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The Role of the Amygdala in Anxiety Disorders

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Abstract

Benzodiazepines: While benzodiazepine receptors exist throughout the brain, there is a particularly high density in amygdala regions [215,216]. There is much evidence from animal models to suggest that it is the action of benzodiazepines in the amygdala that mediates their anxiolytic effect. For example, early evidence demonstrated that local amygdala infusion of benzodiazepines produces anxiolytic-like effects in conflict models of anxiety [217-220]. These effects can be reversed by systemic [217,219] or direct amygdala administration of benzodiazepine antagonists [220]. Anti-conflict effects are most apparent when the benzodiazepines are injected into the BLA, and are absent when injected into the CeA [219,220]. While anti-conflict effects of benzodiazepines have been observed in the CeA, these were with substantially higher doses [221]. Further studies suggest that the BLA and not the CeA is essential for the anxiolytic effects of benzodiazepines in the EPM [149,222,223]. However, with regards to the shock probe burying test, it appears that the CeA is responsible for benzodiazepine-induced impairment of passive avoidance [223]. Although contradictory results exist on the role of benzodiazepines in the BLA versus CeA, particularly when animals are tested on the EPM [9,84,224] have suggested that distinct benzodiazepine receptor subtypes located within subregions of the amygdala may differentially alter avoidance responses to “potential threat” (EPM and BLA) versus “discrete, unambiguous threat” (shock probe burying and CeA). β-Blockers: The evaluation of β-blockers (with propranolol being the prototypical agent) in animal models has revolved mainly around their utility in models of memory and fear conditioning. Within the BLA, stress hormone elicited increases in norepinephrine have been found to enhance the consolidation of emotionally relevant memories [231,232]. This appears to be particularly true with contextual fear conditioning [178] and reconsolidation of fear memory following extinction [180,197,233; Table 4]. In particular, local infusions of propranolol are able to block reconsolidation of fear [180,233]. Recently, it has been demonstrated that β-adrenoreceptor activation within the BLA decreases surface expression of GABAA receptors, and this phenomenon is necessary for the reinstatement of fear following extinction [234]. It is proposed that propranolol, through blocking the decrease in GABAA receptor surface expression, prevents fear reinstatement by maintaining feed forward inhibition from BLA interneurons and thus dampening activity of BLA projections [234]. This finding is noteworthy as it suggests that hyperactive noradrenergic activity in PTSD [235,236] may lead to reduced GABAA availability, explaining a potential mechanism for the relative ineffectiveness of benzodiazepines in PTSD populations [237,238].
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The Role of the Amygdala in Anxiety Disorders
Gina L. Forster, Andrew M. Novick, Jamie L. Scholl and Michael J. Watt
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/50323
1. Introduction
1.1. Defining anxiety and fear
Anxiety is a term often used to encompass feelings of apprehension, dread, unease or
similarly unpleasant emotions. Trait anxiety defines the affect of an organism over time and
across situations, whereas state anxiety is the response or adaptation to a given situation [1].
Anxiety can be differentiated from fear, both biologically and behaviorally [see 1 for an
extensive review]. Converging theories and evidence from clinical psychology and
comparative neuroscience suggest that fear can be considered a negatively-valenced
emotion that is brief, focused on the present, occurs in situations of specific threat, and aids
in avoidance or escape [1,2]. Anxiety, on the other hand, is a negatively-valenced emotion
that is characterized by sustained hyperarousal in response to uncertainty, is thus future-
focused, and aids in defensive approach or risk assessment [1,2]. Both anxiety and fear are
emotions experienced by all individuals and can serve to be adaptive in shaping decisions
and behaviors related to survival of an organism [1,3]. However, when excessive, or
pathological, or triggered inappropriately, fear and anxiety form the basis of a variety of
anxiety disorders [3,4,5; Table 1]. As illustrated by Table 1, some anxiety disorders such as
generalized anxiety disorder (GAD) or obsessive-compulsive disorder (OCD) are
characterized by excessive anxiety as defined above [1]. However, other anxiety disorders
are characterized, at least in part, by excessive and inappropriate fear, such as posttraumatic
stress disorder (PTSD), specific phobias and social anxiety disorder [1,3; Table 1]. Thus, it is
important to understand the neurobiology of both anxiety and fear to obtain a
comprehensive picture of the physiological basis of anxiety disorders.
1.2. Anxiety disorders
One in three people will develop one of the anxiety disorders outlined by Table 1 within
their life-time, with the life-time prevalence at least two times more likely for women [5,6].
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62
Furthermore, individuals may present with one or more comorbid anxiety disorders, and
anxiety disorders are highly likely to be comorbid with other psychiatric illnesses, such as
major depressive disorder, psychosis, mania, and substance abuse disorder [4-6]. Several
non-psychiatric disorders are also associated with anxiety disorders, and these include
hyperthyroidism, Cushing’s disease and mitral value prolapse [4,5]. Thus, anxiety disorders
are one of the most prevalent psychiatric disorders, posing great personal, economic, and
societal burdens [4-6].
Generalized Anxiety Disorder (GAD)
Excessive worry occurring more days than not over at least a 6 month period, accompanied
by restlessness, fatigue, sleep disturbances, muscle tension or irritability.
Posttraumatic Stress Disorder (PTSD)
Characterized by a history of trauma and symptoms related to avoidance, re-experiencing,
and physiological hyperarousal in the face of triggering cue.
Obsessive-Compulsive Disorder (OCD)
Compulsions (repeated actions) produced to reduce anxiety associated with obsessions
(unwanted, intrusive thoughts).
Panic Disorder
Characterized by panic attacks; a period of intense fear or discomfort accompanied by a
variety of physiological symptoms (e.g. sweating, trembling, chest pains, tachycardia).
Agoraphobia
Fear and avoidance of situations from which escape would be difficult in the event of
having panic-like symptoms.
Specific Phobia
Excessive or unreasonable fear in anticipation or in response to a specific object or
situation.
Social Anxiety Disorder (Social Phobia)
Excessive/unreasonable fear and avoidance of social situations (including performances) in
which the person is exposed to unfamiliar people or possible scrutiny by others.
Table 1. Major Classes of Anxiety Disorders [4,5,7]
1.3. Goals of the current review
The neurobiological bases of anxiety and fear appear to be very similar across species [1],
thus complementary findings from both animal models (most often rodents) and human
studies can contribute to theories of the neurobiological basis of anxiety disorders. State fear
within animal models is most often studied by measures of freezing and fear-potentiated
startle, both acquired via classical conditioning of rodents [1,8]. State anxiety, on the other
hand, is most often studied using apparatus such as an open field, elevated plus maze, or
light-dark box, which all take advantage of the rodent’s preference for familiar, dark, and/or
enclosed areas [1,9]. Notably, these paradigms do not rely on the processes underlying
classical conditioning, although McNaughton and Corr [2] caution against defining fear
verses anxiety as conditioned versus unconditioned responses. While trait fear is not well-
The Role of the Amygdala in Anxiety Disorders 63
defined by animal studies [1], trait anxiety is often examined in animal models by the use of
selective breeding, resulting in high- and low-anxiety strains and lines of rodents [for
example, see 1, 10]. However, one can argue that experimental manipulations (such as early-
life stress or amphetamine withdrawal) that drive a group of animals towards greater fear-
and anxiety-like phenotypes also examine the underlying basis of trait fear or anxiety [e.g.
11, 12]. As noted by Sylver et al [1] clinical studies most often examine trait anxiety, whereas
experiments involving animal models most often focus on state anxiety and fear, and then
relate these findings to concepts associated with trait anxiety. Regardless, both human and
animal studies suggest an important role for the amygdala, and subregions within, in
mediating fear and anxiety, and in the manifestation of anxiety disorders (Sections 2 and 3).
Therefore, the goals of this review are to first evaluate and integrate classical and recent
findings from human studies and relevant animal models that reveal the specific role the
amygdala plays in fear and anxiety, and then to elucidate how anxiolytic drugs may affect
the amygdala function to ameliorate heightened fear and/or anxiety. This is important,
given that traditional drug and cognitive behavioral therapy (CBT) are effective in reducing
symptoms of the various anxiety disorders for many individuals, but often do not provide
long-term relief, and relapse is a common post-treatment outcome [as reviewed by 3].
Therefore, the final goal of the current review is to identify future potential therapeutic
targets for the treatment of anxiety disorders.
