Neurobiology of Anxiety Disorders and Implications for Treatment

Neurobiology of Anxiety Disorders
and Implications for Treatment
AMIR GARAKANI, M.D.1, SANJAY J. MATHEW, M.D.2, AND DENNIS S. CHARNEY, M.D.3,4
Abstract
The neurobiology of the anxiety disorders, which include panic disorder, post-traumatic stress disorder (PTSD), and specific pho-
bias, among others, has been clarified by advances in the field of classical or Pavlovian conditioning, and in our understanding of
basic mechanisms of memory and learning. Fear conditioning occurs when a neutral conditioned stimulus (such as a tone) is
paired with an aversive, or unconditioned stimulus (such as a footshock), and then in the absence of the unconditioned stimulus,
causes a conditioned fear response. Preclinical studies have shown that the amygdala plays a key role in fear circuitry, and that
abnormalities in amygdala pathways can affect the acquisition and expression of fear conditioning. Drugs such as glutamate N-
methyl-D-aspartate (NMDA) antagonists, and blockers of voltage-gated calcium channels, in the amygdala, may block these
effects. There is also preliminary evidence for the use of centrally acting beta-adrenergic antagonists, like propranolol, to inhibit
consolidation of traumatic memories in PTSD. Finally, fear extinction, which entails new learning of fear inhibition, is central to
the mechanism of effective anti-anxiety treatments. Several pharmacological manipulations, such as D-cycloserine, a partial
NMDA agonist, have been found to facilitate extinction. Combining these medication approaches with psychotherapies that pro-
mote extinction, such as cognitive behavioral therapy (CBT), may offer patients with anxiety disorders a rapid and robust treat-
ment with good durability of effect.
Key Words: Phobia, PTSD, panic, reconsolidation, extinction, amygdala, prefrontal cortex, fear, classical conditioning, Pavlov.
Introduction
experiencing some form of depression in their life-
time (5).
ANXIETY DISORDERS are the most common type of
Our understanding of anxiety disorders, such
psychiatric disorders, with an incidence of 18.1%
as phobias, panic disorder and PTSD, has bene-
and a lifetime prevalence of 28.8% (1, 2). They ac-
fited from research on the neurobiology of fear and
count for a $42.3 billion annual cost in the United
fear conditioning. This article will review this re-
States, with over 50% of the total sum directed to-
search and examine its implications for these anx-
wards nonpsychiatric medical treatment costs (3).
iety disorders, with a focus on identifying potential
According to the National Comorbidity Survey
therapeutic strategies.
Replication, in a given year, only about 37% of pa-
Below is a brief summary of the diagnostic
tients with anxiety disorders utilize any form of
features from the Diagnostic and Statistical Man-
health services, including visits with psychiatrists
ual, Fourth Edition (DSM-IV) for the major “fear-
(13%), other mental health practitioners (16%), or
based” anxiety disorders, which have been associ-
general medical doctors (24.3%) (4). Patients with
ated with pathological fear response (6).
anxiety disorders also have a high comorbidity
Panic disorder (PD) (prevalence: 4.7%) is a
with mood disorders, with up to 90% of patients
syndrome in which a person experiences recurrent
and unexpected attacks, of sudden onset and short
duration (10 – 15 minutes), which consist of the
following symptoms: shortness of breath, palpita-
1Post-Doctoral Research Fellow in Psychiatry, 2Assistant Profes-
tions, chest pain, sweating, chills, nausea, trem-
sor of Psychiatry, and 3Anne and Joel Ehrenkranz Professor of
Psychiatry, Professor of Neuroscience, Professor of Pharmacology
bling, fear of dying or losing control, numbness,
and Biological Chemistry, and Dean for Academic and Scientific
and a feeling of detachment or unreality. PD may
Affairs, Mount Sinai School of Medicine, New York, NY; and
or may not be accompanied by agoraphobia, an
4Senior Vice President for Health Sciences, Mount Sinai Medical
avoidance of situations where a person may feel
Center, New York, NY.
trapped and unable to escape (e.g., trains, large
Address all correspondence to Sanjay J. Mathew, M.D.,
Department of Psychiatry, Box 1217, One Gustave L. Levy Place,
crowds) (6). Post-traumatic stress disorder
New York, NY 10029-6574; email: sanjay.mathew@mssm.edu
(prevalence: 6.8%) is a potentially debilitating
© THE MOUNT SINAI JOURNAL OF MEDICINE Vol. 73 No. 7 November 2006
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chronic illness, caused by witnessing or experienc-
ments are SSRIs (sertraline and paroxetine, includ-
ing a serious traumatic event, in which the person
ing paroxetine CR), while group CBT with expo-
feels a threat to his/her life or the life of others, and
sure therapy is the best psychosocial intervention
experiences intense fear and horror. Typically, pa-
(9). For specific phobias, the optimal treatment is
tients re-experience the traumatic event (e.g.,
CBT and exposure therapy. For all anxiety disor-
nightmares, flashbacks), engage in avoidance of
der, anxiolytic agents such as benzodiazepines can
stimuli associated with the sentinel trauma (e.g.,
be used as a temporary adjunct to aid in minimiz-
impaired recall of events related to the trauma, an-
ing anxiety, in particular when starting a medica-
hedonia, restricted affect), and experience in-
tion therapy. In general, it is important to try to
creased autonomic reactivity (e.g., hypervigilance,
avoid long-term use of benzodiazepines for anxi-
irritability, insomnia, heightened startle response)
ety disorders, since it may lead to tolerance and in-
(6). Phobias, among the most common psychiatric
crease risk of abuse or dependence, although par-
disorders, were previously classified as social pho-
ticularly resistant cases may require longer-term
bia, now called social anxiety disorder (SAD)
administration.
