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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
A
NXIETY DISORDERS
are the most common type of
psychiatric disorders, with an incidence of 18.1%
and a lifetime prevalence of 28.8% (1, 2). They ac-
count for a $42.3 billion annual cost in the United
States, with over 50% of the total sum directed to-
wards nonpsychiatric medical treatment costs (3).
According to the National Comorbidity Survey
Replication, in a given year, only about 37% of pa-
tients with anxiety disorders utilize any form of
health services, including visits with psychiatrists
(13%), other mental health practitioners (16%), or
general medical doctors (24.3%) (4). Patients with
anxiety disorders also have a high comorbidity
with mood disorders, with up to 90% of patients
experiencing some form of depression in their life-
time (5).
Our understanding of anxiety disorders, such
as phobias, panic disorder and PTSD, has bene-
fited from research on the neurobiology of fear and
fear conditioning. This article will review this re-
search and examine its implications for these anx-
iety disorders, with a focus on identifying potential
therapeutic strategies.
Below is a brief summary of the diagnostic
features from the Diagnostic and Statistical Man-
ual, Fourth Edition (DSM-IV) for the major “fear-
based” anxiety disorders, which have been associ-
ated with pathological fear response (6).
Panic disorder (PD) (prevalence: 4.7%) is a
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-
tions, chest pain, sweating, chills, nausea, trem-
bling, fear of dying or losing control, numbness,
and a feeling of detachment or unreality. PD may
or may not be accompanied by agoraphobia, an
avoidance of situations where a person may feel
trapped and unable to escape (e.g., trains, large
crowds) (6). Post-traumatic stress disorder
(prevalence: 6.8%) is a potentially debilitating
©THE MOUNT SINAI JOURNAL OF MEDICINE Vol. 73 No. 7 November 2006 941
1Post-Doctoral Research Fellow in Psychiatry, 2Assistant Profes-
sor of Psychiatry, and 3Anne and Joel Ehrenkranz Professor of
Psychiatry, Professor of Neuroscience, Professor of Pharmacology
and Biological Chemistry, and Dean for Academic and Scientific
Affairs, Mount Sinai School of Medicine, New York, NY; and
4Senior Vice President for Health Sciences, Mount Sinai Medical
Center, New York, NY.
Address all correspondence to Sanjay J. Mathew, M.D.,
Department of Psychiatry, Box 1217, One Gustave L. Levy Place,
New York, NY 10029-6574; email: sanjay.mathew@mssm.edu
942 THE MOUNT SINAI JOURNAL OF MEDICINE November 2006
chronic illness, caused by witnessing or experienc-
ing a serious traumatic event, in which the person
feels a threat to his/her life or the life of others, and
experiences intense fear and horror. Typically, pa-
tients re-experience the traumatic event (e.g.,
nightmares, flashbacks), engage in avoidance of
stimuli associated with the sentinel trauma (e.g.,
impaired recall of events related to the trauma, an-
hedonia, restricted affect), and experience in-
creased autonomic reactivity (e.g., hypervigilance,
irritability, insomnia, heightened startle response)
(6). Phobias, among the most common psychiatric
disorders, were previously classified as social pho-
bia, now called social anxiety disorder (SAD)
(prevalence: 12.1%), or specific phobia. SAD is
defined as persistent fear of showing anxiety
symptoms when exposed to unfamiliar situations
or people and potential scrutiny, which result in
humiliation and avoidance. Affected persons show
avoidance of such social or performance situa-
tions, and when forced, will experience intense
anxiety, and possibly even panic attacks (6). Spe-
cific phobias (prevalence: 12.5%) are marked by a
persistent, excessive fear of a specific object or sit-
uation (classified as animal type, natural environ-
ment type, blood-injection injury type, situational
type, and other type). This causes a potentially
maladaptive avoidance of the phobic stimulus, and
a severe anxiety reaction, such as a panic attack,
when exposed to it (6).