2. Human imaging studies: Amygdala hyperfunction and anxiety
disorders
2.1. Amygdala reactivity and anxiogenic or fearful stimuli
Human imaging studies that explore the neurobiological bases of anxiety or fear processing
typically use functional magnetic resonance imaging (fMRI) or positron emission tomography
(PET) as measures of neural activity or cerebral blood flow. Imaging experiments that are
designed to study neural reactivity to fearful stimuli utilize either conditioned fear paradigms
similar to those used in animal models, or involve the presentation of unconditioned stimuli
such as fearful faces [1]. It has become clear that masked stimuli can elicit conditioned and
unconditioned fear responses from human subjects, suggesting unconscious, implicit
processing of these cues [as reviewed by 1]. Similarly, increased activity of the amygdala is
observed in response to both conditioned and unconditioned fearful stimuli, independent of
whether the subject is aware of the stimulus [1,13-16].
Comparable studies that have examined neural correlates of anxiety in healthy controls are
limited. One of the reasons for this is that many studies use fearful stimuli, such as the
fearful faces or conditioned fear paradigms [1], blurring the distinction between fear and
anxiety. Therefore, conclusions regarding neural bases of anxiety are better drawn from
studies that include trait anxiety as a variable while utilizing fearful stimuli, or those fewer
studies in which an anxiogenic situation is created within the experimental design. Like for
studies of fear processing, the majority of these studies show a relationship between trait
anxiety and greater amygdala reactivity [as reviewed by 17]. For example, a study of healthy
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64
subjects found that reactivity of the amygdala was positively correlated with anticipatory
anxiety, and when the anticipated event was imminent, amygdala activation positively
correlated with the degree of trait anxiety [18]. Furthermore, college students who scored in
the upper 15th percentile for trait anxiety show greater amygdala reactivity to emotional
faces as compared to students who scored in the normative range, suggesting that anxiety-
prone individuals have greater amygdala reactivity [19]. A similar hyperactivity of the
amygdala in high trait anxiety participants is noted when a masked emotional faces or
unattended faces paradigm are used [20,21], suggesting the individual does not need to be
aware of the stimulus to exhibit heightened amygdala activity. Interestingly, Etkin et al., [21]
differentiate between different subregions of the amygdala (see Section 3.1 for more details
on amygdala subregions), with the basolateral amygdala activated during masked
presentations of emotional faces while the dorsal/central amygdala was activated during
unmasked presentations. Thus, there may be subregion specificity within the amygdala
when processing unconscious versus conscious emotionally-valenced stimuli.
When gender has been examined as a factor in populations of healthy subjects, higher trait
anxiety is associated with greater amygdala responses to unattended fearful faces in female
but not male participants [22]. A further factor potentially mediating the relationship
between trait anxiety and amygdala reactivity appears to be perceived social support. To
illustrate, Hyde et al. [17] show a positive correlation between the degree of trait anxiety and
amygdala reactivity to fearful faces in subjects that report below-average social support, but
not in those who report above average support. Related, it is also thought that the degree of
social anxiety rather than trait anxiety may be more closely related to amygdala reactivity to
emotional faces [23]. These factors, and other similar considerations, may explain why some,
but not all, studies show a positive correlation between trait anxiety and amygdala
reactivity in non-patient populations [18-21,23].
2.2. Amygdala reactivity in anxiety disorders
Hyperactivity of the amygdala in response to negatively-valenced stimuli also appears to be
a common finding from a variety of clinical anxiety populations [16]. For example,
individuals suffering from social anxiety disorder show heightened amygdala responses to
both social and non-social highly emotive stimuli as compared to healthy control groups,
with the degree of social anxiety positively correlated with amygdala reactivity [24-27].
Furthermore, activation of the amygdala by non-social stimuli has been correlated with trait
anxiety in social anxiety disorder, leading to the conclusion that social anxiety disorder is
characterized by a more general dysfunction in emotional processing in addition to altered
processing of social stimuli and situations [26]. Importantly, reduced symptoms in a public
speaking situation following either CBT or antidepressant treatment was associated with
reduced amygdala reactivity [24], further suggesting a tight link between symptomology
and amygdala reactivity in social anxiety disorder.
Like social anxiety disorder, a commonly replicated finding from various PTSD populations
is hyperactivity of the amygdala in response to masked fearful faces or trauma-related
The Role of the Amygdala in Anxiety Disorders 65
stimuli [3,28,29]. This manifests as higher amygdala reactivity as compared to non-PTSD
groups and/or a positive correlation between severity of PTSD symptoms and amygdala
reactivity [28,30-33]. Furthermore, in a group of unmedicated acute PTSD subjects (1 month
post trauma), the degree of PTSD symptoms also positively correlated with activity of the
amygdala in response to masked fearful faces [34]. Thus, amygdala hyperactivity observed
in chronic PTSD appears early in the disorder. However, it should be noted that in these
same individuals, the degree of PTSD symptoms negatively correlated with activity in the
amygdala in response to unmasked fearful faces [34]. This suggests amygdala hypoactivity
in response to consciously-processed fearful stimuli in the early stages of PTSD, further
implying a dissociation in amygdala activity in response to consciously-processed versus
unconsciously-processed fearful stimuli. Interestingly, activity of the amygdala in response
to fearful stimuli might not only be characteristic of PTSD, but might predict treatment
outcome. Bryant et al [33] show that individuals diagnosed with PTSD that do not respond
to CBT (8 one weekly sessions) show significantly greater pre-treatment amygdala
activation in response to masked fearful faces as compared to those PTSD subjects who did
respond to CBT, as defined by a 50% or more reduction in scores on the Clinician-
Administered PTSD Scale (CAPS). Therefore, hyper-function of the amygdala might provide
a useful tool for future selections of treatment options for PTSD.
Similar to PTSD and social anxiety disorder, amygdala hyperactivity as a result of highly
emotional stimuli presentation or symptom provocation has been observed in specific
phobia, panic disorder, and OCD [35-38]. Given the prevalence of GAD, it is surprising that
few studies have assessed amygdala reactivity in GAD participants. Somewhat more
surprising is that of those studies that have determined amygdala activity in response to
emotive stimuli in adult GAD populations, a lack of amygdala hyperactivity has been
observed [27,39,40]. This stands in contrast to findings from pediatric GAD, where
hyperactivity of the amygdala is apparent in response to emotional stimuli and positively
correlated with symptom severity [41,42]. However, recent findings examining amygdala
function within paradigms that elicit anticipatory anxiety or emotional conflict have
implicated a role for amygdala hyper-reactivity in adult GAD populations. For example,
Nitschke et al. [43] report greater anticipatory amygdala activation in response to both
emotional and neutral images in adult GAD subjects. Furthermore, Etkin et al [44] found
that adult participants with GAD exhibited poor performance on a task that involved
emotional conflict (incongruent visual emotional stimuli), accompanied by a failure of the
frontal cortex to exert negative top-down control of amygdala activity (see Section 3.1 for
more on top-down control of the amygdala). Therefore, amygdala hypofunction in adult
GAD might be better revealed by imaging studies that create anxiogenic or conflict
situations, rather than the standard presentation of fearful stimuli. While this conclusion
requires direct testing, the findings that anxiogenic but not fearful stimuli reveal
hypofunction of the amygdala in GAD, whereas fearful stimuli consistently elicit amygdala
hyper-reactivity in other anxiety disorders (such as social anxiety disorder, PTSD and also
pediatric GAD), suggests a neural dichotomy between GAD and other anxiety disorders on
the anxiety to fear continuum.
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66
In summary, there appears to be reasonable overlap across various experimental paradigms
and study populations to conclude that the amygdala is reactive to fearful stimuli and
anxiogenic situations, and exhibits hyper-function to emotive stimuli, anxiogenic situations
and/or symptom provocation in anxiety disorders. However, which neurotransmitters and
subregions of the amygdala mediate these responses if often better answered by animal
studies, where spatial and neurochemical resolution is greatly improved over human
imaging studies.
3. Amygdala subregions, connectivity, neurotransmission and
fear/anxiety
3.1. The role of amygdala subregions in mediating fear and anxiety
As discussed above, hyper-function of the amygdala appears to be a key component of
human anxiety disorders. However, the contribution of particular amygdalar subregions in
the development and maintenance of this hyperactive state in humans is still being
established. Only very recently have refinements in the acquisition and analysis of fMRI
data allowed subregion function to be segregated effectively during emotional tasks such as
avoidance learning [45] and facial expression recognition [21,46]. Similarly, effective
structural identification of human amygdalar subregions and assessment of their functional
connectivity using imaging techniques is still fairly new [for example, see 47-51]. Therefore,
most of our understanding of causal neurochemical pathways in amygdalar circuitry related
to fear and anxiety has derived from extensive studies using rodent and non-human primate
models [for example, see 9,52-58].