(prevalence: 12.1%), or specific phobia. SAD is
The past decade has witnessed a rapid growth
defined as persistent fear of showing anxiety
in our knowledge of the neurobiological basis of
symptoms when exposed to unfamiliar situations
anxiety, through our examination of the behavioral
or people and potential scrutiny, which result in
components of the fear response. Significant ad-
humiliation and avoidance. Affected persons show
vances in the spatial and temporal resolution of
avoidance of such social or performance situa-
brain imaging techniques have clarified the neu-
tions, and when forced, will experience intense
roanatomical pathways responsible for processes
anxiety, and possibly even panic attacks (6). Spe-
relevant to fear and anxiety in humans, such as fear
cific phobias (prevalence: 12.5%) are marked by a
conditioning, acquisition, consolidation and recon-
persistent, excessive fear of a specific object or sit-
solidation, and extinction (see Table 1 for a glos-
uation (classified as animal type, natural environ-
sary of terms). Animal studies, primarily on ro-
ment type, blood-injection injury type, situational
dents, have shown that the amygdala, in connec-
type, and other type). This causes a potentially
tion with a complex network including the pre-
maladaptive avoidance of the phobic stimulus, and
frontal cortex (PFC), thalamus and hippocampus,
a severe anxiety reaction, such as a panic attack,
is integral to multiple aspects of emotional pro-
when exposed to it (6).
cessing, including mediating adaptive and patho-
Although anxiety disorders present with differ-
logical fear responses (10). Neural circuits, de-
ent symptoms, severity and natural histories, the
fined by brain imaging and the use of pharmaco-
therapeutic interventions for all these disorder are
logical challenge studies, have yielded clues about
similar. For PD, the Food and Drug Administration
receptor and gene expression that may elucidate
(FDA)-approved medication treatments are either
the potential causes and vulnerabilities to anxiety
a selective serotonin reuptake inhibitor (SSRI)
disorders.
such as fluoxetine; sertraline; paroxetine or parox-
This article will review research relating to the
etine controlled release; or venlafaxine XR, a se-
basic mechanisms of the neurobiology of fear and
lective serotonin-norepinephrine reuptake in-
the application of this research to anxiety disorders
hibitor (SNRI) (7). The other recommended treat-
(in particular specific phobias, SAD, PD and
ment for PD is cognitive behavioral therapy
PTSD), and will suggest potential therapeutic
(CBT), or specifically, panic control therapy, a 12-
strategies for the future. As many of the initial
week psychotherapy treatment that involves ad-
pharmacological findings derived from animal
dressing cognitive distortions, psychoeducation,
models are now being applied to patients in the
breathing exercises, progressive muscle relaxation,
anxiety clinic, there is an emergence of a new
and progressive exposure (8). Both CBT and med-
translational field in psychiatry.
ication treatment have been shown to be equally
effective, although evidence that combination
Classical Fear Conditioning
treatment is better has been disputed. For PTSD,
the evidence-based, first-line treatments are SSRIs
The original model of classical conditioning
(sertraline and paroxetine), and CBT using pro-
was most famously demonstrated by Ivan Pavlov
longed exposure (PE). In PE, the patient imagines
(11). It begins with the observation that certain
the traumatic event out loud to reduce anxiety re-
stimuli, referred to as unconditioned stimuli (US),
lated to talking about it, and then is exposed to the
reliably yield an unconditioned response (UR).
places or things that trigger distressing thoughts or
When a neutral stimulus is paired with the US it
feelings. For SAD, the approved medication treat-
may also yield the same response through condi-

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TABLE 1
Then, the tester presented the food while at the
Terms Used in Conditioning
same time ringing a bell (a neutral stimulus), and
repeated the pairing several times. Finally, the
Term
Definition
food was taken away and the tester again rang the
Classical Conditioning
A process by which previously
bell (CS), which produced salivation (CR).
neutral stimuli acquire meaning
Pavlovian fear conditioning occurs when a
to the organism.
neutral stimulus is paired with an aversive stimu-
lus. For instance, in the Little Albert experiments
Unconditioned Stimulus
A trigger that produces an auto
(12), an 11-month-old boy was given a rat (CS) to
(US)
matic, unlearned response.
play with, and showed no fear response. Then,
Unconditioned Response
A naturally occurring reaction to
when again presented with the rat and simultane-
(UR)
an US.
ously a very loud noise (US), Albert began to cry
(UR). With repeated pairing of the rat and loud
Conditioned Stimulus (CS)
A neutral trigger that, through
noise, Albert was shown the rat alone (CS) and
classical conditioning, is able to
produce a conditioned response.
began crying (CR). Even stimuli similar to a rat
(any small, white, furry object) would create a fear
Conditioned Response (CR)
The learned reaction to a CS.
response in the boy. Although fear responses serve
an evolutionary valuable function in protection
Generalization
The ability to respond similarly
from potential dangers, they may also be maladap-
to stimuli which are qualita-
tively different but functionally
tive in that any contextual stimulus can become as-
equivalent.
sociated with recurrent fear and anxiety (i.e., gen-
eralization). In typical fear-conditioning rodent
Acquisition
The initial stage of learning,
models, a US such as a mild electric footshock is
where a neutral stimulus (CS) is
used to elicit a CR, like behavioral freezing or al-
associated with a meaningful
stimulus (US) and obtains the
terations in blood pressure or heart rate.
capacity to elicit a similar re-
sponse (CR).
