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]. 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. |
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-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 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 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.
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 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 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-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 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 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 |
Amygdala | Decreased 5-HT (induced by MDMA) | Increased anxiety behavior | Faria et al. [145] |
Amygdala | Decreased 5-HIAA (induced by stress) | Increased anxiety behavior | Niwa et al. [146] |
Amygdala | 5-HT1A agonist | No change in anxiety behavior | Zangrossi and Graeff [149] |
Amygdala | 5-HT2B/2C agonist | Increased anxiety behavior | Cornelio and Nunes-De-Souza [150] |
Amygdala | 5-HT3 agonist | Decreased social interaction | Higgans et al. [151] |
Amygdala | 5-HT3 agonist | Decreased anxiety behavior | Costall et al. [147] |
Amygdala | 5-HT3 antagonist | Increased social interaction | Higgans et al. [151] |
Amygdala | 5-HT3 antagonist | Decreased anxiety behavior | Costall et al. [147] |
Amygdala | 5-HT3 antagonist | Decreased anxiety behavior | 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 behavior | Zangrossi and Graeff [149] |
BLA | 5-HT2A/2C agonist | No change in anxiety behavior | Cruz et al [148] |
BLA | 5-HT2C agonist | Increased anxiety behavior | Vincente et al. [154] |
MeA | 5-HT2A antagonist | Increased anxiety behavior | Zangrossi and Graeff [149] |
MeA | 5-HT2 agonist | No change in anxiety behavior | Duxon et al. [155] |
MeA | 5-HT2B agonist | Increased social interaction | Duxon et al. [156] |
MeA | 5-HT2B agonist | Decreased anxiety behavior | Duxon et al. [155] |
MeA | 5-HT2B/2C agonist | No change in anxiety behavior | Duxon et al. [155] |
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] |
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), 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 |
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] |
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 conditioned fear behavior | Guarraci et al. [172] |
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] |
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 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 |
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] |
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] |
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 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.
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 modulation of the amygdala during processing of threatening/emotional stimuli, further studies are needed to clarify the neural correlates of benzodiazepine-induced anxiolysis.
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 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
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.
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
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 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, 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 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.
AcknowledgementThis 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.
References
- 1.
Sylvers P. Lilienfeld S. O. La Prairie J. L. 2011 Differences between Trait Fear and Trait Anxiety: Implications for Psychopathology. Clin Psychol Rev.31 122 137 S0272-7358(10)00131-5 [pii] 10.1016/j.cpr.2010.08.004. - 2.
Mc Naughton N. Corr P. J. 2004 A Two-Dimensional Neuropsychology of Defense: Fear/Anxiety and Defensive Distance. Neuroscience & Biobehavioral Reviews.28 285 305 j.neubiorev.2004.03.005. - 3.
Graham BM, Milad MR 2011 The Study of Fear Extinction: Implications for Anxiety Disorders. Am J Psychiatry.168 1255 1265 appi.ajp.2011.11040557 appi.ajp.2011.11040557 [pii]. - 4.
Ninan PT 2001 Recent Perspectives on the Diagnosis and Treatment of Generalized Anxiety Disorder. Am J Manag Care. 7, S367 376 - 5.
Alexander J. L. Dennerstein L. Kotz K. Richardson G. 2007 Women, Anxiety and Mood: A Review of Nomenclature, Comorbidity and Epidemiology. Expert Rev Neurother. 7, S45 58 - 6.
Katzman MA 2009 Current Considerations in the Treatment of Generalized Anxiety Disorder. CNS Drugs.23 103 120 - 7.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association;1994 - 8.
Inoue T. Kitaichi Y. Koyama T. 2011 SSRIs and Conditioned Fear. Progress in Neuro-Psychopharmacology and Biological Psychiatry.35 1810 1819 j.pnpbp.2011.09.002. - 9.
Engin E. Treit D. 2008 The Effects of Intra-Cerebral Drug Infusions on Animals’ Unconditioned Fear Reactions: A Systematic Review. Prog Neuropsychopharmacol Biol Psychiatry.32 1399 1419 j.pnpbp.2008.03.020. - 10.