Anatomical arrangement of the mammalian amygdala appears to have been evolutionarily
conserved, with particular subregions being connected to homologous brain structures
across species [as reviewed by 59]. The lateral (LA) nucleus of the amygdala is reciprocally
connected with the auditory, somatosensory and visual sensory association centers in the
temporal and insular cortices [59], and in rats also receives further auditory information via
projections from the posterior thalamus [59,60]. The medial amygdala (MeA) is reciprocally
connected with the accessory olfactory bulb and many hypothalamic and preoptic nuclei
[59,61], creating a locus for assimilation of olfactory stimuli and information regarding
internal hormonal state [62,63]. Information summated within the LA and MeA is then
conveyed to the adjacent basal (B) and accessory basal (AB) nuclei [64], which also receive
projections from the CA1 and subiculum areas of the ventral hippocampus [65-67]. The
B/AB nuclei send excitatory and inhibitory projections back to the LA and MeA [64,68],
creating a localized circuit that may assist in fine-tuning the filtering of sensory input into
these regions [64]. Excitatory projections from this basolateral (BLA) complex target the
central nucleus of the amygdala (CeA) either directly or via a series of GABAergic
interneurons known as intercalated (ITC) cells located between the BLA and CeA [69],
providing an effective means of gating CeA activity and output through a combination of
direct excitation and feed-forward inhibition [64,70,71]. The CeA itself, principally the medial
sector, sends GABAergic projections to brainstem, hypothalamic and basal forebrain regions
The Role of the Amygdala in Anxiety Disorders 67
that control expression of autonomic, hormonal and behavioral responses to emotive
situations 72,73]. It should also be noted that in addition to activating the CeA, the BLA
projects to the adjacent bed nucleus of the stria terminalis (BNST), which in turn targets many
of the same regions as the CeA to produce similar behavioral and physiological responses [73].
The MeA is also able to regulate these responses not only via its influence on hypothalamic
nuclei and brainstem targets, but by modulating activity in the BNST and CeA [61,64].
The functional connectivity between the BLA, MeA and CeA ensures that sensory and
contextual information associated with emotional situations, such as fearful or anxiogenic
circumstances, is channeled to effector regions to produce appropriate responses necessary
for survival. The BLA and CeA, unlike the MeA, do not appear necessary for expression of
unconditioned fear responses to olfactory stimuli in rodents, e.g., to novel presentation of
predator odor [74-76], although the BLA does appear to play a role in responses to other
types of unconditioned stimuli [77,78]. However, the functional arrangement of the BLA and
CeA with other regions facilitates learning about the situation, such that appropriate
reactions are maintained if cues associated with initial exposure are experienced again. The
BLA in particular appears to play a crucial role in encoding positive or negative salience to
relevant stimuli for future reference, as indicated by numerous studies showing that the
BLA is required for fear learning and acquisition of conditioned fear responses [see 56,60].
Once fear conditioning is acquired, the CeA is necessary for expression of the conditioned
response [56,60], the magnitude of which will be influenced by BLA gating of CeA activity
and output. Similarly, the BLA is needed for acquisition and expression of fear extinction
[79,80], which requires a subject to learn that expression of a previously conditioned fear
response is no longer necessary when the conditioned stimulus no longer predicts an
aversive event [57,81]. To achieve this, the BLA must integrate new sensory information
(absence of the unconditioned aversive stimulus) that will result in a dampening of CeA
excitation. This may result from increased BLA excitation of ITC cells during fear extinction
acquisition to enhance feed-forward inhibition of the CeA [79,82,83], followed by structural
remodeling within the BLA during consolidation of the extinction memory to inhibit later
BLA output [79]. However, while the roles of the BLA and CeA in fear behaviors are well
established, their contribution to anxiety is less clear, especially for the CeA. Animal studies
suggest that changes in BLA and CeA activity can alter state anxiety [9; also see Section 3.2.].
However, most investigations have focused on the BLA with the exact role of the CeA
remaining ill-defined [for example, see 84,85], although it appears that BLA to CeA circuitry
can directly regulate anxiety-like behavior as measured on the elevated plus maze [EPM,
86]. This direct control is thought to result from BLA excitation of GABAergic neurons in the
lateral CeA to induce feed-forward inhibition of output from the medial CeA [86], similar to
that induced by BLA excitation of ITC cells during fear extinction. Thus, suppression of CeA
output may be equally important for mediating expression of both fear and anxiety.
Alternatively, some studies have suggested that it is BLA activation of the BNST, not of the
CeA, that is responsible for mediating anxiety-like behavior as measured using light-
potentiated startle responses in rodents [56,87,88]. Startle responses are also potentiated by
corticotropin releasing factor (CRF) infused into the BNST [56]. This effect is presumed to
result through facilitation of glutamate release from BLA afferents by CRF neurons that
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68
originate in the lateral CeA [88,89], implying that even if BNST is the principal output center
for certain types of anxiety-like behaviors, the CeA may still play some modulatory role.
Furthermore, the MeA has been strongly implicated in animal models of state anxiety [for
example, see 90-93 and see Section 3.2], but whether its effects involve modulation of CeA
activity is unknown. To direct translational research into the neurological underpinning of
anxiety disorders more effectively, animal studies employing as wide a range of state
anxiety paradigms as possible, along with animal models that generate trait anxiety, are
required to establish the exact nature of CeA involvement and of amygdala subregion
interplay in mediating anxiety-like behavior.
It is important to remember that while the amygdala can mediate fear and anxiety-like
behavior, other brain regions play a major role in expression of these states, presumably by
influencing activity in particular amygdalar subregions to alter the balance of output from
the CeA. For example, input from the ventral hippocampus to the B/AB nuclei within the
BLA is required for expression of conditioned fear responses to contextual cues in rodents
and humans [60,94,95], and so receipt of this information presumably increases BLA
activity, to in turn enhance CeA output in the aversive context. In rodents, the ventromedial
prefrontal cortex (vmPFC) also appears to be crucial in regulating amygdalar activity,
especially during fearful experiences [79]. The prelimbic (PL) subregion of the vmPFC can
enhance conditioned fear expression via excitatory projections to the BLA and CeA [96-98].
In contrast, expression of conditioned fear appears to be decreased by activation of the
infralimbic (IL) subregion of the vmPFC [99, but see 100]. The IL cortex is also required for
effective consolidation and recall of fear extinction memories [79,98]. Both decreased
conditioned fear responding and fear extinction require suppression of CeA output, which
is thought to result in part via IL cortex stimulation of the series of inhibitory ITC cells that
project to the CeA [71,79,96,101]. The bidirectional roles of the PL and IL cortices in
regulating conditioned fear through opposing influences on CeA activity and output imply
that imbalance in the influence of either cortical structure could contribute to amygdala
hyperactivity seen in anxiety disorders characterized by excessive and inappropriate fear
(see Table 1). This is supported by fMRI studies investigating neural correlates of impaired
fear extinction in PTSD patients, who compared to healthy subjects show hyperactivity of
the amygdala during extinction learning [102]. This enhanced amygdala function in PTSD
patients is accompanied by greater activation of the dorsal anterior cingulate cortex (dACC,
functionally equivalent to the rodent PL cortex, [3,57], which is also present during recall of
the extinction memory [102]. This is in line with rodent studies demonstrating potentiated
fear conditioning upon PL cortex activation [98]. However, PTSD individuals exhibit
hypoactivation of the ventral portion of the vmPFC (equivalent to rodent IL cortex, [3,57])
during extinction learning and recall [102,103]. Human imaging studies also suggest that
impaired regulation of amygdala activity by the ventral vmPFC may contribute to anxiety
disorders characterized by hypervigilance in the absence of conditioned stimuli, such as in
GAD. Specifically, the strength of the connection between the vmPFC and the amygdala, as
measured using diffusion tensor imaging, predicts levels of self-reported trait anxiety, such
that weaker connections are seen in more anxious individuals [104]. As mentioned earlier
(Section 2.2), participants with GAD exhibited a failure of the vmPFC to exert negative top-
The Role of the Amygdala in Anxiety Disorders 69
down control of amygdala activity during a task that involved emotional conflict [44].
Further, resting state fMRI revealed that in anxious individuals, vmPFC activity was
negatively correlated with amygdala activity, while a positive relationship was observed for
low anxious subjects [105]. The combination of animal and human studies strongly indicates
that inadequate suppression by the ventral portion of the vmPFC, most likely of the CeA, is
a key factor in amygdala hyperactivity underlying the emergence of excessive fear and
anxiety states.
3.2. Monoaminergic neurotransmission in the amygdala: Relation to fear and
anxiety
The monoamine neurotransmitters (serotonin, dopamine and norepinephrine) have long
been associated with fear and anxiety, and drugs that alter monoaminergic function are
often effective across the range of anxiety disorders [8, 9, 52, 55]. Animal studies suggest a
variety of anxiogenic stressors or fearful stimuli increase monoamine levels in the amygdala.
