, Keim SR. LY354740, a potent group II metabotropic glutamate recep-
tor agonist prevents lactate-induced panic-like response in panic-prone rats.
Neuropharmacology. 2000;39:1139-1146.
84. Helton DR, Tizzano JP, Monn JA, Schoepp DD, Kallman MJ. Anxiolytic and side-
effect profile of LY354740: a potent, highly selective, orally active agonist for group II
metabotropic glutamate receptors. Pharmacol Exp Ther. 1998;284:651-660.
85. Johnson MP, Barda D, Britton TC, et al. Metabotropic glutamate 2 receptor potentia-
tors: receptor modulation, frequency-dependent synaptic activity, and efficacy in pre-
clinical anxiety and psychosis model(s). Psychopharmacology (Berl). 2005;179:271-283.
86. Steckler T, Lavreysen H, Oliveira AM, et al. Effects of mGlu1 receptor blockade on
anxiety-related behaviour in the rat lick suppression test. Psychopharmacology (Berl).
2005;179:198-206.
87. Mirza NR, Bright JL, Stanhope KJ, Wyatt A, Harrington NR. Lamotrigine has an
anxiolytic-like profile in the rat conditioned emotional response test of anxiety: a
potential role for sodium channels? Psychopharmacology (Berl). 2005;180:159-168.
88. Tizzano JP, Griffey KI, Schoepp DD. The anxiolytic action of mGlu2/3 receptor ago-
nist, LY354740, in the fear-potentiated startle model in rats is mechanistically distinct
from diazepam. Pharmacol Biochem Behav. 2002;73:367-374.
89. Grillon C, Cordova J, Levine LR, Morgan CA 3rd. Anxiolytic effects of a novel group
II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle
paradigm in humans. Psychopharmacology (Berl). 2003;168:446-454.
90. Levine LR, Gaydos B, Sheehan D, Goddard A, Feighner J, Potter W, Schoepp D.
LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress.
Neuropharmacology. 2001;43:294-295.
91. Kellner M, Muhtz C, Stark K, Yassouridis A, Arlt J, Wiedemann K. Effects of a
metabotropic glutamate(2/3) receptor agonist (LY544344/LY354740) on panic anxi-
ety induced by cholecystokinin tetrapeptide in healthy humans: preliminary results.
Psychopharmacology (Berl). 2005;179:310-315.
92. Bremner JD, Mletzko T, Welter S, et al. Treatment of post-traumatic stress disorder
with phenytoin: An open label pilot study. Neuropsychopharmacology. 2004;29:S91.
93. Heresco-Levy U, Kremer I, Javitt DC, et al. Pilot-controlled trial of D-cycloserine for the
treatment of post-traumatic stress disorder. Int J Neuropsychopharmacol. 2002;5:301-307.
94. Ressler KJ, Rothbaum BO, Tannenbaum L, et al. Cognitive enhancers as adjuncts to
psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of
fear. Arch Gen Psychiatry. 2004;61:1136-1144.
95. Berlant J, van Kammen DP. Open-label topiramate as primary or adjunctive therapy
in chronic civilian posttraumatic stress disorder: a preliminary report. J Clin Psychiatry.
2002;63:15-20.
96. Berlant JL. Prospective open-label study of add-on and monotherapy topiramate in civilians
with chronic nonhallucinatory posttraumatic stress disorder. BMC Psychiatry. 2004;4:24.
97. van Ameringen M, Mancini C, Pipe B, Oakman J, Bennett M. An open trial of topiramate
in the treatment of generalized social phobia. J Clin Psychiatry. 2004;65:1674-1678.
98. Coric V, Taskiran S, Pittenger C, et al. Riluzole augmentation in treatment-resistant
obsessive-compulsive disorder: an open-label trial. Biol Psychiatry. 2005;58:424-428.
99. Mathew, SJ, Amiel, JM, Coplan, JD, Fitterling, HA, Sackeim, HA, Gorman, JM.
Riluzole in generalized anxiety disorder: an open-label trial. Am J Psychiatry. In press.