ME Keck Sartori. S. B. Welt T. Müller M. B. Ohl F. Holsboer F. Landgraf R. Singewald N. 2005 Differences in Serotonergic Neurotransmission between Rats Displaying High or Low Anxiety/Depression-Like Behaviour: Effects of Chronic Paroxetine Treatment. J Neurochem.92 1170 1179 j.1471-4159.2004.02953.x. - 11.
Lukkes JL, Mokin MV, Scholl JL, Forster GL 2009 Adult Rats Exposed to Early-Life Social Isolation Exhibit Increased Anxiety and Conditioned Fear Behavior, and Altered Hormonal Stress Responses. Horm Behav.55 248 256 - 12.
Vuong SM, Oliver HA, Scholl JL, Oliver KM, Forster GL 2010 Increased Anxiety-Like Behavior of Rats During Amphetamine Withdrawal Is Reversed by Crf2 Receptor Antagonism. Behavioural Brain Research.208 278 281 - 13.
Furmark T. Fischer H. Wik G. Larsson M. Fredrikson M. 1997 The Amygdala and Individual Differences in Human Fear Conditioning. Neuroreport.8 3957 3960 - 14.
Whalen P. J. Bush G. Mc Nally R. J. Wilhelm S. Mc Inerney S. C. MA Jenike Rauch. S. L. 1998 The Emotional Counting Stroop Paradigm: A Functional Magnetic Resonance Imaging Probe of the Anterior Cingulate Affective Division. Biol Psychiatry.44 1219 1228 - 15.
Liddell B. J. Brown K. J. Kemp A. H. MJ Barton Das. P. Peduto A. Gordon E. Williams L. M. 2005 A Direct Brainstem-Amygdala-Cortical ‘Alarm’ System for Subliminal Signals of Fear. Neuroimage.24 235 243 j.neuroimage.2004.08.016. - 16.
Etkin A,Wager TD 2007 Functional Neuroimaging of Anxiety: A Meta-Analysis of Emotional Processing in Ptsd, Social Anxiety Disorder, and Specific Phobia. Am J Psychiatry.164 1476 1488 appi.ajp.2007.07030504. - 17.
Hyde L. W. Gorka A. Manuck S. B. Hariri A. R. 2011 Perceived Social Support Moderates the Link between Threat-Related Amygdala Reactivity and Trait Anxiety. Neuropsychologia.49 651 656 j.neuropsychologia.2010.08.025. - 18.
Carlson J. M. Greenberg T. Rubin D. Mujica-Parodi L. R. 2011 Feeling Anxious: Anticipatory Amygdalo-Insular Response Predicts the Feeling of Anxious Anticipation. Soc Cogn Affect Neurosci.6 74 81 scan/nsq017. - 19.
Stein MB, Simmons AN, Feinstein JS, Paulus MP 2007 Increased Amygdala and Insula Activation During Emotion Processing in Anxiety-Prone Subjects. Am J Psychiatry.164 318 327 appi.ajp.164.2.318. - 20.
Bishop S. Duncan J. Brett M. Lawrence A. D. 2004 Prefrontal Cortical Function and Anxiety: Controlling Attention to Threat-Related Stimuli. Nat Neurosci.7 184 188 - 21.
Etkin A. Klemenhagen K. C. Dudman J. T. Rogan M. T. Hen R. Kandel E. R. Hirsch J. 2004 Individual Differences in Trait Anxiety Predict the Response of the Basolateral Amygdala to Unconsciously Processed Fearful Faces. Neuron.44 1043 1055 j.neuron.2004.12.006. - 22.
Dickie EW, Armony JL 2008 Amygdala Responses to Unattended Fearful Faces: Interaction between Sex and Trait Anxiety. Psychiatry Research: Neuroimaging.162 51 57 j.pscychresns.2007.08.002. - 23.