Neuroanatomy of Anxiety
Short-term memory
Memory of a limited amount of
The area of the brain responsible for the acqui-
material that is held for a short
period of time.
sition and expression of fear conditioning is the
amygdala (13). Located within the medial temporal
Long-term memory
Memory with a very high capac-
lobe, the amygdala is comprised of 13 nuclei, three
ity which lasts over a long pe-
of which, the basal amygdala (BA), lateral amyg-
riod of time.
dala (LA), and central nuclei, are involved in the
Consolidation
The process by which short-
pathways of fear response (14). Stimuli received by
term memory is converted into
the sensory thalamus are transmitted to the LA, and
long-term memory.
then are transferred to the central nucleus (CA)
(“short loop” pathway). The BA also serves as a
Retrieval
Locating and returning to con-
connection between the LA and central nucleus.
sciousness information stored in
long-term memory.
The “long loop” pathway sends signals to the LA
from the sensory cortex, insula, and prefrontal cor-
Reconsolidation
A process by which a previously
tex (15, 66; Figure). From there, the information
consolidated memory, which has
projects to the effector sites in the brain stem and
been retrieved and becomes la-
hypothalamus, which produce the autonomic and
bile, undergoes another consoli-
dation.
behavioral manifestations of the acute fear response
(16). It has been shown that the LA is the area re-
Extinction
The process by which a CS loses
sponsible for memory consolidation and plasticity
the ability to elicit a CR.
in fear conditioning (17, 18). Disruption or lesions
of the LA or CA can disrupt the acquisition of con-
ditioned fear and long-term contextual fear memory
(19 – 21); there is evidence that lesions of the BA
tioning. Under these conditions the neutral stimu-
can affect fear responses (22). The molecular mech-
lus is referred to as the conditioned stimulus and
anism by which fear acquisition occurs in the LA is
the response to the CS is the conditioned response
long-term potentiation (LTP) (23). It is proposed
(CR). Pavlov’s experiment involved a dog that was
that consolidation of memory occurs during a
presented with food (US) and salivated (UR).
process in which calcium enters the cell via N-

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agent in patients with moderate-to-severe
Alzheimer’s disease, most likely by improving
neuronal plasticity and reducing excitotoxicity in
the hippocampus (37). It has also been found to
have anxiolytic properties in some animal studies
(38, 39), but not in others (40, 41). It has not yet
been studied as a primary anxiolytic agent in hu-
mans. Interestingly, Zarate and colleagues (42)
found in a double-blind, placebo-controlled trial,
that memantine was not effective in the treatment
of major depressive disorder, suggesting poten-
tially different pathways for mood modulation.
Lamotrigine, a glutamate antagonist that acts by
Figure. Fear conditioning circuitry.
blockade of voltage-dependent sodium channels
In auditory fear conditioning, animals learn to fear an in-
and calcium channels, is indicated for treatment of
nocuous tone. By pairing tone and shock, the tone acquires the
seizures and bipolar disorder. Mirza and others
capacity to elicit defensive reactions, such as freezing (arrow
used a conditioned emotional response (CER)
pointing up). Tone and shock stimuli converge in the lateral
amygdala (LA), resulting in associative plasticity in the tone—
model in rats, with the pairing of houselight (CS)
LA pathway. Subsequent presentations of the tone can now ac-
to electric footshock, to determine if the CS would
tivate LA neurons. The LA then communicates with the central
associate with reduced lever pressing to receive
nucleus (CE), which controls the expression of fear by way of
food. One of their findings was that a Na+ agonist
connections to specific circuits that mediate freezing behavior.
blocked the anxiolytic effects of lamotrigine, while
The LA connects with CE directly and by way of connections
to other amygdala areas, including the intercalated cell masses
a Ca2+ channel agonist did not, suggesting that the
(ICM), which gate the output, and the basal nucleus (B), which
anxiolytic properties may be mediated by blockade
processes contextual information from the hippocampus.
of sodium channels (43). Hertzberg and colleagues
used lamotrigine in a small double-blind trial of
Reproduced with permission, for electronic and print re-
patients with PTSD, and found it to be more effi-
production, from Sotres-Bayon F, Cain CK, Ledoux JE. Brain
mechanisms of fear extinction: historical perspectives on the
cacious than placebo in reducing the severity of
contribution of prefrontal cortex. Biol Psychiatry 2006,
symptoms of PTSD, including re-experience and
60(4):329 – 336.
avoidance (44). VGCC inhibitors provide another
potential avenue for treatment of anxiety disorders
(see Table 1). For example, pregabalin, an anticon-
methyl-D-aspartate (NMDA) receptors and through
vulsant that binds to the alpha-2-delta protein to
voltage-gated calcium channels (VGCCs) (24).
block VGCC, has shown promise as a therapeutic
Blockage of the VGCCs will disrupt short-term
agent for generalized anxiety disorder (GAD) (45),
memory but not long-term memory, indicating that
and might gain FDA approval by the end of 2007.
this pathway requires only NMDA receptors to be
active (25 – 27). Some animal studies have shown
Consolidation and Reconsolidation
that blockage of NMDA receptor by the antagonist
D,L-2-amino-5-phosphonovaleric acid (APV, AP5),
The conversion of labile, short-term memory
will block fear acquisition, but not expression
into long-term memory is called consolidation, in
(28 – 30), although more recently studies have
a process dependent on protein synthesis (46, 47).
shown that both processes are inhibited (31 – 33).