100. Linden AM, Shannon H, Baez M, Yu JL, Koester A, Schoepp DD. Anxiolytic-like
activity of the mGLU2/3 receptor agonist LY354740 in the elevated plus maze
test is disrupted in metabotropic glutamate receptor 2 and 3 knock-out mice.
Psychopharmacology (Berl). 2005;179:284-291.
101. Arnold PD, Rosenberg DR, Mundo E, Tharmalingam S, Kennedy JL, Richter MA.
Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-
compulsive disorder: a preliminary study. Psychopharmacology (Berl). 2004;174:530-538.
102. Chakrabarty K, Bhattacharyya S, Christopher R, Khanna S. Glutamatergic dysfunc-
tion in OCD. Neuropsychopharmacology. 2005;30:1735-1740.
103. Cunningham MO, Dhillon A, Wood SJ, Jones RS. Reciprocal modulation of
glutamate and GABA release may underlie the anticonvulsant effect of phenytoin.
Neuroscience. 2000;95:343-351.
104. Richardson R, Ledgerwood L, Cranney J. Facilitation of fear extinction by D-cyclo-
serine: theoretical and clinical implications. Learn Mem. 2004;11:510-516.
105. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC:
American Psychiatric Association; 1994.
106. Yamasue H, Kasai K, Iwanami A, et al. Voxel-based analysis of MRI reveals anterior
cingulate gray-matter volume reduction in posttraumatic stress disorder due to terror-
ism. Proc Natl Acad Sci U S A. 2003;100:9039-9043.
107. Rauch SL, Shin LM, Segal E, et al. Selectively reduced regional cortical volumes
in post-traumatic stress disorder. Neuroreport. 2003;14:913-916.
108. Bremner JD, Randall P, Scott TM, et al. MRI-based measurement of hippocam-
pal volume in patients with combat-related posttraumatic stress disorder. Am J
Psychiatry. 1995;152:973-981.
109. Bremner JD, Vythilingam M, Vermetten E, et al. MRI and PET study of deficits in
hippocampal structure and function in women with childhood sexual abuse and post-
traumatic stress disorder. Am J Psychiatry. 2003;160:924-932.
110. Fennema-Notestine C, Stein MB, Kennedy CM, Archibald SL, Jernigan TL. Brain
morphometry in female victims of intimate partner violence with and without post-
tramatic stress disorder. Biol Psychiatry. 2002;52:1089-1101.
111. Stein MB, Koverola C, Hanna C, Torchia MG, McClarty B. Hippocampal volume in
women victimized by childhood sexual abuse. Psychol Med. 1997;27:951-959.
112. Kitayama N, Vaccarino V, Kutner M, Weiss P, Bremner JD. Magnetic resonance
imaging (MRI) measurement of hippocampal volume in posttraumatic stress disor-
der: a meta-analysis. J Affect Disord. 2005;88:79-86.
113. MacMillan S, Szeszko PR, Moore GJ, et al. Increased amygdala: hippocampal volume
ratios associated with severity of anxiety in pediatric major depression. J Child Adolesc
Psychopharmacol. 2003;13:65-73.
114. De Bellis MD, Casey BJ, Dahl RE, et al. A pilot study of amygdala volumes in pediat-
ric generalized anxiety disorder. Biol Psychiatry. 2000;48:51-57.
115. Szeszko PR, MacMillan S, McMeniman M, et al. Amygdala volume reductions in
pediatric patients with obsessive-compulsive disorder treated with paroxetine: pre-
liminary findings. Neuropsychopharmacology. 2004;29:826-832.
116. Nordahl TE, Semple WE, Gross M, et al. Cerebral glucose metabolic differences in
patients with panic disorder. Neuropsychopharmacology. 1990;3:261-272.
117. Britton JC, Phan KL, Taylor SF, Fig LM, Liberzon I. Corticolimbic blood flow in posttrau-
matic stress disorder during script-driven imagery. Biol Psychiatry. 2005;57:832-840.
118. Stein MB, Goldin PR, Sareen J, Zorrilla LT, Brown GG. Increased amygdala
activation to angry and contemptuous faces in generalized social phobia. Arch Gen
Psychiatry. 2002;59:1027-1034.