Ball T. M. Sullivan S. Flagan T. CA Hitchcock Simmons. A. Paulus M. P. Stein M. B. 2012 Selective Effects of Social Anxiety, Anxiety Sensitivity, and Negative Affectivity on the Neural Bases of Emotional Face Processing. Neuroimage.59 1879 1887 j.neuroimage.2011.08.074. - 24.
Furmark T. Tillfors M. Marteinsdottir I. Fischer H. Pissiota A. Langstrom B. Fredrikson M. 2002 Common Changes in Cerebral Blood Flow in Patients with Social Phobia Treated with Citalopram or Cognitive-Behavioral Therapy. Arch Gen Psychiatry.59 425 433 - 25.
Shah S. G. Klumpp H. Angstadt M. Nathan P. J. Phan K. L. 2009 Amygdala and Insula Response to Emotional Images in Patients with Generalized Social Anxiety Disorder. Journal of Psychiatry & Neuroscience.34 296 302 - 26.
Brühl A. B. Rufer M. Delsignore A. Kaffenberger T. Jäncke L. Herwig U. 2011 Neural Correlates of Altered General Emotion Processing in Social Anxiety Disorder. Brain Res.1378 72 83 j.brainres.2010.12.084. - 27.
Blair K. Shaywitz J. Smith B. W. Rhodes R. Geraci M. Jones M. Mc Caffrey D. Vythilingam M. Finger E. Mondillo K. Jacobs M. DS Charney Blair. R. J. Drevets W. C. DS Pine 2008 Response to Emotional Expressions in Generalized Social Phobia and Generalized Anxiety Disorder: Evidence for Separate Disorders. Am J Psychiatry.165 1193 1202 appi.ajp.2008.07071060. - 28.
Rauch SL, Shin LM, Phelps EA 2006 Neurocircuitry Models of Posttraumatic Stress Disorder and Extinction: Human Neuroimaging Research--Past, Present, and Future. Biol Psychiatry.60 376 382 - 29.
Jovanovic T. Norrholm S. D. 2011 Neural Mechanisms of Impaired Fear Inhibition in Posttraumatic Stress Disorder. Frontiers in Behavioral Neuroscience. 5, 10.3389/fnbeh.2011.00044. - 30.
Liberzon I. Abelson J. L. Flagel S. B. Raz J. Young E. A. 1999 Neuroendocrine and Psychophysiologic Responses in Ptsd: A Symptom Provocation Study. Neuropsychopharmacology.21 40 50 - 31.
Shin LM, Orr SP, Carson MA, Rauch SL, Macklin ML, Lasko NB, Peters PM, Metzger LJ, Dougherty DD, Cannistraro PA, Alpert NM, Fischman AJ, Pitman RK 2004 Regional Cerebral Blood Flow in the Amygdala and Medial Prefrontal Cortex During Traumatic Imagery in Male and Female Vietnam Veterans with Ptsd. Arch Gen Psychiatry.61 168 176 - 32.
Shin L. M. Wright C. I. Cannistraro P. A. MM Wedig Mc Mullin. K. Martis B. Macklin M. L. Lasko N. B. Cavanagh S. R. Krangel T. S. Orr S. P. Pitman R. K. Whalen P. J. Rauch S. L. 2005 A Functional Magnetic Resonance Imaging Study of Amygdala and Medial Prefrontal Cortex Responses to Overtly Presented Fearful Faces in Posttraumatic Stress Disorder. Arch Gen Psychiatry.62 273 281 - 33.
Bryant R. A. Felmingham K. Kemp A. Das P. Hughes G. Peduto A. Williams L. 2008 Amygdala and Ventral Anterior Cingulate Activation Predicts Treatment Response to Cognitive Behaviour Therapy for Post-Traumatic Stress Disorder. Psychological Medicine.38 555 561 doi:10.1017/S0033291707002231. - 34.
Armony J. L. Corbo V. Clement M. H. Brunet A. 2005 Amygdala Response in Patients with Acute Ptsd to Masked and Unmasked Emotional Facial Expressions. Am J Psychiatry.162 1961 1963 - 35.