While originally thought to occur once, the process
Gene studies have shown high expression of
in which transient information is permanently
NMDA receptors in the hippocampus as well, indi-
stored may require new protein synthesis after re-
cating the importance of this brain structure in
trieval (48, 49). The memory trace, upon retrieval,
Pavlovian conditioning (34). As in the amygdala,
is unstable and is required to undergo reconsolida-
blockage of these receptors will inhibit conditioned
tion before it can be restored (50). Typically, mem-
fear responses (35, 36).
ories are not stored individually, but instead as as-
The application of these preclinical findings to
sociated complexes, in which all related compo-
humans is, currently, limited, but potential avenues
nents are stored together (51). Recently, Debiec
include the use of NMDA receptor antagonists and
and colleagues (52) used a second-order fear con-
calcium channel blockers to impair memory con-
ditioning (SOFC) paradigm, meaning that one CS
solidation and thereby treat anxiety symptoms.
was linked to another CS to cause an US (53), to
Memantine, a non-competitive NMDA receptor
test whether a blockade of protein synthesis would
antagonist, is widely used as a memory-enhancing
disrupt one memory, or the entire associative net-

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work. They showed that only directly reactivated
cortex (mPFC) and hippocampus. The LA is re-
memories become labile, but that indirectly reacti-
sponsible for decreased firing with continued pre-
vated memories within the association complex are
sentation of the CS, while the mPFC inhibits firing
not affected (54). These findings may play a role in
of amygdala neurons, under the modulation of the
understanding how stressful events can be un-
hippocampus (66). It is the mPFC that is thought to
learned, without causing amnesia for memories
regulate extinction of long-term memory (67). This
temporally associated with the conditioned fear
has been supported by studies showing blocking of
stimulus.
extinction after lesion of the mPFC (68), and by
Reconsolidation offers a model for anxiety as a
blockade of protein synthesis in the mPFC (69). Ex-
fear response in the absence of a US. It occurs via
posure to chronic stress can also affect the mPFC’s
repeated activation of a memory, which enhances
ability to modulate extinction, via retraction of den-
its retention (55). It is well established that emo-
drites (70, 71). Miracle and colleagues showed that
tionally laden stimuli, when compared to neutral
rats exposed to restraint stress showed reduction in
stimuli, are more likely to be recalled, and are likely
extinction 24 hours after initial extinction (72).
to cause amnesia for words preceding it (56).
Much like in fear acquisition, an important
Reconsolidation requires involvement of
component of extinction is activation of gluta-
NMDA receptors and beta-adrenergic receptors,
matergic NMDA receptors in the amygdala. It has
with induction by the cyclic adenosine monophos-
been shown that NMDA receptor antagonists, like
phate response element binding protein (CREB)
AP5, can cause blockade of extinction, as measured
(54). Propranolol, a central-acting, beta-adrenergic
by startle response (73). Conversely, partial NMDA
receptor antagonist, has been consistently shown
agonists, such as D-cycloserine (DCS), have been
to block recognition and recall of emotionally
shown to facilitate extinction. Walker and others
laden words and memories (57 – 61), while pre-
used systemic administration, and direct amygdalar
serving neutral words. The drug also acts to restore
infusion, of DCS into rats, and found a decrease in
the amnesia caused by the emotional stimulus.
fear-potentiated startle to CS compared to control
Furthermore, propranolol acts to block reconsoli-
animals (74). Ledgerwood’s group confirmed these
dation only and does not interfere with integration
findings, and also determined that DCS not only
of new memories (62). These findings have led re-
aided in extinction of the original CS, but also re-
searchers to test beta blockers in humans with trau-
duced but didn’t extinguish fear response to a CS
matic experiences, in one case investigating the ef-
paired with another CS, (75). This suggests that
fects on recall of distressing memories (63). Pit-
DCS may have an effect on extinction of general-
man and colleagues conducted the only random-
ized fearful stimuli, such as all furry objects, which
ized controlled trial of propranolol in acute trauma
caused crying in Little Albert (see above).
victims, who were administered the medication or
Investigation of the use of DCS in humans with
placebo within 6 hours of exposure to trauma and
anxiety disorders is already underway. Since DCS
continued for 10 days (64). Although they found
acts only to enhance extinction to fear responses,
less severe symptoms of PTSD, as measured on the
and is not a direct anxiolytic, it is used with expo-
Clinician-Administered PTSD Scale (CAPS), in
sure therapy or CBT to show an effect. This was ev-
those receiving propranolol vs. placebo at 1 and 3
idenced by one small study that used DCS in PTSD
months (with three months being the point where
patients with limited effect, but did not employ con-
PTSD can first be diagnosed), the results were not
comitant psychotherapy (76). Ressler and col-
statistically significant. With improved study de-
leagues used 2 single-dose administrations of DCS
sign and larger sample size, further studies are un-
2 – 4 hours prior to exposure therapy in patients
derway to test the efficacy of beta-adrenergic re-
with phobic avoidance of heights, and found
ceptors in the prevention of PTSD.
marked reductions in fear and avoidance symptoms
that persisted for 3 months after treatment (77). A
Extinction
recent trial used DCS to augment group exposure
therapy in patients with social anxiety disorder, and
In Pavlov’s experiment of classical condition-
found rapid improvement in symptoms in patients
ing, the dog ceased to salivate when the bell was
compared to controls, who received exposure ther-
rung (CS) but no food was presented (US) (11).
apy and pill placebo (78). In summary, DCS has
This phenomenon is known as extinction. It does
shown promise an adjunct treatment for patients
not involve, as the name implies, erasure of old in-
with anxiety disorder by enhancing the learning as-
formation, but rather it is caused by the integration
sociated with the treatment.