119. Birbaumer N, Grodd W, Diedrich O, et al. fMRI reveals amygdala activation to
human faces in social phobics. Neuroreport. 1998;9:1223-1226.
120. Freeman TW, Cardwell D, Karson CN, Komoroski RA. In vivo proton magnetic
resonance spectroscopy of the medial temporal lobes of subjects with combat-related
posttraumatic stress disorder. Magn Reson Med. 1998;40:66-71.
121. De Bellis MD, Keshavan MS, Spencer S, Hall J. N-Acetylaspartate concentration
in the anterior cingulate of maltreated children and adolescents with PTSD. Am J
Psychiatry. 2000;157:1175-1177.
122. Brown S, Freeman T, Kimbrell T, Cardwell D, Komoroski R. In vivo proton magnetic
resonance spectroscopy of the medial temporal lobes of former prisoners of war with and
without posttraumatic stress disorder. J Neuropsychiatry Clin Neurosci. 2003;15:367-370.
123. Davidson JR, Krishnan KR, Charles HC, et al. Magnetic resonance spectroscopy in
social phobia: preliminary findings. J Clin Psychiatry. 1993;54:19-25.
124. Tupler LA, Davidson JR, Smith RD, Lazeyras F, Charles HC, Krishnan KR. A repeat
proton magnetic resonance spectroscopy study in social phobia. Biol Psychiatry.
1997;42:419-424.
125. Mathew SJ, Mao X, Coplan JD, et al. Dorsolateral prefrontal cortical pathology in
generalized anxiety disorder: a proton magnetic resonance spectroscopic imaging
study. Am J Psychiatry. 2004;161:1119-1121.
126. Grachev ID, Apkarian AV. Chemical mapping of anxiety in the brain of healthy
humans: an in vivo 1H-MRS study on the effects of sex, age, and brain region. Hum
Brain Mapp. 2000;11:261-272.
127. Phan KL, Fitzgerald DA, Cortese BM, Seraji-Bozorgzad N, Tancer ME, Moore GJ.
Anterior cingulate neurochemistry in social anxiety disorder: 1H-MRS at 4 Tesla.
Neuroreport. 2005;16:183-186.
128. Rosenberg DR, MacMaster FP, Keshavan MS, Fitzgerald KD, Stewart CM, Moore GJ.
Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disor-
der patients taking paroxetine. J Am Acad Child Adolesc Psychiatry. 2000;39:1096-1103.
129. Phan KL, Fitzgerald DA, Cortese BM, et al. Response to emotionally salient faces
and glutamate concentrations in the rostral anterior cingulate cortex in social pho-
bia: preliminary combined spectroscopic and functional magnetic resonance imaging
studies at 4 Telsa. Neuropsychopharmacology. 2004;29:S193.
130. Rosenberg DR, Mirza Y, Russell A, et al. Reduced anterior cingulate glutamatergic
concentrations in childhood OCD and major depression versus healthy controls. J
Am Acad Child Adolesc Psychiatry. 2004;43:1146-1153.
131. Keshavan MS. Development, disease and degeneration in schizophrenia: a unitary
pathophysiological model. J Psychiatr Res. 1999;33:513-521.
132. Rosenberg DR, Keshavan MS. A.E. Bennett Research Award. Toward a neurodevelop-
mental model of of obsessive-compulsive disorder. Biol Psychiatry. 1998;43:623-640.
133. Szeszko PR, MacMillan S, McMeniman M, et al. Brain structural abnormalities in
psychotropic drug-naive pediatric patients with obsessive-compulsive disorder. Am J
Psychiatry. 2004;161:1049-1056.
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... Glutamate neurotransmitter systems have been implicated in the etiology of PTSD [38][39][40]. Glutamate is the natural ligand to N-methyl-D-aspartate (NMDA) receptors, and this system has been implicated in the acquisition of fearful associations between environmental cues and aversive stimuli, extinction of fear responses, as well as in the regulation of behavioral responses to fear [38][39][40][41]. The PFC has extensive glutamatergic projections to several key limbic structures, including the amygdala and the hippocampus. ...