Dilger S. Straube T. Mentzel-J H. Fitzek C. Reichenbach J. R. Hecht H. Krieschel S. Gutberlet I. Miltner W. H. R. 2003 Brain Activation to Phobia-Related Pictures in Spider Phobic Humans: An Event-Related Functional Magnetic Resonance Imaging Study. Neurosci Lett.348 29 32 s0304-3940(03)00647-5. - 36.
Schienle A. Schäfer A. Walter B. Stark R. Vaitl D. 2005 Brain Activation of Spider Phobics Towards Disorder-Relevant, Generally Disgust- and Fear-Inducing Pictures. Neurosci Lett.388 1 6 j.neulet.2005.06.025. - 37.
van den Heuvel. O. A. Veltman D. J. Groenewegen H. J. Witter M. P. Merkelbach J. Cath D. C. van Balkom A. J. L. M. van Oppen P. van Dyck R. 2005 Disorder-Specific Neuroanatomical Correlates of Attentional Bias in Obsessive-Compulsive Disorder, Panic Disorder, and Hypochondriasis. Arch Gen Psychiatry.62 922 933 archpsyc.62.8.922. - 38.
Straube T. Mentzel-J H. Miltner W. H. R. 2006 Neural Mechanisms of Automatic and Direct Processing of Phobogenic Stimuli in Specific Phobia. Biol Psychiatry.59 162 170 j.biopsych.2005.06.013. - 39.
Whalen P. J. Johnstone T. Somerville L. H. Nitschke J. B. Polis S. Alexander A. L. Davidson R. J. Kalin N. H. 2008 A Functional Magnetic Resonance Imaging Predictor of Treatment Response to Venlafaxine in Generalized Anxiety Disorder. Biol Psychiatry.63 858 863 j.biopsych.2007.08.019. - 40.
ME Palm Elliott. R. Mc Kie S. Deakin J. F. W. Anderson I. M. 2011 Attenuated Responses to Emotional Expressions in Women with Generalized Anxiety Disorder. Psychological Medicine.41 1009 1018 doi:10.1017/S0033291710001455. - 41.
Mc Clure E. B. Adler A. Monk C. S. Cameron J. Smith S. EE Nelson Leibenluft. E. Ernst M. DS Pine 2007 fMRI Predictors of Treatment Outcome in Pediatric Anxiety Disorders. Psychopharmacology (Berl).191 97 105 s00213-006-0542-9. - 42.
Monk C. S. Telzer E. H. Mogg K. Bradley B. P. Mai X. Louro H. M. Chen G. Mc Clure-Tone E. B. Ernst M. DS Pine 2008 Amygdala and Ventrolateral Prefrontal Cortex Activation to Masked Angry Faces in Children and Adolescents with Generalized Anxiety Disorder. Arch Gen Psychiatry.65 568 576 archpsyc.65.5.568. - 43.
Nitschke J. B. Sarinopoulos I. Oathes D. J. Johnstone T. Whalen P. J. Davidson R. J. Kalin N. H. 2009 Anticipatory Activation in the Amygdala and Anterior Cingulate in Generalized Anxiety Disorder and Prediction of Treatment Response. Am J Psychiatry.166 302 310 appi.ajp.2008.07101682 [pii] 10.1176/appi.ajp.2008.07101682. - 44.
Etkin A. Prater K. E. Hoeft F. Menon V. Schatzberg A. F. 2010 Failure of Anterior Cingulate Activation and Connectivity with the Amygdala During Implicit Regulation of Emotional Processing in Generalized Anxiety Disorder. Am J Psychiatry.167 545 554 appi.ajp.2009.09070931. - 45.
Prevost C. Mc Cabe J. A. Jessup R. K. Bossaerts P. O’Doherty J. P. 2011 Differentiable Contributions of Human Amygdalar Subregions in the Computations Underlying Reward and Avoidance Learning. Eur J Neurosci.34 134 145 j.1460-9568.2011.07686.x. - 46.
Boll S. Gamer M. Kalisch R. Buchel C. 2011 Processing of Facial Expressions and Their Significance for the Observer in Subregions of the Human Amygdala. Neuroimage.56 299 306 S1053-8119(11)00160-1 [pii] 10.1016/j.neuroimage.2011.02.021. - 47.