of new memory (65). The amygdala plays a key
The inability of a person to extinguish a mal-
role in fear extinction, as do the medial prefrontal
adaptive fear response to a CS, due to a disruption

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November 2006
in the process of extinction, can result in persistent
used to understand the causes of anxiety. Imaging
anxiety. Two pathways for the treatment of anxiety
studies, using functional magnetic resonance
presented so far are the disruption of consolidation
imaging (MRI) and positron emission tomography
of emotional or traumatic memories (see above),
(PET) scanning, have helped trace and pinpoint the
and facilitation of the extinguishing of aversive
areas of the brain responsible for induction, main-
stimuli. The second area is under intense investi-
tenance, and unlearning of fear. Although the
gation. In addition to using DCS, there are other
amygdala and prefrontal cortex are the primary
potential agents being used in animal studies to aid
sites of fear acquisition and extinction, other areas
in enhancing extinction. These include yohimbine,
are being shown to play important roles as well. In
an alpha-2-adrenoreceptor antagonist (79), L-type
addition, there are neurochemical pathways, not
VGCC agonists (27, 80), cannabinoid receptor 1
well understood, that may be proven to play a role
agonists (81, 82), and mu-opioid receptor blockers
in anxiety disorders.
(Table 2; 83, 84). Investigation of the applicability
The DSM-IV currently categorizes the anxiety
of these mechanisms to humans is warranted.
disorders by clinical signs and symptoms. The
Committee of the DSM-V Prelude Project, is con-
Conclusion
sidering re-classifying the anxiety disorders by sev-
eral hypothetical approaches, including by etiology
Using Pavlovian conditioning as a model, the
(vulnerability genes and gene/environment interac-
pathophysiology of the fear response has been
tions) or by pathophysiology (neural pathways that
clarified over the past several years. Many animal
give rise to certain symptoms) (85). This may be
studies have shown how these learning paradigms
sensible, given the high comorbidity between mood
can be applied to humans, and how they can be
and anxiety disorders. Using deficits in neural cir-
TABLE 2
Experimental Therapeutics for Anxiety Disorders
Therapeutic Aim:
Acceleration of extinction of pathological fear responses
Clinical Application:
Adjunct to cognitive behavioral therapy for specific phobias, social anxiety, and/or PTSD
Preclinical Rationale
Neurobiological
Drug
Prototypic
References
Mechanism
Target
Drug
pharmacologic or genetic
eCBs depress
CB1 (eCB)
AM404, an inhibitor
81, 82
disruption of eCB
inhibitory
receptor
of eCB break-down
neurotransmission in rodents
networks involved
and reuptake
decreases fear extinction
in aversive
but not memory acquisition
learning
yohimbine facilitates
NE enhances the
?2-adrenergic yohimbine
79
extinction of cue and
learning of fear
receptor
contextual fear in mice
extinction
D-cycloserine infusion into
long-term retention of
glycine
D-cycloserine
77, 78
amygdala strengthens
extinction requires
modulatory
extinction of fear-
activation of NMDA
site of NMDA
potentiated startle in rats
glutamate receptors
receptor
in amygdala
in the vlPAG of rats, blockade
activation of vlPAG
µ opioid
RB101(S), inhibitor
83, 84
of µ opioid receptors retards
µ opioid receptors
receptors
of enkephalin-
fear extinction, while
contributes to
in vlPAG
catabolizing enzymes
inhibition of enkephalin
extinction of
degradation enhances it
conditioned fear
the LVGCC inhibitors
LVGCCs are essential
LVGCC
L-type calcium channel
27, 80
nifedipine and nimodipine
for fear extinction
agonists
impair fear extinction in mice
but not acquisition or
expression of conditioned fear
PTSD = post-traumatic stress disorder, eCB = endocannabinoid; KO = knockout; LTP = long-term potentiation; LVGCC = L-type
voltage gated calcium channel; Nac = nucleus accumbens; NE = norepinephrine; vlPAG = ventrolateral quadrant of periaqueduc-
tal gray; NMDA = N=methyl-D-aspartate.

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cuits as a means of categorization, certain disorders
18. Shumyatsky G, Tsvetkov E, Malleret G, et al. Identification of a
marked by amygdala-centric fear pathways (such as
signaling network in lateral nucleus of amygdala important
for inhibiting memory specifically related to learned fear.
PD, PTSD, phobias) will be grouped together, while
Cell 2002; 111:905 – 918.
GAD may be re-classified as a mood disorder.
19. Wallace KJ, Rosen JB. Neurotoxic lesions of the lateral nucleus
While unable to cover all topics related to the
of the amygdala decrease conditioned fear but not uncondi-
neurobiology of fear and anxiety, our report re-
tioned fear of a predator odor: comparison with electrolytic
viewed the pertinent findings in the area of fear con-
lesions. J Neurosci 2001; 21(10):3619 – 3627.
ditioning, including acquisition, reconsolidation, and
20. Blair HT, Sotres-Bayon F, Moita MA, Ledoux JE. The lateral
amygdala processes the value of conditioned and uncondi-
extinction. Finally, through investigation of these
tioned aversive stimuli. Neuroscience 2005; 133(2):561 – 569.
pathways and neuropeptide systems, novel therapeu-
21. Goosens KA, Maren S. Contextual and auditory fear condition-
tic interventions can be found for a wide range of
ing are mediated by the lateral, basal, and central amyg-
anxiety disorders, such as generalized anxiety,
daloid nuclei in rats. Learn Mem 2001; 8(3):148 – 155.
panic, phobias, and PTSD.