... Glutamate neurotransmitter systems have been implicated in the etiology of PTSD [38][39][40]. Glutamate is the natural ligand to N-methyl-D-aspartate (NMDA) receptors, and this system has been implicated in the acquisition of fearful associations between environmental cues and aversive stimuli, extinction of fear responses, as well as in the regulation of behavioral responses to fear [38][39][40][41]. The PFC has extensive glutamatergic projections to several key limbic structures, including the amygdala and the hippocampus. ...
... The resilience or susceptibility to developing stress-induced disorders is impacted by the social environment [39]. Glutamate neurotransmitter systems have been implicated in the etiology of PTSD [38][39][40], as well as in the acquisition and extinction of fearful memories [41,68]. The PFC has extensive projections to and from several key limbic structures implicated in fear and psychiatric disease, including the amygdala and hippocampus. ...
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We have previously reported that socially partnered stress sensitive Wistar-Kyoto (WKY) rats exhibited a reduced response to cued fear-conditioning (CFC) compared to their socially isolated counterparts. Given that altered glutamatergic neurotransmission in the limbic and forebrain regions have been implicated in stress-induced psychiatric disorders, the present study investigated the effects of CFC on [³H] MK-801 binding to N-methyl-D-aspartate (NMDA) receptors in socially isolated (CFC-SI) and socially partnered (CFC-SP) WKY rats, in comparison to the stress resilient Wistar (WIS) rats. Binding of [³H] MK-801 to NMDA receptors was measured in the prefrontal cortex (PFC), basolateral amygdala (BLA), central amygdala (CeA), and the CA1/CA2, CA3 and dentate gyrus (DG) of the hippocampus. Extinction of CFC in a socially isolated environment resulted in higher NMDA binding in the PFC in WKY rats but lower binding in the PFC in WIS rats. While extinction of CFC in a socially partnered environment did not alter NMDA binding in WKY rats, higher NMDA binding was seen in the BLA, CA1/CA2 and DG in WIS rats. Our results suggest that NMDA-mediated mechanisms of fear extinction in a socially isolated or socially partnered environment may be different in the two phenotypes and may involve other central mechanisms.
... Preclinical and clinical pharmacology studies have also implicated the glutamatergic system in these disorders through known and suspected drug mechanisms (23,(54)(55)(56). For example, ketamine is a non-competitive antagonist of the NMDA glutamate receptor, which has been shown to quickly reduce depressive symptoms, anxiety, and PTSD (57)(58)(59)(60)(61). ...
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The objective of this pilot study was to examine the effects of the low glutamate diet on anxiety, post-traumatic stress disorder (PTSD), and depression in veterans with Gulf War Illness (GWI). The low glutamate diet removes dietary excitotoxins and increases consumption of micronutrients which are protective against glutamatergic excitotoxicity. This study was registered at ClinicalTrials.gov (NCT#03342482). Forty veterans with GWI completed psychiatric questionnaires at baseline and after 1-month following the low glutamate diet. Participants were then randomized into a double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG; a dietary excitotoxin) vs. placebo over three consecutive days per week, with assessments on day three. Data were analyzed across the full sample and with participants categorized by baseline symptom severity. Pre-post-dietary intervention change scores were analyzed with Wilcoxon signed-rank tests and paired sample t-tests across the full sample, and changes across symptom severity categories were analyzed using ANOVA. Crossover challenge results were analyzed with linear mixed modeling accounting for challenge material (MSG v. placebo), sequence (MSG/placebo v. placebo/MSG), period (challenge week 1 v. week 2), pre-diet baseline symptom severity category (minimal/mild, moderate, or severe), and the challenge material*symptom severity category interaction. A random effect of ID (sequence) was also included. All three measures showed significant improvement after 1 month on the diet, with significant differences between baseline severity categories. Individuals with severe psychological symptoms at baseline showed the most improvement after 1 month on the diet, while those with minimal/mild symptoms showed little to no change. Modeling results from the challenge period demonstrated a significant worsening of anxiety from MSG in only the most severe group, with no significant effects of MSG challenge on depression nor PTSD symptoms. These results suggest that the low glutamate diet may be an effective treatment for depression, anxiety, and PTSD, but that either (a) glutamate is only a direct cause of symptoms in anxiety, or (b) underlying nutrient intake may prevent negative psychiatric effects from glutamate exposure. Future, larger scale clinical trials are needed to confirm these findings and to further explore the potential influence of increased micronutrient intake on the improvements observed across anxiety, PTSD, and depression.