To illustrate, increased serotonin (5-HT) release or increased activity of 5-HT neurons in the
amygdala have been observed in response to restraint or footshock, or in association with
expression of conditioned fear behavior [106-110]. Similarly, dopamine (DA) and
norepinephrine (NE) levels in the amygdala are increased following restraint, handling
stress, footshock or during the expression of conditioned fear behavior [107,111-118]. The
source of monoamines to the amygdala arise from monoaminergic cell body regions in the
brainstem. Specifically, the dorsal raphe nucleus (dRN) provides 5-HT innervation to the
amygdala, while NE and DA innervation of the amygdala arise from the locus coeruleus
(LC) and ventral tegmental area (VTA) respectively [55,119,120]. Regulation of
monoaminergic activity in the amygdala thus can occur at the level of these brainstem cell
body regions, or within the terminal regions of the amygdala.
One of the important mediators of amygdala monoaminergic activity in response to
anxiogenic or fearful stimuli is CRF. A strong body of evidence implicates central CRF in
mediating fear and anxiety [12,121-128], and recent clinical studies suggest an important
role for CRF in anxiety disorders [129]. Like anxiogenic and fearful stimuli, central infusion
of CRF or CRF receptor agonists increases 5-HT, NE and DA levels in the amygdala [130-
133], and stress-induced increases in monoamine levels in the amygdala are prevented by
CRF receptor antagonists [108,111]. It is thought that CRF regulation of monoaminergic
activity in the amygdala occurs at the level of the monoaminergic cell bodies. The
monoaminergic cell body regions receive CRF innervation from the CeA and BNST, and
CRF type 1 and 2 (CRF1 and CRF2) receptors are localized to the dRN, LC and VTA [134-
140]. Direct infusion of CRF or CRF receptor agonists into the dRN stimulates 5-HT release
in the CeA or BLA [131-133]. Interestingly, CRF-induced 5-HT release in the amygdala
appears to be dependent on CRF2 receptor activation in the dRN [131,133], and CRF2
receptors are known to increase 5-HT neuronal firing rates in the dRN [141]. Importantly,
increased neuronal surface expression of CRF2 receptors occurs in the dRN as a result of
stress [142], and increased expression of CRF2 receptors in the dRN has been observed in rat
models of high anxiety [11,128,137,143]. Furthermore, CRF2 receptor antagonists infused
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70
directly into the dRN reduce heightened anxiety-like behavior in rat models of
amphetamine withdrawal or early life stress [12,128]. Combined, these findings suggest that
CRF2 receptor modulation of 5-HT activity in the amygdala may play an important role in
heightened anxiety. While similar studies have not been performed to elucidate the role of
CRF receptors in the LC and VTA in mediating NE and DA activity in the amygdala and
anxiety states, some indirect evidence suggests an important role for CRF receptors in the
LC and VTA stress responses [136,138,144]. Overall, it is clear that further investigations are
needed to ascertain the role of CRF receptors in mediating NE and DA activity in the
amygdala and how CRF modulation of this activity could relate to fear or anxiety.
Studies demonstrating increased monoamine activity in the amygdala in response to
anxiogenic or fearful stimuli, and CRF modulation of these responses (as described above)
do not allow conclusions to be made about the specific role of each monoamine in mediating
anxiety or fear. Direct manipulation of monoaminergic activity within the amygdala or
specific amygdala subregions, and the measurement of resultant anxiety-like or fear-related
behaviors, have gone some way to providing a picture of how monoamine function in the
amygdala might translate to anxiety or fear. Table 2 summarizes such studies directly
manipulating 5-HT levels or 5-HT receptor activity in the amygdala. When 5-HT or 5-HT
activity is decreased in the entire amygdala [145,146], a consistent increase in anxiety-like
behavior is observed (Table 2). This would suggest that increased 5-HT activity in the
amygdala would thus be associated with decreased anxiety, implying an anxiolytic role of 5-
HT. However, this does not appear to be supported by experiments that directly manipulate
5-HT receptor activity in the amygdala with 5-HT receptor ligands (Table 2). For example,
activation of postsynaptic excitatory 5-HT2 or 5-HT3 receptors in the amygdala decreases
social interaction and increases anxiety-like behavior, whereas antagonism of 5-HT3
receptors in particular increases social interaction and decreases anxiety-like behaviors,
suggesting that 5-HT actions on postsynaptic receptors is anxiogenic (Table 2), although, see
[147] for an exception to this pattern. Similarly, activation of excitatory 5HT2 receptors in the
BLA generally increases anxiety-like behavior (Table 2), suggesting an anxiogenic role for
postsynaptic 5-HT receptors in the BLA (although an exception to this is observed, [148]). In
contrast, inhibitors of 5-HT2 receptors in the MeA increase anxiety-like behavior while
activation of these receptors increases social interaction and decreases anxiety behavior
(Table 2). Thus like the some findings from the amygdala as a whole (Table 2), 5-HT activity
in the MeA appears to play an anxiolytic role. The role of 5-HT or 5-HT receptors has not
been well studied in the CeA. However, rats undergoing amphetamine withdrawal that
exhibit greater anxiety-like behavior have greater 5-HT release in the CeA [12,133],
suggesting a similar anxiogenic relationship between 5-HT and anxiety as for the BLA.
Future work should determine whether 5-HT in the CeA reduces anxiety-like behaviors as is
suggestive for the MeA, or in contrast, increases anxiety-like behaviors as appears to be the
case for the BLA. Overall, the findings summarized in Table 2 suggest a dichotomy in the
potential role of 5-HT in the amygdala in mediating anxiety depending on whether the
entire amygdala or a specific subregion is targeted. Potential confounds in comparing the
studies listed in Table 2 could be the different paradigms used to measure anxiety-like
The Role of the Amygdala in Anxiety Disorders 71
behaviors and the relative selectivity of 5-HT receptor ligands across different experiments.
Future studies directly comparing the effects of 5-HT manipulations within the different
amygdala subregions across several well-validated tests of anxiety-like behaviors will better
elucidate the role of amygdala 5-HT in mediating anxiety.
Amygdala Subregion
Monoamine or
Receptor Involvement
Behavioral Outcome Citation
A
nxiety-like Behavio
r
Amygdala Decreased 5-HT
(induced by MDMA)
Increased anxiety
behavior
Faria et al. [145]
Amygdala Decreased 5-HIAA
(induced by stress)
Increased anxiety
b
ehavior
Niwa et al. [146]
Amygdala 5-HT1A agonist No change in anxiety
b
ehavior
Zangrossi and Graeff
[149]
Amygdala 5-HT2B/2C agonist Increased anxiety
b
ehavior
Cornelio and Nunes-
De-Souza [150]
Amygdala 5-HT3agonist Decreased social
interaction
Higgans et al. [151]
Amygdala 5-HT3agonist Decreased anxiety
b
ehavior
Costall et al. [147]
Amygdala 5-HT3antagonist Increased social
interaction
Higgans et al. [151]
Amygdala 5-HT3antagonist Decreased anxiety
b
ehavior
Costall et al. [147]
Amygdala 5-HT3antagonist Decreased anxiety
b
ehavior
Tomkins et al. [152]
BLA 5-HT1A agonist Decreased social
interaction
Gonzalez et al. [153]
BLA 5-HT1A agonist No change in anxiety
behavior
Gonzalez et al. [153]
BLA 5-HT2A agonist Increased anxiety
b
ehavior
Zangrossi and Graeff
[149]
BLA 5-HT2A
/
2C agonist No change in anxiety
b
ehavior
Cruz et al [148]
BLA 5-HT2C agonist Increased anxiety
behavior
Vincente et al. [154]
MeA 5-HT2A antagonist Increased anxiety
b
ehavior
Zangrossi and Graeff
[149]
MeA 5-HT2agonist No change in anxiety
b
ehavior
Duxon et al. [155]
MeA 5-HT2B agonist Increased social
interaction
Duxon et al. [156]
MeA 5-HT2B agonist Decreased anxiety
b
ehavior
Duxon et al. [155]
The Amygdala – A Discrete Multitasking Manager
72
Amygdala Subregion
Monoamine or
Receptor Involvement
Behavioral Outcome Citation
MeA 5-HT2B/2C agonist No change in anxiety
behavior
Duxon et al. [155]
Fear-related Behavio
r
CeA Increased 5-HT Increased
unconditioned
freezing
Forster et al. [132]
BLA Increased 5-HT Decreased
conditioned freezing
Inoue et al. [157]
BLA Increased 5-HT Decreased
unconditioned tonic
immobility
Leite-Panissi et al.
[158]
BLA 5-HT1A agonist Decreased
conditioned freezing
Li et al. [159]
BLA 5-HT1A agonist Decreased acquisition
and expression of
conditioned defeat
Morrison et al. [160]
BLA 5-HT1A/2 agonist Decreased
unconditioned tonic
immobility
Leite-Panissi et al.