22. Anglada-Figueroa D, Quirk GJ. Lesions of the basal amygdala
block expression of conditioned fear but not extinction. J
Neurosci 2005; 25(42):9680 – 9685.
References
23. Chapman PF, Kairiss EW, Keenan CL, Brown TH. Long-term
synaptic potentiation in the amygdala. Synapse 1990;
1. Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and
6(3):271 – 278.
comorbidity of 12-month DSM-IV disorders in the National
24. Bauer EP, Schafe GE, LeDoux JE. NMDA receptors and L-type
Comorbidity Survey Replication. Arch Gen Psychiatry 2005;
voltage-gated calcium channels contribute to long-term poten-
62(6):617 – 627.
tiation and different components of fear memory formation in
2. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence
the lateral amygdala. J Neurosci 2002; 22(12):5239 – 5249.
and age-of-onset distributions of DSM-IV disorders in the
25. Rodrigues SM, Schafe GE, LeDoux JE. Intra-amygdala block-
National Comorbidity Survey Replication. Arch Gen Psychi-
ade of the NR2B subunit of the NMDA receptor disrupts the
atry 2005; 62(6):593 – 602.
acquisition but not the expression of fear conditioning. J
3. Greenberg PE, Sisitsky T, Kessler RC, et al. The economic bur-
Neurosci 2001; 21:6889 – 6896.
den of anxiety disorders in the 1990s. J Clin Psychiatry
26. Walker DL, Davis M. Involvement of NMDA receptors within
1999; 60(7):427 – 435.
the amygdala in short- versus long-term memory for fear
4. Wang PS, Lane M, Olfson M, et al. Twelve-month use of mental
conditioning as assessed with fear-potentiated startle. Behav
health services in the United States: results from the National
Neurosci 2000; 114:1019 – 1033.
Comorbidity Survey Replication. Arch Gen Psychiatry 2005;
27. Cain CK, Blouin AM, Barad M. L-type voltage-gated calcium
62(6):629 – 640.
channels are required for extinction, but not for acquisition
5. Gorman JM. Comorbid depression and anxiety spectrum disor-
or expression, of conditional fear in mice. J Neurosci 2002;
ders. Depress Anxiety 1996-97; 4(4):160 – 168.
22(20):9113 – 9121.
6. Diagnostic and statistical manual of mental disorders. 4th ed.,
28. Roesler R, Vianna MR, De-Paris F, et al. Infusions of AP5 into
Washington (DC): American Psychiatric Association; 2000.
the basolateral amygdala impair the formation, but not the
7. American Psychiatric Association Practice guidelines for the
expression, of step-down inhibitory avoidance. Braz J Med
treatment of psychiatric disorders: compendium 2006. Wash-
Biol Res 2000; 33(7):829 – 834.
ington (DC): American Psychiatric Publishing; 2006.
29. Fendt M. Injections of the NMDA receptor antagonist
8. Barlow DH, Craske MG. Mastery of your anxiety and panic. 3rd
aminophosphonopentanoic acid into the lateral nucleus of
ed. New York: Graywind Publications, Inc.; 2000.
the amygdala block the expression of fear-potentiated startle
9. Davidson JR, Foa EB, Huppert JD, et al. Fluoxetine, comprehen-
and freezing. J Neurosci 2001; 21(11):4111 – 4115.
sive cognitive behavioral therapy, and placebo in generalized
30. Miserendino MJ, Sananes CB, Melia KR, Davis M. Blocking of
social phobia. Arch Gen Psychiatry 2004; 61(10):1005 – 1013.
acquisition but not expression of conditioned fear-potenti-
10. Phelps EA, LeDoux JE. Contributions of the amygdala to emo-
ated startle by NMDA antagonists in the amygdala. Nature
tion processing: from animal models to behavior. Neuron
1990; 345(6277):716 – 718.
2005; 48(2):175 – 187.
31. Jasnow AM, Cooper MA, Huhman KL. N-methyl-D-aspartate
11. Pavlov IP. Conditioned reflexes. London: Oxford University
receptors in the amygdala are necessary for the acquisition
Press; 1927. p. 246.
and expression of conditioned defeat. Neuroscience 2004;
12. Watson JB, Raynor R. Conditioned emotional reactions. J Exp
123(3):625 – 634.
Psychol 1920; 3:1 – 14.
32. Maren S, Aharonov G, Stote DL, Fanselow MS. N-methyl-D-
13. Pare D, Quirk GJ, Ledoux JE. New vistas on amygdala net-
aspartate receptors in the basolateral amygdala are required
works in conditioned fear. J Neurophysiol 2004; 92(1):1 – 9.
for both acquisition and expression of conditional fear in
14. Rosen JB. The neurobiology of conditioned and unconditioned
rats. Behav Neurosci 1996; 110(6):1365 – 1374.
fear: a neurobehavioral system analysis of the amygdala.
33. Lee HJ, Choi JS, Brown TH, Kim JJ. Amygdalar NMDA recep-
Behav Cogn Neurosci Rev 2004; 3(1):23 – 41.
tors are critical for the expression of multiple conditioned
15. LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci
fear responses. J Neurosci 2001; 21(11):4116 – 4124.
2000; 23:155 – 184.
34. Mei B, Li C, Dong S, et al. Distinct gene expression profiles in
16. Cahill L, McGaugh JL. Mechanisms of emotional arousal and last-
hippocampus and amygdala after fear conditioning. Brain
ing declarative memory. Trends Neurosci 1998; 21:294 – 299.
Res Bull 2005; 67(1 – 2):1 – 12.