Although anxiety disorders present with differ-
ent symptoms, severity and natural histories, the
therapeutic interventions for all these disorder are
similar. For PD, the Food and Drug Administration
(FDA)-approved medication treatments are either
a selective serotonin reuptake inhibitor (SSRI)
such as fluoxetine; sertraline; paroxetine or parox-
etine controlled release; or venlafaxine XR, a se-
lective serotonin-norepinephrine reuptake in-
hibitor (SNRI) (7). The other recommended treat-
ment for PD is cognitive behavioral therapy
(CBT), or specifically, panic control therapy, a 12-
week psychotherapy treatment that involves ad-
dressing cognitive distortions, psychoeducation,
breathing exercises, progressive muscle relaxation,
and progressive exposure (8). Both CBT and med-
ication treatment have been shown to be equally
effective, although evidence that combination
treatment is better has been disputed. For PTSD,
the evidence-based, first-line treatments are SSRIs
(sertraline and paroxetine), and CBT using pro-
longed exposure (PE). In PE, the patient imagines
the traumatic event out loud to reduce anxiety re-
lated to talking about it, and then is exposed to the
places or things that trigger distressing thoughts or
feelings. For SAD, the approved medication treat-
ments are SSRIs (sertraline and paroxetine, includ-
ing paroxetine CR), while group CBT with expo-
sure therapy is the best psychosocial intervention
(9). For specific phobias, the optimal treatment is
CBT and exposure therapy. For all anxiety disor-
der, anxiolytic agents such as benzodiazepines can
be used as a temporary adjunct to aid in minimiz-
ing anxiety, in particular when starting a medica-
tion therapy. In general, it is important to try to
avoid long-term use of benzodiazepines for anxi-
ety disorders, since it may lead to tolerance and in-
crease risk of abuse or dependence, although par-
ticularly resistant cases may require longer-term
administration.
The past decade has witnessed a rapid growth
in our knowledge of the neurobiological basis of
anxiety, through our examination of the behavioral
components of the fear response. Significant ad-
vances in the spatial and temporal resolution of
brain imaging techniques have clarified the neu-
roanatomical pathways responsible for processes
relevant to fear and anxiety in humans, such as fear
conditioning, acquisition, consolidation and recon-
solidation, and extinction (see Table 1 for a glos-
sary of terms). Animal studies, primarily on ro-
dents, have shown that the amygdala, in connec-
tion with a complex network including the pre-
frontal cortex (PFC), thalamus and hippocampus,
is integral to multiple aspects of emotional pro-
cessing, including mediating adaptive and patho-
logical fear responses (10). Neural circuits, de-
fined by brain imaging and the use of pharmaco-
logical challenge studies, have yielded clues about
receptor and gene expression that may elucidate
the potential causes and vulnerabilities to anxiety
disorders.
This article will review research relating to the
basic mechanisms of the neurobiology of fear and
the application of this research to anxiety disorders
(in particular specific phobias, SAD, PD and
PTSD), and will suggest potential therapeutic
strategies for the future. As many of the initial
pharmacological findings derived from animal
models are now being applied to patients in the
anxiety clinic, there is an emergence of a new
translational field in psychiatry.
Classical Fear Conditioning
The original model of classical conditioning
was most famously demonstrated by Ivan Pavlov
(11). It begins with the observation that certain
stimuli, referred to as unconditioned stimuli (US),
reliably yield an unconditioned response (UR).
When a neutral stimulus is paired with the US it
may also yield the same response through condi-
Vol. 73 No. 7 NEUROBIOLOGY OF ANXIETY DISORDERS—GARAKANI 943
tioning. Under these conditions the neutral stimu-
lus is referred to as the conditioned stimulus and
the response to the CS is the conditioned response
(CR). Pavlov’s experiment involved a dog that was
presented with food (US) and salivated (UR).
Then, the tester presented the food while at the
same time ringing a bell (a neutral stimulus), and
repeated the pairing several times. Finally, the
food was taken away and the tester again rang the
bell (CS), which produced salivation (CR).
Pavlovian fear conditioning occurs when a
neutral stimulus is paired with an aversive stimu-
lus. For instance, in the Little Albert experiments
(12), an 11-month-old boy was given a rat (CS) to
play with, and showed no fear response. Then,
when again presented with the rat and simultane-
ously a very loud noise (US), Albert began to cry
(UR). With repeated pairing of the rat and loud
noise, Albert was shown the rat alone (CS) and
began crying (CR). Even stimuli similar to a rat
(any small, white, furry object) would create a fear
response in the boy. Although fear responses serve
an evolutionary valuable function in protection
from potential dangers, they may also be maladap-
tive in that any contextual stimulus can become as-
sociated with recurrent fear and anxiety (i.e., gen-
eralization). In typical fear-conditioning rodent
models, a US such as a mild electric footshock is
used to elicit a CR, like behavioral freezing or al-
terations in blood pressure or heart rate.
Neuroanatomy of Anxiety
The area of the brain responsible for the acqui-
sition and expression of fear conditioning is the
amygdala (13). Located within the medial temporal
lobe, the amygdala is comprised of 13 nuclei, three
of which, the basal amygdala (BA), lateral amyg-
dala (LA), and central nuclei, are involved in the
pathways of fear response (14). Stimuli received by
the sensory thalamus are transmitted to the LA, and
then are transferred to the central nucleus (CA)
(“short loop” pathway). The BA also serves as a
connection between the LA and central nucleus.