Ball T. Rahm B. Eickhoff S. B. Schulze-Bonhage A. Speck O. Mutschler I. 2007 Response Properties of Human Amygdala Subregions: Evidence Based on Functional MRI Combined with Probabilistic Anatomical Maps. PLoS One. 2, e307. 10.1371/journal.pone.0000307. - 48.
Ball T. Derix J. Wentlandt J. Wieckhorst B. Speck O. Schulze-Bonhage A. Mutschler I. 2009 Anatomical Specificity of Functional Amygdala Imaging of Responses to Stimuli with Positive and Negative Emotional Valence. J Neurosci Methods.180 57 70 S0165-0270(09)00144-7 [pii] 10.1016/j.jneumeth.2009.02.022. - 49.
Etkin A. Prater K. E. Schatzberg A. F. Menon V. MD Greicius 2009 Disrupted Amygdalar Subregion Functional Connectivity and Evidence of a Compensatory Network in Generalized Anxiety Disorder. Arch Gen Psychiatry.66 1361 1372 pii] 10.1001/archgenpsychiatry.2009.104. - 50.
Entis J. J. Doerga P. Barrett L. F. Dickerson B. C. 2012 A Reliable Protocol for the Manual Segmentation of the Human Amygdala and Its Subregions Using Ultra-High Resolution MRI. Neuroimage.60 1226 1235 S1053-8119(12)00002-X [pii] 10.1016/j.neuroimage.2011.12.073. - 51.
Kim N. Kim H. J. Hwang J. Yoon S. J. Cho H. B. Renshaw P. F. Lyoo I. K. Kim J. E. 2011 Amygdalar Shape Analysis Method Using Surface Contour Aligning, Spherical Mapping, and Probabilistic Subregional Segmentation. Neurosci Lett.488 65 69 S0304-3940(10)01446-1 [pii] 10.1016/j.neulet.2010.11.005. - 52.
Millan MJ 2003 The Neurobiology and Control of Anxious States. Prog Neurobiol.70 83 244 S030100820300087X [pii]. - 53.
Kalin NH, Sheltona SE 2003 Nonhuman Primate Models to Study Anxiety, Emotion Regulation, and Psychopathology. Annals of the New York Academy of Sciences.1008 189 200 annals.1301.021. - 54.
Kalin NH, Shelton SE, Davidson RJ 2004 The Role of the Central Nucleus of the Amygdala in Mediating Fear and Anxiety in the Primate. J Neurosci.24 5506 5515 JNEUROSCI.0292-04.2004 24/24/5506 [pii]. - 55.
CA Lowry Johnson. P. L. Hay-Schmidt A. Mikkelsen J. Shekhar A. 2005 Modulation of Anxiety Circuits by Serotonergic Systems. Stress.8 233 246 - 56.
Davis M. 2006 Neural Systems Involved in Fear and Anxiety Measured with Fear-Potentiated Startle. Am Psychol.61 741 756 pii] 10.1037/0003-066X.61.8.741. - 57.
Milad MR, Rauch SL, Pitman RK, Quirk GJ 2006 Fear Extinction in Rats: Implications for Human Brain Imaging and Anxiety Disorders. Biol Psychol.73 61 71 - 58.
Davis M. Antoniadis E. A. Amaral D. G. Winslow J. T. 2008 Acoustic Startle Reflex in Rhesus Monkeys: A Review. Rev Neurosci.19 171 185 - 59.
Price JL 2003 Comparative Aspects of Amygdala Connectivity. Ann N Y Acad Sci.985 50 58 - 60.
LeDoux JE 2000 Emotion Circuits in the Brain. Annu Rev Neurosci.23 155 184 annurev.neuro.23.1.155. - 61.
Canteras NS, Simerly RB, Swanson LW 1995 Organization of Projections from the Medial Nucleus of the Amygdala: A Phal Study in the Rat. J Comp Neurol.360 213 245 cne.903600203. - 62.