... Previous functional neuroimaging studies have demonstrated that the OFC was especially important in top-down modulation of emotional processing and in-depth regulation of emotional meaning including aversive error processing, cognitive re-appraisal of emotional stimuli, and emotion feedback (Kanai & Rees, 2011b;Petrovic et al., 2015). These findings were in accordance with the study which indicated that the OFC was a critical region of learning from the past experience and emotional processing (Cortese & Phan, 2005). In addition, it is worth noting that the same brain area is reported in many structural magnetic resonance imaging researches. ...
... Glutamate signaling has an important role in learning and memory through the plasticity, or modification, of channel properties and synaptic anatomy, most notably in the HIP of the mammalian central nervous system. 81 In this regard, glutamate-induced excitotoxicity, which is prominent in the HIP, has been associated with decreased neuronal regeneration and dendritic branching, leading to impaired spatial learning, 82 and recent studies have reported a link between GluR receptors and RTT. Remarkably, de novo variants in GRIA2 cause neurodevelopmental disorders, including RTT-like features. ...
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Noncoding RNAs play regulatory roles in physiopathology, but their involvement in neurodevelopmental diseases is poorly understood. Rett syndrome is a severe, progressive neurodevelopmental disorder linked to loss-of-function mutations of the MeCP2 gene, for which no cure is yet available. Analysis of the noncoding RNA profile corresponding to the brain-abundant circRNA and T-UCR populations in a mouse model of the disease reveals widespread dysregulation, and enrichment in glutamatergic excitatory signaling and microtubule cytoskeleton pathways of the corresponding host genes. Proteomic analysis of patients’ hippocampal samples confirms the abnormal levels of several cytoskeleton-related proteins, together with key alterations in neurotransmission. Importantly, the glutamate receptor GRIA3 gene displays altered biogenesis in patients and in vitro human cells, and is influenced by the expression of two ultraconserved RNAs. We also describe the post-transcriptional regulation of SIRT2 by circRNAs, which modulates the acetylation and total protein levels of GluR-1. As a consequence, both regulatory mechanisms converge on the biogenesis of AMPA receptors, with an impact on neuronal differentiation. In both cases, the noncoding RNAs antagonize the MeCP2-directed regulation. Taken together, our findings indicate that noncoding transcripts may contribute to key alterations in Rett syndrome and are not only useful tools for revealing dysregulated processes, but also molecules of biomarker value.
... Due to the role of glutamate in regulating the cell cycle (Coloff et al., 2016;Murakami et al., 2012;Newsholme et al., 2003), its altering level in vitiligo can indicate implicated cell metabolism and increased cell death. On the other hand, some studies previously reported the influence of glutamate imbalance through glutamatergic neurotransmission with anxiety and stress (Amiel & Mathew, 2007;Bergink et al., 2004;Cortese & Phan, 2005). Our findings indicated that glutamate also engaged in this prevalent psychiatric disorder in patients, which has been described in vitiligo frequently (Hamidizadeh et al., 2020;Henning, 2020;Kussainova et al., 2020;Vernwal, 2017). ...
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Introduction Vitiligo pathogenesis is complicated, and several possibilities were suggested. However, it is well-known that the metabolism of pigments plays a significant role in the pathogenicity of the disease. Objectives We explored the role of amino acids in vitiligo using targeted metabolomics. Methods The amino acid profile was studied in plasma using liquid chromatography. First, 22 amino acids were derivatized and precisely determined. Next, the concentrations of the amino acids and the molar ratios were calculated in 31 patients and 34 healthy individuals. Results The differential concentrations of amino acids were analyzed and eight amino acids, i.e., cysteine, arginine, lysine, ornithine, proline, glutamic acid, histidine, and glycine were observed differentially. The ratios of cysteine, glutamic acid, and proline increased significantly in Vitiligo patients, whereas arginine, lysine, ornithine, glycine, and histidine decreased significantly compared to healthy individuals. Considering the percentage of skin area, we also showed that glutamic acid significantly has a higher amount in patients with less than 25% involvement compared to others. Finally, cysteine and lysine are considered promising candidates for diagnosing and developing the disorder with high accuracy (0.96). Conclusion The findings are consistent with the previously illustrated mechanism of Vitiligo, such as production deficiency in melanin and an increase in immune activity and oxidative stress. Furthermore, new evidence was provided by using amino acids profile toward the pathogenicity of the disorder.