The “long loop” pathway sends signals to the LA
from the sensory cortex, insula, and prefrontal cor-
tex (15, 66; Figure). From there, the information
projects to the effector sites in the brain stem and
hypothalamus, which produce the autonomic and
behavioral manifestations of the acute fear response
(16). It has been shown that the LA is the area re-
sponsible for memory consolidation and plasticity
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
can affect fear responses (22). The molecular mech-
anism by which fear acquisition occurs in the LA is
long-term potentiation (LTP) (23). It is proposed
that consolidation of memory occurs during a
process in which calcium enters the cell via N-
TABLE 1
Terms Used in Conditioning
Term Definition
Classical Conditioning A process by which previously
neutral stimuli acquire meaning
to the organism.
Unconditioned Stimulus A trigger that produces an auto
(US) matic, unlearned response.
Unconditioned Response A naturally occurring reaction to
(UR) an US.
Conditioned Stimulus (CS) A neutral trigger that, through
classical conditioning, is able to
produce a conditioned response.
Conditioned Response (CR) The learned reaction to a CS.
Generalization The ability to respond similarly
to stimuli which are qualita-
tively different but functionally
equivalent.
Acquisition The initial stage of learning,
where a neutral stimulus (CS) is
associated with a meaningful
stimulus (US) and obtains the
capacity to elicit a similar re-
sponse (CR).
Short-term memory Memory of a limited amount of
material that is held for a short
period of time.
Long-term memory Memory with a very high capac-
ity which lasts over a long pe-
riod of time.
Consolidation The process by which short-
term memory is converted into
long-term memory.
Retrieval Locating and returning to con-
sciousness information stored in
long-term memory.
Reconsolidation A process by which a previously
consolidated memory, which has
been retrieved and becomes la-
bile, undergoes another consoli-
dation.
Extinction The process by which a CS loses
the ability to elicit a CR.
944 THE MOUNT SINAI JOURNAL OF MEDICINE November 2006
methyl-D-aspartate (NMDA) receptors and through
voltage-gated calcium channels (VGCCs) (24).
Blockage of the VGCCs will disrupt short-term
memory but not long-term memory, indicating that
this pathway requires only NMDA receptors to be
active (25–27). Some animal studies have shown
that blockage of NMDA receptor by the antagonist
D,L-2-amino-5-phosphonovaleric acid (APV, AP5),
will block fear acquisition, but not expression
(28–30), although more recently studies have
shown that both processes are inhibited (31–33).
Gene studies have shown high expression of
NMDA receptors in the hippocampus as well, indi-
cating the importance of this brain structure in
Pavlovian conditioning (34). As in the amygdala,
blockage of these receptors will inhibit conditioned
fear responses (35, 36).
The application of these preclinical findings to
humans is, currently, limited, but potential avenues
include the use of NMDA receptor antagonists and
calcium channel blockers to impair memory con-
solidation and thereby treat anxiety symptoms.
Memantine, a non-competitive NMDA receptor
antagonist, is widely used as a memory-enhancing
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
blockade of voltage-dependent sodium channels
and calcium channels, is indicated for treatment of
seizures and bipolar disorder. Mirza and others
used a conditioned emotional response (CER)
model in rats, with the pairing of houselight (CS)
to electric footshock, to determine if the CS would
associate with reduced lever pressing to receive
food. One of their findings was that a Na
+
agonist
blocked the anxiolytic effects of lamotrigine, while
a Ca
2+
channel agonist did not, suggesting that the
anxiolytic properties may be mediated by blockade
of sodium channels (43). Hertzberg and colleagues
used lamotrigine in a small double-blind trial of
patients with PTSD, and found it to be more effi-
cacious than placebo in reducing the severity of
symptoms of PTSD, including re-experience and
avoidance (44). VGCC inhibitors provide another
potential avenue for treatment of anxiety disorders
(see Table 1). For example, pregabalin, an anticon-
vulsant that binds to the alpha-2-delta protein to
block VGCC, has shown promise as a therapeutic
agent for generalized anxiety disorder (GAD) (45),
and might gain FDA approval by the end of 2007.
Consolidation and Reconsolidation
The conversion of labile, short-term memory
into long-term memory is called consolidation, in
a process dependent on protein synthesis (46, 47).