Newman SW 1999 The Medial Extended Amygdala in Male Reproductive Behavior a Node in the Mammalian Social Behavior Network. Annals of the New York Academy of Sciences.877 242 257 j.1749-6632.1999.tb09271.x. - 63.
Herman J. P. MM Ostrander Mueller. N. K. Figueiredo H. 2005 Limbic System Mechanisms of Stress Regulation: Hypothalamo-Pituitary-Adrenocortical Axis. Progress in Neuro-Psychopharmacology and Biological Psychiatry.29 1201 1213 j.pnpbp.2005.08.006. - 64.
Pitkanen A. Savander V. Le Doux J. E. 1997 Organization of Intra-Amygdaloid Circuitries in the Rat: An Emerging Framework for Understanding Functions of the Amygdala. Trends Neurosci.20 517 523 S0166223697011259 [pii]. - 65.
Canteras NS, Swanson LW 1992 Projections of the Ventral Subiculum to the Amygdala, Septum, and Hypothalamus: A Phal Anterograde Tract-Tracing Study in the Rat. J Comp Neurol.324 180 194 cne.903240204. - 66.
Canteras NS, Simerly RB, Swanson LW 1992 Connections of the Posterior Nucleus of the Amygdala. J Comp Neurol.324 143 179 cne.903240203. - 67.
Richter-Levin G. Akirav I. 2000 Amygdala-Hippocampus Dynamic Interaction in Relation to Memory. Mol Neurobiol.22 11 20 MN:22:1-3:011 [pii] 10.1385/MN:22:1-3:011. - 68.
Savander V. Miettinen R. Ledoux J. E. Pitkanen A. 1997 Lateral Nucleus of the Rat Amygdala Is Reciprocally Connected with Basal and Accessory Basal Nuclei: A Light and Electron Microscopic Study. Neuroscience.77 767 781 S0306-4522(96)00513-1 [pii]. - 69.
Pare D. Smith Y. 1993 The Intercalated Cell Masses Project to the Central and Medial Nuclei of the Amygdala in Cats. Neuroscience.57 1077 1090 P [pii]. - 70.
Royer S. Martina M. Pare D. 1999 An Inhibitory Interface Gates Impulse Traffic between the Input and Output Stations of the Amygdala. J Neurosci.19 10575 10583 - 71.
Pare D. Quirk G. J. Ledoux J. E. 2004 New Vistas on Amygdala Networks in Conditioned Fear. J Neurophysiol.92 1 9 jn.00153.2004 92/1/1 [pii]. - 72.
Le Doux J. E. Iwata J. Cicchetti P. Reis D. J. 1988 Different Projections of the Central Amygdaloid Nucleus Mediate Autonomic and Behavioral Correlates of Conditioned Fear. J Neurosci.8 2517 2529 - 73.
Davis M. Whalen P. J. 2001 The Amygdala: Vigilance and Emotion. Mol Psychiatry.6 13 34 - 74.
Dielenberg RA, McGregor IS 2001 Defensive Behavior in Rats Towards Predatory Odors: A Review. Neuroscience & Biobehavioral Reviews.25 597 609 s0149-7634(01)00044-6. - 75.
Müller M. Fendt M. 2006 Temporary Inactivation of the Medial and Basolateral Amygdala Differentially Affects Tmt-Induced Fear Behavior in Rats. Behavioural Brain Research.167 57 62 j.bbr.2005.08.016. - 76.
Rosen J. B. Pagani J. H. Rolla K. L. Davis C. 2008 Analysis of Behavioral Constraints and the Neuroanatomy of Fear to the Predator Odor Trimethylthiazoline: A Model for Animal Phobias. Neurosci Biobehav Rev.32 1267 1276 S0149-7634(08)00068-7 [pii] 10.1016/j.neubiorev.2008.05.006. - 77.
Ramos C. Leite-Panissi R. Monassi R. Menescal-Oliveira De L. 1999 Role of the Amygdaloid Nuclei in the Modulation of Tonic Immobility in Guinea Pigs. Physiol Behav.67 717 724 S003193849900133X [pii]. - 78.