17. Blair HT, Schafe GE, Bauer EP, et al. Synaptic plasticity in the
35. Zhao MG, Toyoda H, Lee YS, et al. Roles of NMDA NR2B
lateral amygdala: a cellular hypothesis of fear conditioning.
subtype receptor in prefrontal long-term potentiation and
Learn Mem 2001; 8(5):229 – 242.
contextual fear memory. Neuron 2005; 47(6):859 – 872.

---

948
THE MOUNT SINAI JOURNAL OF MEDICINE
November 2006
36. Melik E, Babar E, Ozen E, Ozgunen T. Hypofunction of the dor-
57. Przybyslawski J, Roullet P, Sara SJ. Attenuation of emotional
sal hippocampal NMDA receptors impairs retrieval of mem-
and nonemotional memories after their reactivation: role of
ory to partially presented foreground context in a single-trial
beta adrenergic receptors. J Neurosci 1999;
fear conditioning in rats. Eur Neuropsychopharmacol 2006;
19(15):6623 – 6628.
16(4):241 – 247.
58. Cahill L, Prins B, Weber M, McGaugh JL. Beta-adrenergic acti-
37. Parsons CG, Danysz W, Quack G. Memantine is a clinically
vation and memory for emotional events. Nature 1994;
well tolerated N-methyl-D-aspartate (NMDA) receptor
371(6499):702 – 704.
antagonist—a review of preclinical data. Neuropharmacol-
59. Strange BA, Hurlemann R, Dolan RJ. An emotion-induced ret-
ogy 1999; 38(6):735 – 767.
rograde amnesia in humans is amygdala- and beta-adrener-
38. Bertoglio LJ, Carobrez AP. Anxiolytic-like effects of
gic-dependent. Proc Natl Acad Sci U S A 2003;
NMDA/glycine-B receptor ligands are abolished during the
100:13626 – 13631.
elevated plus-maze trial 2 in rats. Psychopharmacology
60. van Stegeren AH, Goekoop R, Everaerd W, et al. Noradrenaline
(Berl) 2003; 170(4):335 – 342.
mediates amygdala activation in men and women during
39. Bertoglio LJ, Carobrez AP. Scopolamine given pre-Trial 1 pre-
encoding of emotional material. NeuroImage 2005;
vents the one-trial tolerance phenomenon in the elevated
24:898 – 909.
plus-maze Trial 2. Behav Pharmacol 2004; 15(1):45 – 54.
61. Hurlemann R, Hawellek B, Matusch A, et al. Noradrenergic
40. Karcz-Kubicha M, Jessa M, Nazar M, et al. Anxiolytic activity
modulation of emotion-induced forgetting and remembering.
of glycine-B antagonists and partial agonists—no relation to
J Neurosci 2005; 25(27):6343 – 6439.
intrinsic activity in the patch clamp. Neuropharmacology
62. D?biec J, Ledoux JE. Disruption of reconsolidation but not con-
1997; 36(10):1355 – 1367.
solidation of auditory fear conditioning by noradrenergic
41. Harvey BH, Bothma T, Nel A, et al. Involvement of the NMDA
blockade in the amygdala. Neuroscience 2004;
receptor, NO-cyclic GMP and nuclear factor K-beta in an
129(2):267 – 272.
animal model of repeated trauma. Hum Psychopharmacol
63. Reist C, Duffy JG, Fujimoto K, Cahill L. beta-Adrenergic
2005; 20(5):367 – 373.
blockade and emotional memory in PTSD. Int J Neuropsy-
42. Zarate CA Jr, Singh JB, Quiroz JA, et al. A double-blind,
chopharmacol 2001; 4(4):377 – 383.
placebo-controlled study of memantine in the treatment of
64. Pitman RK, Sanders KM, Zusman RM, et al. Pilot study of sec-
major depression. Am J Psychiatry 2006; 163(1):153 – 155.
ondary prevention of posttraumatic stress disorder with pro-
43. Mirza NR, Bright JL, Stanhope KJ, et al. Lamotrigine has an
pranolol. Biol Psychiatry 2002; 51:183 – 188.
anxiolytic-like profile in the rat conditioned emotional
65. Bouton ME. Context and behavioral processes in extinction.
response test of anxiety: a potential role for sodium chan-
Learn Mem 2004; 11(5):485 – 494.
nels? Psychopharmacology (Berl) 2005; 180(1):159 – 168.
66. Sotres-Bayon F, Cain CK, LeDoux JE. Brain mechanisms of
44. Hertzberg MA, Butterfield MI, Feldman ME, et al. A prelimi-
fear extinction: historical perspectives on the contribution of
nary study of lamotrigine for the treatment of posttraumatic
prefrontal cortex. Biol Psychiatry 2006; 60(4):329 – 336.
stress disorder. Biol Psychiatry 1999; 45(9):1226 – 1229.
67. Quirk GJ, Russo GK, Barron JL, Lebron K. The role of ventro-
45. Rickels K, Pollack MH, Feltner DE, et al. Pregabalin for treat-
medial prefrontal cortex in the recovery of extinguished fear.
ment of generalized anxiety disorder: a 4-week, multicenter,
J Neurosci 2000; 20(16):6225 – 6231.
double-blind, placebo-controlled trial of pregabalin and
68. Milad MR, Quirk GJ. Neurons in medial prefrontal cortex signal
alprazolam. Arch Gen Psychiatry 2005; 62(9):1022 – 1030.
memory for fear extinction. Nature 2002; 420(6911):70 – 74.