[158]
Abbreviations: 5-HIAA = 5-Hydroxyindoleacetic acid (5-HT metabolite); 5-HT = serotonin; BLA = basolateral
amygdala; CeA = central nucleus of the amygdala; MDMA = 3,4-methylenedioxy-N-methylamphetamine; MeA =
medial amygdala.
Table 2. The Role of Serotonin in Anxiety-Like and Fear-Related Behaviors
Determining the role of amygdala 5-HT in fear-related behavior has mainly utilized studies
of freezing or immobility responses in rodents, and of 5-HT manipulation in the BLA (Table
2). From these studies, it seems clear that 5-HT in the BLA decreases the expression of
unconditioned and conditioned fear responses, likely via activation of the inhibitory
postsynaptic 5-HT1A receptor (Table 2). Thus, it has been suggested that 5-HT in the
BLA/amygdala ameliorates fear [8]. This conclusion is in contrast to the apparent role for
BLA 5-HT in enhancing anxiety (Table 2), suggesting a fear versus anxiety dissociation for
the role of 5-HT in the BLA. This dissociation, if upheld by more in-depth future work,
could prove important information for the development of treatment strategies for the
various anxiety disorders that differ in the degree of anxiety-like and fear-like
symptomology (as discussed in Section 1.1).
A role for amygdala DA in anxiety has not been as well explored as for 5-HT. However, a
summary of studies that have manipulated DA function in the amygdala provides a
consistent picture of the role of amygdala DA in mediating anxiety in animal models (Table
3). Indirect evidence suggests that decreased DA in the amygdala leads to increased anxiety,
and this is supported by direct manipulation of the CeA (Table 3). For example, decreased
DA or DA receptor antagonism within the CeA all increase anxiety-like behavior (Table 3),
The Role of the Amygdala in Anxiety Disorders 73
suggesting that DA activity in the CeA is anxiolytic. This role for DA in the CeA is in direct
contrast to the BLA, where converging evidence suggests that decreased DA function in the
BLA decreases anxiety-like behaviors while increased DA receptor activity in the BLA
increases anxiety (Table 3). Thus, DA activity in the BLA is anxiogenic, revealing an
opposite role for DA activity in the CeA and BLA in mediating anxiety-like behaviors in
animal models.
Amygdala Subregion
Monoamine or
Receptor Involvement
Behavioral Outcome
Citation
Anxiety-like Behavior
Amygdala Decreased DA Decreased rearing in
open field indicative
of increased anxiety
behavior
Summavielle et al.
[163]
CeA Decreased DA Decreased voluntary
activity indicative of
increased anxiety
behavior
Izumo et al. [164]
CeA D1 antagonist Increased anxiety
behavior
Rezayof et al. [165]
CeA D2/3 antagonist Increased anxiety
behavior
de la Mora et al. [166]
BLA DA depletion Decreased anxiety in
males but not females
Sullivan et al. [167]
BLA D1 agonist Increased anxiety
behavior
Banaej et al. [168]
BLA D2 agonist Increased anxiety
behavior
Banaej et al. [168]
BLA D1 antagonist Decreased anxiety
behavior
Banaej et al. [168]
BLA D1 antagonist Decreased anxiety
behavior
de la Mora et al. [169]
BLA D2 antagonist Decreased anxiety
behavior
Banaej et al. [168]
Fear-related Behavior
Amygdala D2 antagonist Decreased acquisition
and retention of fear
conditioning
Greba et al. [170]
CeA D1 agonist Increased conditioned
fear behavior
Guarraci et al. [171]
CeA D1 antagonist Inhibited conditioned
fear behavior
Guarraci et al. [171]
CeA D2 antagonist Decreased Guarraci et al. [172]
The Amygdala – A Discrete Multitasking Manager
74
Amygdala Subregion
Monoamine or
Receptor Involvement
Behavioral Outcome
Citation
conditioned fear
behavior
BLA DA depletion Decreased fear
conditioning
Seldon et al. [173]
BLA D1 antagonist Inhibited acquisition
of fear conditioning
Greba and Kokkinidis
[174]
BLA D2 antagonist Inhibited fear
potentiated startle
De Oliveira et al. [175]
Abbreviations: BLA = basolateral amygdala; CeA = central nucleus of the amygdala; DA = dopamine.
Table 3. The Role of Dopamine in Anxiety-Like and Fear-Related Behaviors
In contrast, the role of DA in mediating fear-related behaviors does not appear to differ
based on amygdala subregion (Table 3). Reducing DA function in the amygdala reduces or
inhibits processes associated with fear conditioning, while increasing DA receptor activity
increases conditioned fear (Table 3). Thus, DA in the amygdala is required for fear
conditioning, and enhanced DA levels in the amygdala as elicited by fearful stimuli and
conditioned cues [107,112] would thus facilitate fear conditioning. It should be noted that
the studies summarized by Table 3 indicate a role for both excitatory D1 receptors and
inhibitory D2 receptors. Dopamine D2 receptors are localized both pre- and post-
synaptically, with pre-synaptic D2 autoreceptors limiting DA neuronal activity and DA
release [161,162]. Thus, antagonism of presynaptic D2 receptors would actually increase DA
within the amygdala. Since the effects of D2 receptor antagonism on fear-related behaviors is
characteristic of reduced, not enhanced, DA function in the amygdala, it may be concluded
that the results of D2 receptor antagonism summarized by Table 3 are due to postsynaptic D2
receptor effects. However, this conclusion requires direct testing.
Very few studies have examined the role of amygdala NE in mediating anxiety-like
behavior in animal models, surprising given that anxiogenic stimuli increase NE in this
region [for example, see 111,115,116] and drugs that alter NE neurotransmission are used to
treat anxiety disorders [8]. There appears to be little role for NE receptors in the CeA in
mediating anxiety-like behavior, although infusion of a α1 antagonist can increase social
interaction following an anxiogenic stimulus [restraint; 176; Table 4]. It is clear that more
experiments are required to delineate the role of amygdala NE in mediating anxiety.
Studies determining the role of NE in fear-related behaviors have concentrated on the BLA,
due to the importance of this amygdala subregion in conditioned fear responses (see Section
3.1.). The major focus of the studies summarized by Table 4 has been on the role of NE in
fear conditioning and reconsolidation of fear memories in conditioned fear paradigms.
Taken as a whole, findings suggest that NE in the BLA facilitates fear conditioning and fear
memory, via activation of adrenergic β receptors (Table 4). Recent evidence suggests a role
for α1 receptors in the BLA in mediating fear memory, in this case, activation of α1 receptors
by NE would appear to decrease fear memory (Table 4). Thus, it is possible that NE in the
The Role of the Amygdala in Anxiety Disorders 75
BLA could have opposing effects on reconsolidation of fear memory based on the balance of
α1 versus β receptor activity – a hypothesis that requires direct testing. The role of NE in the
BLA (and β receptors in particular) in fear memory has generated interest in targeting this
NE system for the treatment of anxiety disorders where enhancement in fear memory is
apparent, such as PTSD [for example, see 177]. Whether NE within the BLA plays a role in
other aspects of fear processing (e.g. unconditioned fear responses to non-olfactory based
stimuli) or NE within other amygdala subregions mediate fear should be subjects of future
investigations to fully elucidate the role of amygdala NE in fear.
Amygdala Subregion
Monoamine or
Receptor Involvement
Behavioral Outcome
Citation
Anxiety-like Behavior
CeA α1 antagonist Increased social
interaction
Cecchi et al. [176]
CeA α1 antagonist No effect on anxiety
behavior
Cecchi et al. [176]
CeA β1/2 antagonist No effect on social
interaction
Cecchi et al. [176]
CeA β1/2 antagonist No effect on anxiety
behavior
Cecchi et al. [176]
Fear-related Behavior
BLA Increased NE Increased memory
and retention of fear
conditioning
LaLumiere et al. [178]
BLA Decreased NE Impaired fear
conditioning
Seldon et al. [173]
BLA Decreased NE Impaired fear
memory
Debiec and LeDoux
[177]
BLA α1 antagonist Increased fear
memory
Lazzaro et al. [179]
BLA β1/2 antagonist Impaired of fear
memory
Debiec and LeDoux
[180]
BLA β1 antagonist Impaired fear
memory (as enhanced
by glucocorticoids)
Roozendaal et al.
[181]
Abbreviations: BLA = basolateral amygdala; CeA = central nucleus of the amygdala; NE = norepinephrine.