While originally thought to occur once, the process
in which transient information is permanently
stored may require new protein synthesis after re-
trieval (48, 49). The memory trace, upon retrieval,
is unstable and is required to undergo reconsolida-
tion before it can be restored (50). Typically, mem-
ories are not stored individually, but instead as as-
sociated complexes, in which all related compo-
nents are stored together (51). Recently, Debiec
and colleagues (52) used a second-order fear con-
ditioning (SOFC) paradigm, meaning that one CS
was linked to another CS to cause an US (53), to
test whether a blockade of protein synthesis would
disrupt one memory, or the entire associative net-
Figure. Fear conditioning circuitry.
In auditory fear conditioning, animals learn to fear an in-
nocuous tone. By pairing tone and shock, the tone acquires the
capacity to elicit defensive reactions, such as freezing (arrow
pointing up). Tone and shock stimuli converge in the lateral
amygdala (LA), resulting in associative plasticity in the tone—
LA pathway. Subsequent presentations of the tone can now ac-
tivate LA neurons. The LAthen communicates with the central
nucleus (CE), which controls the expression of fear by way of
connections to specific circuits that mediate freezing behavior.
The LA connects with CE directly and by way of connections
to other amygdala areas, including the intercalated cell masses
(ICM), which gate the output, and the basal nucleus (B), which
processes contextual information from the hippocampus.
Reproduced with permission, for electronic and print re-
production, from Sotres-Bayon F, Cain CK, Ledoux JE. Brain
mechanisms of fear extinction: historical perspectives on the
contribution of prefrontal cortex. Biol Psychiatry 2006,
60(4):329–336.
Vol. 73 No. 7 NEUROBIOLOGY OF ANXIETY DISORDERS—GARAKANI 945
work. They showed that only directly reactivated
memories become labile, but that indirectly reacti-
vated memories within the association complex are
not affected (54). These findings may play a role in
understanding how stressful events can be un-
learned, without causing amnesia for memories
temporally associated with the conditioned fear
stimulus.
Reconsolidation offers a model for anxiety as a
fear response in the absence of a US. It occurs via
repeated activation of a memory, which enhances
its retention (55). It is well established that emo-
tionally laden stimuli, when compared to neutral
stimuli, are more likely to be recalled, and are likely
to cause amnesia for words preceding it (56).
Reconsolidation requires involvement of
NMDA receptors and beta-adrenergic receptors,
with induction by the cyclic adenosine monophos-
phate response element binding protein (CREB)
(54). Propranolol, a central-acting, beta-adrenergic
receptor antagonist, has been consistently shown
to block recognition and recall of emotionally
laden words and memories (57–61), while pre-
serving neutral words. The drug also acts to restore
the amnesia caused by the emotional stimulus.
Furthermore, propranolol acts to block reconsoli-
dation only and does not interfere with integration
of new memories (62). These findings have led re-
searchers to test beta blockers in humans with trau-
matic experiences, in one case investigating the ef-
fects on recall of distressing memories (63). Pit-
man and colleagues conducted the only random-
ized controlled trial of propranolol in acute trauma
victims, who were administered the medication or
placebo within 6 hours of exposure to trauma and
continued for 10 days (64). Although they found
less severe symptoms of PTSD, as measured on the
Clinician-Administered PTSD Scale (CAPS), in
those receiving propranolol vs. placebo at 1 and 3
months (with three months being the point where
PTSD can first be diagnosed), the results were not
statistically significant. With improved study de-
sign and larger sample size, further studies are un-
derway to test the efficacy of beta-adrenergic re-
ceptors in the prevention of PTSD.
Extinction
In Pavlov’s experiment of classical condition-
ing, the dog ceased to salivate when the bell was
rung (CS) but no food was presented (US) (11).
This phenomenon is known as extinction. It does
not involve, as the name implies, erasure of old in-
formation, but rather it is caused by the integration
of new memory (65). The amygdala plays a key
role in fear extinction, as do the medial prefrontal
cortex (mPFC) and hippocampus. The LA is re-
sponsible for decreased firing with continued pre-
sentation of the CS, while the mPFC inhibits firing
of amygdala neurons, under the modulation of the
hippocampus (66). It is the mPFC that is thought to
regulate extinction of long-term memory (67). This
has been supported by studies showing blocking of
extinction after lesion of the mPFC (68), and by
blockade of protein synthesis in the mPFC (69). Ex-
posure to chronic stress can also affect the mPFC’s
ability to modulate extinction, via retraction of den-
drites (70, 71). Miracle and colleagues showed that
rats exposed to restraint stress showed reduction in
extinction 24 hours after initial extinction (72).