... Glutamate is one of the most abundant excitatory neurotransmitters in the brain, and aberrant regulation of glutamate signaling has been implicated in many neurodegenerative and neuropsychiatric brain disorders, such as Alzheimer's disease [1,2], Huntington's disease [3,4], ALS [5], epilepsy [6], schizophrenia [7,8], as well as mood disorders, such as depression, anxiety, and many more [9,10]. Recent developments in reprogramming technologies enable the direct conversion of various cell types into neurons and glia, which enables the study of cellular processes in health and disease [11][12][13][14]. ...
Chapter
The detection of neurotransmitter release from reprogrammed human cell is an important demonstration of their functionality. Electrochemistry has the distinct advantages over alternative methods that it allows for the measuring of the analyte of interest at a high temporal resolution. This is necessary for fast events, such as neurotransmitter release and reuptake, which happen in the order of milliseconds to seconds. The precise description of these kinetic events can lead to insights into the function of cells in health and disease and allows for the exploration of events that might be missed using methods that look at absolute concentration values or methods that have a slower sampling rate. In the present chapter, we describe the use of constant potential amperometry and enzyme-coated multielectrode arrays for the detection of glutamate in vitro. These biosensors have the distinct advantage of “self-referencing,” a method providing high selectivity while retaining outstanding temporal resolution. Here, we provide a step-by-step user guide for a commercially available system and its application for in vitro systems such as reprogrammed cells.
... Interestingly, researchers have also fortified the pivotal role of the GLUR receptors in mediating anxiety-like behavior as well as synaptic plasticity among different layers of the hippocampus viz. CA1, CA2, CA3, and DG (Cortese & Phan, 2005;Fachim et al., 2016;Wiley et al., 2011;Yang et al., 2015). Following NMDA-induced excitotoxicity, a decline in the expression of the GLUR1 is suggested to be a major reason for the impaired long-term potentiation (LTP) and cognitive impairment (Fachim et al., 2016;Wiley et al., 2011;Yang et al., 2015). ...
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Glutamate excitotoxicity and endoplasmic reticulum (ER) recently have been found to be instrumental in the pathogenesis of various neurodegenerative diseases. However, the paucity of literature deciphering the inter-linkage among glutamate receptors, behavioral alterations, and ER demands thorough exploration. Reckoning the aforesaid concerns, a prospective study was outlined to delineate the influence of ER stress inhibition via 4-phenylbutyric acid (PBA) on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) excitotoxicity-induced behavioral aspects and possible ER stress-glutamate linkage. Male SD rats were randomly divided into four groups namely sham (surgical control+vehicle, group 1), AMPA-induced excitotoxic group 2 receive a single intra-hippocampal injection of 10 mM AMPA, group 3 received AMPA along with PBA (i.p, 100 mg/kg body weight) for 15 days, and group 4 received PBA alone. Behavioral analyses were performed prior to the sacrifice of animals and hippocampus was extracted thereafter for further analysis. AMPA-induced excitotoxicity exhibited significant impairment of locomotion as well as cognitive functions. The levels of neurotransmitters such as dopamine, homo vanillic acid (HVA), norepinephrine, and serotonin were reduced accompanied by reduced expression of GLUR1 and GLUR4 (glutamate receptor) as well as loss of neurons in different layers of hippocampus. ER stress markers were upregulated upon AMPA excitotoxicity. However, chemical chaperone PBA supplementation remarkably mitigated the behavioral alterations along with expression of glutamate and ER stress intermediates/markers in AMPA excitotoxic animals. Therefore, the present exploration convincingly emphasizes the significance of ER stress and its inhibition via PBA in combating cognitive impairment as well as improving locomotion in excitotoxic animals.