Table 4. The Role of Norepinephrine in Anxiety-Like and Fear-Related Behaviors
In summary, it is clear that more work is required to fully understand the role of amygdala
monoamines in mediating fear and anxiety. However, several patterns of interest emerge
from the current literature, namely that there are distinct subregion differences in the role
The Amygdala – A Discrete Multitasking Manager
76
each monoamine plays in mediating anxiety and fear, with the one monoamine possibly
playing opposing roles depending on subregion or depending on whether anxiety or fear
measures are employed. Therefore, these findings suggest neurochemical dissociations
between amygdala subregions and monoamines in mediating fear or anxiety.
4. The amygdala as a potential site of anxiolytic drug action
Psychopharmacological management of anxiety disorders includes the benzodiazepines,
antidepressants, 5-HT1A agonists and various “off-label” drugs such as β-blockers, mood
stabilizers and antipsychotics. The mechanism by which these drugs produce anti-anxiety
effects has yet to be definitively established and represents a frequently updated field of
research. Because these drugs bind to target receptors throughout the brain, it is unlikely
that their efficacy can be attributed to action in one particular region. However, given the
role that the amygdala plays in fear and anxiety, modification of amygdala function by
pharmacological agents represents a likely mechanism of action as well as a target to guide
future drug development. The evidence for amygdala involvement in anxiolytic action
comes from both human imaging studies as well as work in animal models.
4.1. Human imaging studies: Effects of anxiolytics on amygdala activity and
emotion
Given the highly complex and subjective nature of anxiolytic drug response in humans,
neuroimaging represents an invaluable tool for drug evaluation and discovery.
Benzodiazepines: Benzodiazepines exert their anxiolytic action through binding to GABAA
receptors, which leads to enhanced GABA activity and a subsequent increase in inhibitory
tone. Despite the long history and current prevalence of benzodiazepine use for anxiety
disorders [182,183], there is a paucity of human neuroimaging studies utilizing this class of
drug, especially compared to those using antidepressants. This may have to do with eclipse
of benzodiazepines by antidepressants as first line agents for many anxiety disorders [182].
Various studies have utilized healthy volunteers undergoing experimental challenges in an
attempt to elucidate the neurobiology underlying the anxiolytic effect of benzodiazepines.
These studies have found that benzodiazepines have the ability to impair functions related
to amygdala activity including fear conditioning [184-186], recognition of fearful emotional
faces [187], and memory for emotional stimuli relative to neutral stimuli [188,189].
Neuroimaging work appears to support a role for the amygdala in benzodiazepine action,
although this may be dependent upon the nature of the accompanying neuropsychological
challenge. Specifically, lorazepam was found to decrease amygdala activation during an
emotional face assessment task without modifying baseline levels of anxiety or task
recognition [190]. A similar finding was found with diazepam, which decreased amygdala
response to fearful faces, and also impaired fearful face recognition [191]. However, during
anticipation of aversive electrical stimulation, lorazepam failed to produce changes in
amygdala activity [192]. Thus, while there is support for benzodiazepine induced
The Role of the Amygdala in Anxiety Disorders 77
modulation of the amygdala during processing of threatening/emotional stimuli, further
studies are needed to clarify the neural correlates of benzodiazepine-induced anxiolysis.
β-Blockers: The β-blocker propranolol has a substantial history of being utilized to reduce
somatic symptoms of fear and anxiety in situations such as stage fright [193] and acute panic
[194-195]. More recently, research on the role of amygdala NE and β-receptors in facilitating
emotional memory formation (see Table 4 and associated text) has caused much excitement
and controversy about the use of propranolol to prevent PTSD [196-198]. Thus far, initial
trials have demonstrated limited efficacy [199,200]. Despite lack of success in the application
of propranolol to PTSD, neuroimaging studies in healthy human subjects have confirmed
the ability of propranolol to modulate amygdala activation to emotional stimuli.
Propranolol was found to decrease amygdala activation to emotional faces irrespective of
emotional valence [201]. Furthermore, supporting a role for the amygdala NE in the
encoding and consolidation of emotional stimuli, a separate study found that propranolol
was able to decrease amygdala reactivity to emotional pictures of high valence as well as
decrease the subject’s memory for them [202].
Selective Serotonin Re-uptake Inhibitors: Antidepressant drugs, and selective serotonin re-
uptake inhibitors (SSRIs) in particular, have become first line drugs for many of the anxiety
disorders [182,203]. As such, there has been comparatively more work investigating these
drugs in humans using advanced imaging techniques.
Most antidepressants are unique from benzodiazepines and β-blockers in that a time lag
exists between initial treatment and onset of anxiolytic effects. In line with a potential
anxiogenic role of serotonin in the amygdala (see Table 2 and associated text), some patients
have reported an initial exacerbation of anxiety upon acute dosing of SSRIs [203]. In studies
on healthy subjects, acute dosing of the SSRI citalopram can enhance recognition of fearful
faces as well as increase emotion-potentiated startle response [204-206]. These effects are
reversed when citalopram treatment is continued for 7 days [207,208].
Attempts to correlate the acute versus sub-chronic effects of SSRIs with neural activation
have resulted in unexpected findings. On one hand, sub-chronic citalopram treatment was
found to decrease amygdala activation to unconscious fearful stimuli [209], suggesting a
relationship between repeated SSRI treatment, changes in emotional processing, and
decreased amygdala activity. However, acute doses of citalopram have also been found to
decrease amygdala activation to fearful faces [208,210,211]. Divergent effects of acute versus
sub-chronic citalopram on emotional recognition but similar effects on amygdala response
could suggest that the amygdala does not play a core role in acute SSRI-induced anxiety or
chronic SSRI-induced anxiolysis. However, it has been emphasized that the effects of
serotonergic challenge on fear recognition and amygdala activation appear to be dependent
upon the individual’s baseline sensitivity to threat [212], gender [213] and genotype [214].
Thus differences in subject profiles both between and within studies could have confounded
results.
Overall, it appears that pharmacotheraputics commonly used to treat anxiety disorders may
modulate amygdala function. In particular, it appears that anxiolytics can reduce amygdala
The Amygdala – A Discrete Multitasking Manager
78
reactivity to highly emotive or fearful stimuli. Given that amygdala hyper-reactivity to
similar stimuli is the most common finding across all anxiety disorders (with the exception
of adult GAD – see Section 2.2), it is possible that the anxiolytic effects of these drugs may be
in part, mediated by dampening amygdala function.
4.2. Evidence delineating effects of anxiolytic drugs on amygdala function in
animal models of anxiety states
Benzodiazepines: While benzodiazepine receptors exist throughout the brain, there is a
particularly high density in amygdala regions [215,216]. There is much evidence from
animal models to suggest that it is the action of benzodiazepines in the amygdala that
mediates their anxiolytic effect. For example, early evidence demonstrated that local
amygdala infusion of benzodiazepines produces anxiolytic-like effects in conflict models of
anxiety [217-220]. These effects can be reversed by systemic [217,219] or direct amygdala
administration of benzodiazepine antagonists [220]. Anti-conflict effects are most apparent
when the benzodiazepines are injected into the BLA, and are absent when injected into the
CeA [219,220]. While anti-conflict effects of benzodiazepines have been observed in the CeA,
these were with substantially higher doses [221]. Further studies suggest that the BLA and
not the CeA is essential for the anxiolytic effects of benzodiazepines in the EPM
[149,222,223]. However, with regards to the shock probe burying test, it appears that the
CeA is responsible for benzodiazepine-induced impairment of passive avoidance [223].
Although contradictory results exist on the role of benzodiazepines in the BLA versus CeA,
particularly when animals are tested on the EPM [9,84,224] have suggested that distinct
benzodiazepine receptor subtypes located within subregions of the amygdala may
differentially alter avoidance responses to “potential threat” (EPM and BLA) versus
“discrete, unambiguous threat” (shock probe burying and CeA).
As discussed in the human studies in Section 4.1 above [184,188,189], a key aspect of
benzodiazepine action may be the ability to modulate emotional memory. Here the BLA
once again appears to be a main site of benzodiazepine action. Lesions of the BLA, but not
the CeA, block the benzodiazepine induced deficits in inhibitory avoidance memory
[225,226]. Similar impairments were seen by direct injection of benzodiazepine into the BLA
and not the CeA [227]. Enhancement of memory consolidation could be induced by BLA
infusion of a benzodiazepine antagonist [228]. Given that individuals with anxiety disorders
may be hypervigilant to cues associated with threatening stimuli and biased to form
memories regarding such stimuli [229,230], the pro-amnestic effects of benzodiazepines in
the BLA may represent a putative mechanism of action.