46. McGaugh JL. Memory—a century of consolidation. Science
69. Santini E, Ge H, Ren K, et al. Consolidation of fear extinction
2000; 287(5451):248 – 251.
requires protein synthesis in the medial prefrontal cortex. J
47. Davis HP, Squire LR. Protein synthesis and memory: a review.
Neurosci 2004 Jun 23; 24(25):5704 – 5710.
Psychol Bull 1984; 96(3):518 – 559.
70. Cook SC, Wellman CL. Chronic stress alters dendritic morphol-
48. Dudai Y. The neurobiology of consolidations, or, how stable is
ogy in rat medial prefrontal cortex. J Neurobiol 2004;
the engram? Annu Rev Psychol 2004; 55:51 – 86.
60(2):236 – 248.
49. Nader K, Schafe GE, LeDoux JE. The labile nature of consoli-
71. Radley JJ, Sisti HM, Hao J, et al. Chronic behavioral stress
dation theory. Nat Rev Neurosci 2000; 1(3):216 – 219.
induces apical dendritic reorganization in pyramidal neurons of
50. Debiec J, LeDoux JE, Nader K. Cellular and systems reconsoli-
the medial prefrontal cortex. Neuroscience 2004; 125(1):1 – 6.
dation in the hippocampus. Neuron 2002; 36(3):527 – 538.
72. Miracle AD, Brace MF, Huyck KD, et al. Chronic stress impairs
51. Anderson JR, Bower GH. Human associative memory. 1st ed.
recall of extinction of conditioned fear. Neurobiol Learn
Washington (DC): VH Winston & Sons: 1973.
2006; 85(3):213 – 218.
52. Debiec J, Doyere V, Nader K, Ledoux JE. Directly reactivated,
73. Falls WA, Miserendino MJ, Davis M. Extinction of fear-potenti-
but not indirectly reactivated, memories undergo reconsoli-
ated startle: blockade by infusion of an NMDA antagonist
dation in the amygdala. Proc Natl Acad Sci U S A 2006;
into the amygdala. J Neurosci 1992; 12(3):854 – 863.
103(9):3428 – 3433.
74. Walker DL, Ressler KJ, Lu KT, Davis M. Facilitation of condi-
53. Gewirtz JC, Davis M. Using pavlovian higher-order conditioning
tioned fear extinction by systemic administration or intra-
paradigms to investigate the neural substrates of emotional
amygdala infusions of D-cycloserine as assessed with fear-
learning and memory. Learn Mem 2000; 7(5):257 – 266.
potentiated startle in rats. J Neurosci 2002;
54. Kida S, Josselyn SA, de Ortiz SP, et al. CREB required for the
22(6):2343 – 2351.
stability of new and reactivated fear memories. Nat Neurosci
75. Ledgerwood L, Richardson R, Cranney J. D-cycloserine facili-
2002; 5(4):348 – 355.
tates extinction of learned fear: effects on reacquisition and
55. Sara SJ. Retrieval and reconsolidation: toward a neurobiology of
generalized extinction. Biol Psychiatry 2005;
remembering. Learn Mem 2000; 7:73 – 784.
57(8):841 – 847.
56. Kern RP, Libkuman TM, Otani H, Holmes K. Emotional stim-
76. Heresco-Levy U, Kremer I, Javitt DC, et al. Pilot-controlled trial
uli, divided attention, and memory. Emotion 2005;
of D-cycloserine for the treatment of post-traumatic stress
5(4):408 – 417.
disorder. Int J Neuropsychopharmacol 2002; 5(4):301 – 307.

---

Vol. 73 No. 7
NEUROBIOLOGY OF ANXIETY DISORDERS—GARAKANI
949
77. Ressler KJ, Rothbaum BO, Tannenbaum L, et al. Cognitive
82. Marsicano G, Wotjak CT, Azad SC, et al. The endogenous
enhancers as adjuncts to psychotherapy: use of D-cycloser-
cannabinoid system controls extinction of aversive memo-
ine in phobic individuals to facilitate extinction of fear. Arch
ries. Nature 2002; 418:530 – 534.
Gen Psychiatry 2004; 61(11):1136 – 1144.
83. McNally GP, Lee BW, Chiem JY, Choi EA. The midbrain periaque-
78. Hofmann SG, Meuret AE, Smits JA, et al. Augmentation of
ductal gray and fear extinction: opioid receptor subtype and
exposure therapy with D-cycloserine for social anxiety disor-
roles of cyclic AMP, protein kinase A, and mitogen-activated
der. Arch Gen Psychiatry 2006; 63(3):298 – 304.
protein kinase. Behav Neurosci 2005; 119(4):1023 – 1033.
79. Cain CK, Blouin AM, Barad M. Adrenergic transmission facili-
84. McNally GP. Faciliation of fear extinction by midbrain periacque-
tates extinction of conditioned fear in mice. Learn Mem
ductal gray infusions of RB101 (S), an inhibitor of enkephalin-
2004; 11(2):179 – 187.
degrading enzymes. Behav Neurosci 2005; 119(6):1672 – 1677.
80. Cain CK, Godsil BP, Jami S, Barad M. The L-type calcium
85. First MB. Stress-induced and fear circuitry disorders.
channel nifedipine impairs extinction, but not reduced con-
http://dsm5.org/conference7.cfm [accessed Sept 15, 2006].
tingency effects, in mice. Learn Mem 2005; 12(3):277 – 284.
81. Chhatwal JP, Davis M, Maguschak KA, Ressler JK. Enhancing
cannabinoid neurotransmission augments the extinction of
conditioned fear. Neuropsychopharmacology 2005;
30(3):516 – 524.

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