Article
The maturation of key corticolimbic structures and the prefrontal cortex during sensitive periods of brain development from early life through adolescence is crucial for the acquisition of a variety of cognitive and affective processes associated with adult behavior. In this chapter, we first review how key cellular and circuit level changes during adolescence dictate the development of the prefrontal cortex and its capacity to integrate contextual and emotional information from the ventral hippocampus and the amygdala. We further discuss how afferent transmission from ventral hippocampal and amygdala inputs displays unique age-dependent trajectories that directly impact prefrontal functional maturation through adolescence. We conclude by proposing that time-sensitive strengthening of specific corticolimbic synapses is a critical contributing factor for the protracted maturation of cognitive and emotional regulation by the prefrontal cortex.
Chapter
Spontaneous neuronal replacement is almost absent in the postnatal mammalian nervous system. However, several studies have shown that both early postnatal and adult astroglia can be reprogrammed in vitro or in vivo by forced expression of proneural transcription factors, such as Neurogenin-2 or Achaete-scute homolog 1 (Ascl1), to acquire a neuronal fate. The reprogramming process stably induces properties such as distinctly neuronal morphology, expression of neuron-specific proteins, and the gain of mature neuronal functional features. Direct conversion of astroglia into neurons thus possesses potential as a basis for cell-based strategies against neurological diseases. In this chapter, we describe a well-established protocol used for direct reprogramming of postnatal cortical astrocytes into functional neurons in vitro and discuss available tools and approaches to dissect molecular and cell biological mechanisms underlying the reprogramming process.
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The discovery of robust antidepressant effects of ketamine in refractory patients has led to increasing focus on agents targeting glutamatergic signaling as potential novel antidepressant strategy. Among the agents targeting the glutamatergic system, compounds acting at metabotropic glutamate (mGlu) receptors are among the most promising agents under studies for depressive disorders. Further, the receptor diversity, distinct distribution in the CNS, and ability to modulate the glutamatergic neurotransmission in the brain areas implicated in mood disorders make them an exciting target for stress-related disorders. In preclinical models, antidepressant and anxiolytic effects of mGlu5 negative allosteric modulators (NAMs) have been reported. Interestingly, mGlu2/3 receptor antagonists show fast and sustained antidepressant-like effects similar to that of ketamine in rodents. Excitingly, they can also induce antidepressant effects in the animal models of treatment-resistant depression and are devoid of the side-effects associated with ketamine. Unfortunately, clinical trials of both mGlu5 and mGlu2/3 receptor NAMs have been inconclusive, and additional trials using other compounds with suitable preclinical and clinical properties are needed. Although group III mGlu receptors have gained less attention, mGlu7 receptor ligands have been shown to induce antidepressant-like effects in rodents. Collectively, compounds targeting mGlu receptors provide an alternative approach to fill the outstanding clinical need for safer and more efficacious antidepressants. This article is part of the special Issue on “Glutamate Receptors – mGluRs”.
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γ-Aminobutyric acid (GABA) is considered to be the major inhibitory neurotransmitter in the brain and loss of GABA inhibition has been clearly implicated in epileptogenesis. GABA interacts with 3 types of receptor: GAB Aa, GAB Ab and GABAc. The GABAA receptor has provided an excellent target for the development of drugs with an anticonvulsant action. Some clinically useful anti-convulsants, such as the benzodiazepines and barbiturates and possibly valproic acid (sodium valproate), act at this receptor. In recent years 4 new anticonvulsants, namely vigabatrin, tiagabine, gaba-pentin and topiramate, with a mechanism of action considered to be primarily via an effect on GABA, have been licensed. Vigabatrin elevates brain GABA levels by inhibiting the enzyme GABA transaminase which is responsible for intracellular GABA catabolism. In contrast, tiagabine elevates synaptic GABA levels by inhibiting the GABA uptake transporter, GAT1, and preventing the uptake of GABA into neurons and glia. Gabapentin, a cyclic analogue of GABA, acts by enhancing GABA synthesis and also by decreasing neuronal calcium influx via a specific subunit of voltage-dependent calcium channels. Topiramate acts, in part, via an action on a novel site of the GABAA receptor. Although these drugs are useful in some patients, overall, they have proven to be disappointing as they have had little impact on the prognosis of patients with intractable epilepsy. Despite this, additional GABA enhancing anticonvulsants are presently under development. Ganaxolone, retigabine and pregabalin may prove to have a more advantageous therapeutic profile than the presently licensed GABA enhancing drugs. This anticipation is based on 2 characteristics. First, they act by hitherto unique mechanisms of action in enhancing GABA-induced neuronal inhibition. Secondly, they act on additional antiepileptogenic mechanisms. Finally, CGP 36742, a GABAb receptor antagonist, may prove to be particularly useful in the management of primary generalised absence seizures. The exact impact of these new GABA-enhancing drugs in the treatment of epilepsy will have to await their licensing and a period of postmarketing surveillance. As to clarification of their role in the management of epilepsy, this will have to await further clinical trials, particularly direct comparative trials with other anticonvulsants.