Much like in fear acquisition, an important
component of extinction is activation of gluta-
matergic NMDA receptors in the amygdala. It has
been shown that NMDA receptor antagonists, like
AP5, can cause blockade of extinction, as measured
by startle response (73). Conversely, partial NMDA
agonists, such as D-cycloserine (DCS), have been
shown to facilitate extinction. Walker and others
used systemic administration, and direct amygdalar
infusion, of DCS into rats, and found a decrease in
fear-potentiated startle to CS compared to control
animals (74). Ledgerwood’s group confirmed these
findings, and also determined that DCS not only
aided in extinction of the original CS, but also re-
duced but didn’t extinguish fear response to a CS
paired with another CS, (75). This suggests that
DCS may have an effect on extinction of general-
ized fearful stimuli, such as all furry objects, which
caused crying in Little Albert (see above).
Investigation of the use of DCS in humans with
anxiety disorders is already underway. Since DCS
acts only to enhance extinction to fear responses,
and is not a direct anxiolytic, it is used with expo-
sure therapy or CBT to show an effect. This was ev-
idenced by one small study that used DCS in PTSD
patients with limited effect, but did not employ con-
comitant psychotherapy (76). Ressler and col-
leagues used 2 single-dose administrations of DCS
2–4 hours prior to exposure therapy in patients
with phobic avoidance of heights, and found
marked reductions in fear and avoidance symptoms
that persisted for 3 months after treatment (77). A
recent trial used DCS to augment group exposure
therapy in patients with social anxiety disorder, and
found rapid improvement in symptoms in patients
compared to controls, who received exposure ther-
apy and pill placebo (78). In summary, DCS has
shown promise an adjunct treatment for patients
with anxiety disorder by enhancing the learning as-
sociated with the treatment.
The inability of a person to extinguish a mal-
adaptive fear response to a CS, due to a disruption
946 THE MOUNT SINAI JOURNAL OF MEDICINE November 2006
in the process of extinction, can result in persistent
anxiety. Two pathways for the treatment of anxiety
presented so far are the disruption of consolidation
of emotional or traumatic memories (see above),
and facilitation of the extinguishing of aversive
stimuli. The second area is under intense investi-
gation. In addition to using DCS, there are other
potential agents being used in animal studies to aid
in enhancing extinction. These include yohimbine,
an alpha-2-adrenoreceptor antagonist (79), L-type
VGCC agonists (27, 80), cannabinoid receptor 1
agonists (81, 82), and mu-opioid receptor blockers
(Table 2; 83, 84). Investigation of the applicability
of these mechanisms to humans is warranted.
Conclusion
Using Pavlovian conditioning as a model, the
pathophysiology of the fear response has been
clarified over the past several years. Many animal
studies have shown how these learning paradigms
can be applied to humans, and how they can be
used to understand the causes of anxiety. Imaging
studies, using functional magnetic resonance
imaging (MRI) and positron emission tomography
(PET) scanning, have helped trace and pinpoint the
areas of the brain responsible for induction, main-
tenance, and unlearning of fear. Although the
amygdala and prefrontal cortex are the primary
sites of fear acquisition and extinction, other areas
are being shown to play important roles as well. In
addition, there are neurochemical pathways, not
well understood, that may be proven to play a role
in anxiety disorders.
The DSM-IV currently categorizes the anxiety
disorders by clinical signs and symptoms. The
Committee of the DSM-V Prelude Project, is con-
sidering re-classifying the anxiety disorders by sev-
eral hypothetical approaches, including by etiology
(vulnerability genes and gene/environment interac-
tions) or by pathophysiology (neural pathways that
give rise to certain symptoms) (85). This may be
sensible, given the high comorbidity between mood
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 α
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 µopioid RB101(S), inhibitor 83, 84
of µopioid receptors retards µopioid 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.
Vol. 73 No. 7 NEUROBIOLOGY OF ANXIETY DISORDERS—GARAKANI 947
cuits as a means of categorization, certain disorders
marked by amygdala-centric fear pathways (such as
PD, PTSD, phobias) will be grouped together, while
GAD may be re-classified as a mood disorder.
While unable to cover all topics related to the
neurobiology of fear and anxiety, our report re-
viewed the pertinent findings in the area of fear con-
ditioning, including acquisition, reconsolidation, and
extinction. Finally, through investigation of these
pathways and neuropeptide systems, novel therapeu-
tic interventions can be found for a wide range of
anxiety disorders, such as generalized anxiety,
panic, phobias, and PTSD.
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