β-Blockers: The evaluation of β-blockers (with propranolol being the prototypical agent) in
animal models has revolved mainly around their utility in models of memory and fear
conditioning. Within the BLA, stress hormone elicited increases in norepinephrine have
been found to enhance the consolidation of emotionally relevant memories [231,232]. This
appears to be particularly true with contextual fear conditioning [178] and reconsolidation
of fear memory following extinction [180,197,233; Table 4]. In particular, local infusions of
The Role of the Amygdala in Anxiety Disorders 79
propranolol are able to block reconsolidation of fear [180,233]. Recently, it has been
demonstrated that β-adrenoreceptor activation within the BLA decreases surface expression
of GABAA receptors, and this phenomenon is necessary for the reinstatement of fear
following extinction [234]. It is proposed that propranolol, through blocking the decrease in
GABAA receptor surface expression, prevents fear reinstatement by maintaining feed
forward inhibition from BLA interneurons and thus dampening activity of BLA projections
[234]. This finding is noteworthy as it suggests that hyperactive noradrenergic activity in
PTSD [235,236] may lead to reduced GABAA availability, explaining a potential mechanism
for the relative ineffectiveness of benzodiazepines in PTSD populations [237,238].
Despite the action of β-blockers within the amygdala to modulate fear conditioning (see
Table 4), attempts at testing propranolol in other animal models of PTSD have met with
mixed results, echoing the mixed efficacy seen thus far in humans [199,200,239,240]. One
such model is exposure to predator odor in rodents, which produces long lasting increases
in anxiety like behavior [241-243]. The increases in anxiety like behavior following exposure
to predator odor is influenced by a long lasting potentiation in BLA activity [243],
supporting the role of the amygdala in mediating the consequences of fear and trauma.
Propranolol administered 1 minute following exposure to predator odor to rats blocks the
development of anxiogenesis in various tests, including the EPM, one week later [241].
However, when propranolol administration is delayed to 1 hour following predator odor
exposure, no effects are seen when rats are subsequently tested on the EPM 30 days later
[242]. These results highlight once again a potential key role of timing if propranolol is to be
effectively implemented in clinical patients. Similarly, findings that propranolol seems most
effective in blocking the reconsolidation of fearful memories [233, 180, 197] (also see Table 4)
suggests that future work should be aimed at establishing protocols for the integration of
propranolol during exposure therapy, in which extinction and reconsolidation processes are
most active. Specifically, it would seem important that propranolol not be administered
shortly after exposure therapy, as this might interfere reconsolidation processes within the
amygdala. On the other hand, propranolol would likely have utility when PTSD patients
encounter aversive stimuli outside the context of therapy which could potentially
undermine the therapeutic process and lead to reinstatement.
Selective Serotonin Re-uptake Inhibitors: Similar to human studies, animal models of anxiety-
like behavior demonstrate divergent behavioral effects of acute versus chronic SSRI
administration. Increased anxiety-like behavior with acute treatment of SSRIs and its
reversal with chronic treatment has been found in novelty-suppressed feeding [244], EPM
testing [245,246], and the social interaction test [247]. While a large percentage of studies
reveal acute anxiogenic effects and chronic anxiolytic effect, there are exceptions (for review,
see [248]).
Much evidence suggests that enhanced activity at 5-HT2C within the BLA by SSRIs produces
acute anxiogenic effects, while the eventual downregulation of these receptors by chronic
treatment leads to eventual anxiolysis. For example, amygdala or BLA 5-HT2C receptors
have been found to produce anxiety-like responses in a variety of tests [249,250] (see Table
2). Blockade of 5-HT2C receptors within the BLA prevents the acute anxiogenic effect of the
The Amygdala – A Discrete Multitasking Manager
80
SSRI fluoxetine on the Vogel conflict test [251]. Systemic 5-HT2C antagonism also prevents
the increase in fear conditioning [252], decrease in social interaction [247,253], and escape
response to airjet [254] following acute SSRI treatment. Following chronic treatment with
SSRIs, 5-HT2C agonists have attenuated anxiogenic effects on the exacerbation of OCD
symptoms in humans [255,256], on social interaction [257] and hyperlocomotion [258],
suggesting down-regulation of the ability to 5-HT2C receptors in the amygdala to produce
anxiogenic responses following chronic SSRI treatment. Thus, the amygdala (BLA in
particular) may be an important locus of action for the long-term effects of SSRIs on anxiety.
4.3. Future potential anxiolytic targets
The literature reviewed above suggests that in part, the effects of anxiolytic drugs may be
mediated by altering amygdala function – either global dampening of the amygdala by
benzodiazepines, or specific actions on 5-HT and NE receptors within particular amygdala
subregions. However, to improve therapeutic efficacy and reduce relapse, several aspects of
amygdala pharmacology discussed above might provide useful potential anxiolytic targets
in the future.
Findings suggesting down-regulation of anxiogenic 5-HT2C receptors in the amygdala
following chronic SSRI treatment (Section 4.2.) present a potential strategy of reducing onset
latency of SSRIs as well as enhancing their effects. Specifically, blocking 5-HT2C receptors at
the initiation of SSRI treatment would be expected to produce a faster onset of anxiolytic
action. Currently, there are no selective 5-HT2C antagonists available for human use.
However, atypical antipsychotics [259] as well as atypical antidepressants such as
mirtazapine [260] possess 5-HT2C antagonist activity. While there is evidence that
antipsychotic augmentation of SSRIs may improve anxiolytic efficacy, their use has been
limited by poor tolerability [for review see 261]. Although research is lacking, mirtazapine
and the melatonin receptor agonist/5-HT2C receptor antagonist agomelatine [262] may
provide the advantage of targeting anxiogenic 5-HT2C in the amygdala with less side effects.
Furthermore, the recent observation that β-adrenoreceptor activation within the BLA results
in decreased of GABAA receptor surface expression necessary for fear reinstatement [234]
(and see Section 4.2.) suggests that the combination of propranolol and a benzodiazepine
may have unique benefit for PTSD. By blocking β-adrenoreceptors with propranolol, one
might be able to enhance benzodiazepine receptor availability, and increase
benzodiazepine-induced inhibition of fear circuits within the amygdala. While currently
speculative, the use of propranolol to enhance benzodiazepine action in the amygdala may
represent a potential creative treatment strategy in a population that is traditionally
refractory to benzodiazepine treatment.
While current pharmacotherapeutic strategies for the treatment of anxiety disorders target
monoamine function, this has predominantly been related to altering 5-HT or NE levels or
receptor activity [8]. However, Table 3 clearly shows a role for DA in the amygdala in
mediating both fear and anxiety, and the role for DA and both D1 and D2 receptors in
acquisition and retention of conditioned fear in particular appears quite robust. Thus,
The Role of the Amygdala in Anxiety Disorders 81
reducing DA function might serve as means by which to treat anxiety disorders in which
fear plays a major component. The obvious disadvantage of dopaminergic-based
pharmacotheraputics is potential for major cognitive and motoric side-effects, limiting the
treatment options with the currently available dopaminergic agents. Atypical antipsychotic
drugs incorporate DA receptor blocking activity while avoiding many of the motoric and
cognitive issues of traditional agents. There is evidence that atypical agents possess
anxiolytic activity [261], but metabolic side effects make them poorly tolerated. Furthermore,
because atypical antipsychotics also have high affinity for 5-HT receptors, the contribution
of DA modulation to their anxiolytic effects in humans is currently unknown. One potential
strategy may be the use of partial agonists to reduce DA activity in the amygdala via
activation of inhibitory presynaptic D2 autoreceptors. While non-selective for DA, the D2
partial agonist aripiprazole has demonstrated anxiolytic efficacy similar to other atypical
antipsychotic drugs [263]. In the future, more selective DA partial agonists may have
additional benefit without unwanted side-effects.
Finally, CRF has been identified as an important neuropeptide in the regulation of
monoaminergic activity in the amygdala in response to anxiogenic or fearful stimuli (Section
3.2). Furthermore, CRF and its receptors (CRF1 and CRF2) are implicated in fear and anxiety
within animal models and in the development of anxiety disorders [12,121-129]. Upon the
development of non-peptide CRF1 receptor antagonists that cross the blood-brain barrier,
there was great interest in the use of CRF1 receptor antagonist in the treatment of anxiety
disorders. To date, there have been limited phase II clinical trials published regarding the
use of CRF1 receptor antagonists in anxiety disorders [264]. Of those, preliminary findings
suggest the CRF1 receptor antagonist-treated groups did not differ from placebo-treated
groups in anxiety symptomology in both social anxiety disorder and GAD [264]. However,
it has been suggested that efficacious concentrations have not been established for the
various CRF1 receptor antagonists, and it is clear that further clinical trials are necessary.
One potential promising area in the treatment of anxiety disorders may actually lie in CRF2
receptor antagonists. As outlined in Section 3.2, CRF2 receptors mediate 5-HT activity in the
amygdala, are up-regulated in animal models of anxiety, and an antagonist of this receptor
reduces heightened anxiety in rats [11,12,127,128,131,132,137). The challenge lies in
developing non-peptide CRF2 receptor antagonists that cross the blood-brain barrier, so that
the efficacy of such ligands can be determined for anxiety disorders.