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The contribution to fear and fear learning of amygdala Group II metabotropic glutamate receptors was examined in rats. Pretest intra-amygdala infusions of the Group II receptor agonist LY354740 (0.3 or 1.0 μg/side) significantly disrupted fear-potentiated startle. The same rats were unimpaired when later tested without drug. The Group II receptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (3.0 μg/side) mimicked the effect of LY354740, and coadministration of the Group II receptor antagonist LY341495 (0.3 μg/side) prevented it. Pretraining LY354740 (0.3 μg/side) infusions also blocked learning. The effects on learning and performance were significantly less pronounced in rats with misplaced cannulas. Thus, Group II metabotropic receptors within or very near the amygdala regulate fear and fear learning and are a potential target for anxiolytic compounds.
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Repeated restraint stress of rats for 21 days causes atrophy of apical dendrites of hippocampal CA3c pyramidal neurons. This effect is mimicked by daily corticosterone treatment for 21 days and is prevented by the anti-epileptic drug, phenytoin, known to interfere with excitatory amino acid release and action. The present study was designed to investigate the involvement of endogenous corticosterone secretion and excitatory amino acid receptors in the stress-induced hippocampal dendritic atrophy. Treatment of chronically stressed rats with the steroid synthesis blocker cyanoketone prevented stress-induced dendritic atrophy. Cyanoketone-treated animals showed an impaired corticosterone secretion in response to the stressor, while basal levels were maintained. Besides the involvement of endogenous corticosterone secretion, N-methyl-d-aspartate receptors also play a role, since the competitive receptor antagonist, CGP 43487, blocked stress-induced dendritic atrophy. In contrast, NBQX, a competitive inhibitor of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, was ineffective at a dose that blocks ischemic damage.These results indicate that the reversible atrophy induced by 21 days of daily restraint stress requires corticosterone secretion and that excitatory mechanisms involving N-methyl-d-aspartate receptors play a major role in driving the atrophy.
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Background: Neurobiological models for obsessive–compulsive disorder (OCD) have consistently implicated ventral prefrontal cortical and striatal circuits in the pathophysiology of this disorder, but typically have not utilized a developmental framework for conceptualizing the illness.Methods: We describe an integrated series of neurobiologic studies aimed at testing the hypothesis that neurodevelopmental abnormalities of ventral prefrontal–striatal circuits may be involved in and contribute to the etiology and presentation of the illness.Results: Using studies of oculomotor physiology, we have identified a selective deficit in neurobehavioral response suppression in OCD that may be related to failures in the developmental maturation of frontostriatal circuitry. Magnetic resonance imaging studies showed that treatment-naive pediatric OCD patients had significant volumetric abnormalities in ventral prefrontal cortical and striatal regions but no abnormalities in dorsolateral prefrontal cortex. Severity of OCD symptoms but not illness duration was related to ventral prefrontal cortical and striatal volumes.Conclusions: Critical neurodevelopmental changes in ventral prefrontal–striatal circuitry may be associated with the initial presentation of OCD, and a developmentally mediated network dysplasia may underlie OCD. Such dysplasia in ventral prefrontal cortical circuits could manifest clinically by disrupting brain functions that mediate ongoing purposive behaviors.