5. Conclusion
Human imaging studies in non-patient populations suggest amygdala activation in
response to fearful stimuli, and that the magnitude of this response is positively correlated
with trait anxiety. Furthermore, individuals suffering from an anxiety disorder (with the
possible exception of adult GAD) show exaggerated amygdala responses to fearful or
emotive stimuli, which again is positively correlated with the severity of symptoms.
Moreover, reactivity of the amygdala to fearful stimuli is reduced by anxiolytic drugs in
healthy subjects, and long-term pharmacotherapy or CBT reduces amygdala hyper-
reactivity in anxiety disorders. Animal studies corroborate an important role for the
The Amygdala – A Discrete Multitasking Manager
82
amygdala in fear and anxiety, with specific subregions mediating acquisition and expression
of fear, fear memories and anxiety, and the monoamines within each of these regions often
playing a very specific role in facilitating or attenuating fear or anxiety. Both human and
animal studies suggest dysfunction of the amygdala might arise in part, from inadequate
top-down control by regions such as the medial prefrontal cortex, and in part, from altered
neuropeptide regulation of amygdala monoaminergic systems. Overall, the amygdala plays
a critical role in anxiety disorders, and understanding the function of this region in fear and
anxiety states and how dysfunction of the amygdala results in anxiety disorders is critical to
improving long-term treatment outcomes.
Author details
Gina L. Forster*, Andrew M. Novick, Jamie L. Scholl and Michael J. Watt
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota,
Vermillion, SD, USA
Acknowledgement
This work was supported by National Institutes of Health grant R01 DA019921, and
Department of Defense grants W81XWH-10-1-0925 and W81XWH-10-1-0578.
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... It has been shown that olfactory projections to the cortical amygdala can also trigger BLA neurons 52 which synapse with the important contingent of GABA ergic forward inhibitory neurons in the lateral (CeL) and medial (CeM) division of the central amygdala involved in the modulation of fear and anxiety. 42,44,48,49,[53][54][55][56] More recent evidence shows that GABA ergic -PKCδ-positive OFFneurons in the CeL facilitate the release of neuropeptide S (NPS) in the LC and GABA from anterolateral BNST through forward inhibition of GABA ergic neurons in the CeM, and there is concurrent inhibition of NE, DA, and 5-HT release from the midbrain and decreased sympathetic system tone through inhibition of neurons in the posterior HYP. 42,51,[53][54][55][56][57][58][59][60][61] Furthermore, neural inputs from the BLA reach GABA ergic -PKCδ-negative ON-neurons in the CeL. ...
... 42,44,48,49,[53][54][55][56] More recent evidence shows that GABA ergic -PKCδ-positive OFFneurons in the CeL facilitate the release of neuropeptide S (NPS) in the LC and GABA from anterolateral BNST through forward inhibition of GABA ergic neurons in the CeM, and there is concurrent inhibition of NE, DA, and 5-HT release from the midbrain and decreased sympathetic system tone through inhibition of neurons in the posterior HYP. 42,51,[53][54][55][56][57][58][59][60][61] Furthermore, neural inputs from the BLA reach GABA ergic -PKCδ-negative ON-neurons in the CeL. It has been reported that CeL outputs via an intercalated feed-forward series of GABA ergic interneurons and also through CRH neurons can stimulate glutamatergic neurons in the BNST oval area and in the prefrontal cortex, with concurrent stimulation of NE, DA, and serotonin release from the midbrain (LC, VTA, and RN), (Figure 3). ...
... We hypothesize that the PH94B-induced rapid decrease (latency ≤ 400 ms) of sympathetic tone 64 and rapid improvement (latency = 10-15 minutes) in performance anxiety and social interaction anxiety 24,25 are triggered by sensory inputs originating in nasal chemosensory neurons that stimulate subset of OB neurons projecting to the MeA and BLA. There is evidence that MeA and BLA neurons trigger the forward inhibitory GABA ergic -PKCδ-positive OFF-neurons in the CeL and CeM amygdala, which downstream effects mediating behavioral actions that directly mediate social behavior, fear, and anxiety 51,52,56,63,64 (Figure 3). The modulation of neural circuits involved in the pathogenesis of social anxiety disorder [55][56][57]59,[65][66][67][68] appears to be consistent with the PH94B-induced acute anxiolytic effects and autonomic nervous system changes reported in our clinical studies in patients diagnosed with social anxiety disorder. ...
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... The brain regions most crucial in regulating negative emotions such as anxiety are a set of limbic structures with the amygdala being a focal point [8]. A common finding from a variety of clinical anxiety disorders including social anxiety disorder, post-traumatic stress disorder (PTSD), obsessive compulsive disorder, phobias, and panic disorder is hyperactivity of the amygdala in response to negatively valanced stimuli [9]. Of particular interest is the brain GABAergic system, which is central to the regulation of anxiety. ...
... The brain regions most crucial in regulating anxiety are a set of limbic structures, including the amygdala and hippocampus, which are intertwined and intimately connected with the olfactory neuroanatomy via extensive reciprocal axonal connections [7,8]. The amygdala and hippocampus are commonly associated in anxiety disorders, PTSD, and dementia [9][10][11]. Studies have supported the role of GABAergic neurotransmission in the amygdala in regulating anxiety-related behaviours [8]. ...
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... Human and animal studies indicate important roles for the amygdala in mediating fear and anxiety, and in the manifestation of anxiety disorders (Forster et al., 2012), thus we also examined the effects of BLA BayK injection on long-term anxiety in juvenile rats (Fig. 4D). The results show that animals treated with BayK at P7 (DMSO: 62.5 6 12.3 ms, n = 9, BayK: 35.9 6 5.1 ms, n = 15; p = 0.03) exhibit a significant decrease in time spent in the center of the area, indicating a higher level of anxiety at P28 compared with DMSO treatment. ...
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Postnatal CNS development is fine-tuned to drive the functional needs of succeeding life stages; accordingly, the emergence of sensory and motor functions, behavioral patterns and cognitive abilities relies on a complex interplay of signaling pathways. Strictly regulated Ca2+ signaling mediated by L-type channels (LTCCs) is crucial in neural circuit development and aberrant increases in neuronal LTCC activity are linked to neurodevelopmental and psychiatric disorders. In the amygdala, a brain region that integrates signals associated with aversive and rewarding stimuli, LTCCs contribute to NMDA-independent long-term potentiation (LTP) and are required for the consolidation and extinction of fear memory. In vitro studies have elucidated distinct electrophysiological and synaptic properties characterizing the transition from immature to functionally mature basolateral subdivision of the amygdala (BLA) principal neurons. Further, acute increase of LTCC activity selectively regulates excitability and spontaneous synaptic activity in immature BLA neurons, suggesting an age-dependent regulation of BLA circuitry by LTCCs. This study aimed to elucidate whether early life alterations in LTCC activity subsequently affect synaptic strength and amygdala-dependent behaviors in early adulthood. In vivo intra-amygdala injection of an LTCC agonist at a critical period of postnatal neurodevelopment in male rat pups was used to examine synaptic plasticity of BLA excitatory inputs, expression of immediate early genes (IEGs) and glutamate receptors, as well as anxiety and social affiliation behaviors at a juvenile age. Results indicate that enhanced LTCC activity in immature BLA principal neurons trigger persistent changes in the developmental trajectory to modify membrane properties and synaptic LTP at later stages, concomitant with alterations in amygdala-related behavioral patterns.
... In the current study, we aimed to detect the subtle dysfunction of the amygdala network in individuals with HTA from both static and dynamic perspectives. Based on the findings from previous functional connectivity studies in anxiety disorders (Forster et al., 2012;Makovac et al., 2016;Porta-Casteràs et al. 2020), we hypothesized that anomalous sFC and dFC patterns would be observed in the subregions of the amygdala in individuals with HTA: Insufficient control over the negative emotional response of the CMA by the ECN from top to bottom may induce a reduction in the sFC between CMA and ECN; The more salience information detection about self-relevant cognition may show abnormal sFC and dFC between the BLA and SN for HTA individuals; as the SFA is involved in both the processing of socially relevant information and the modulation of approach-avoidance behaviors, it may show abnormal sFC with the visual network related to social information detection. ...
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... The LA is a key brain region for fear extinction and anxiety-like behaviors (Jacques et al., 2019;Erlich et al. 2012;Grosso et al., 2018;Kim et al. 2007Kim et al. , 2015Krabbe et al. 2018;Mahan and Ressler 2012;Schafe et al. 2005;Forster et al., 2012;Ressler 2010). CaMKII plays an important role in memory extinction (Bevilaqua et al., 2006;Szapiro et al., 2003;Burgdorf et al., 2017). ...
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