Macedo CE, Martinez RC, Brandao ML 2006 Conditioned and Unconditioned Fear Organized in the Inferior Colliculus Are Differentially Sensitive to Injections of Muscimol into the Basolateral Nucleus of the Amygdala. Behav Neurosci.120 625 631 pii] 10.1037/0735-7044.120.3.625. - 79.
Quirk G. J. Mueller D. 2008 Neural Mechanisms of Extinction Learning and Retrieval. Neuropsychopharmacology.33 56 72 - 80.
Zimmerman J. M. Maren S. 2010 Nmda Receptor Antagonism in the Basolateral but Not Central Amygdala Blocks the Extinction of Pavlovian Fear Conditioning in Rats. Eur J Neurosci.31 1664 1670 EJN7223 [pii] 10.1111/j.1460-9568.2010.07223.x. - 81.
Sotres-Bayon F. Cain C. K. Le Doux J. E. 2006 Brain Mechanisms of Fear Extinction: Historical Perspectives on the Contribution of Prefrontal Cortex. Biol Psychiatry.60 329 336 - 82.
Likhtik E. Popa D. Apergis-Schoute J. Fidacaro G. A. Pare D. 2008 Amygdala Intercalated Neurons Are Required for Expression of Fear Extinction. Nature.454 642 645 nature07167 [pii] 10.1038/nature07167. - 83.
Amano T. Unal C. T. Pare D. 2010 Synaptic Correlates of Fear Extinction in the Amygdala. Nat Neurosci.13 489 494 nn.2499 [pii] 10.1038/nn.2499. - 84.
Moreira C. M. Masson S. Carvalho M. C. Brandao M. L. 2007 Exploratory Behaviour of Rats in the Elevated Plus-Maze Is Differentially Sensitive to Inactivation of the Basolateral and Central Amygdaloid Nuclei. Brain Res Bull.71 466 474 S0361-9230(06)00305-4 [pii] 10.1016/j.brainresbull.2006.10.004. - 85.
Zarrindast M. R. Solati J. Oryan S. Parivar K. 2008 Effect of Intra-Amygdala Injection of Nicotine and GABA Receptor Agents on Anxiety-Like Behaviour in Rats. Pharmacology.82 276 284 pii] 10.1159/000161129. - 86.
Tye K. M. Prakash R. Kim S. Y. Fenno L. E. Grosenick L. Zarabi H. Thompson K. R. Gradinaru V. Ramakrishnan C. Deisseroth K. 2011 Amygdala Circuitry Mediating Reversible and Bidirectional Control of Anxiety. Nature.471 358 362 nature09820 [pii] 10.1038/nature09820. - 87.
Walker D. L. Toufexis D. J. Davis M. 2003 Role of the Bed Nucleus of the Stria Terminalis Versus the Amygdala in Fear, Stress, and Anxiety. Eur J Pharmacol.463 199 216 S0014299903012822 [pii]. - 88.
Walker D. L. Miles L. A. Davis M. 2009 Selective Participation of the Bed Nucleus of the Stria Terminalis and Crf in Sustained Anxiety-Like Versus Phasic Fear-Like Responses. Prog Neuropsychopharmacol Biol Psychiatry.33 1291 1308 S0278-5846(09)00212-7 [pii] 10.1016/j.pnpbp.2009.06.022. - 89.
Walker D. L. Davis M. 2008 Role of the Extended Amygdala in Short-Duration Versus Sustained Fear: A Tribute to Dr. Lennart Heimer. Brain Struct Funct.213 29 42 s00429-008-0183-3. - 90.
Duncan GE, Knapp DJ, Breese GR 1996 Neuroanatomical Characterization of Fos Induction in Rat Behavioral Models of Anxiety. Brain Res.713 79 91 pii]. - 91.
Herdade K. C. Strauss C. V. Zangrossi Junior. H. Viana M. B. 2006 Effects of Medial Amygdala Inactivation on a Panic-Related Behavior. Behav Brain Res.172 316 323 S0166-4328(06)00292-0 [pii] 10.1016/j.bbr.2006.05.021. - 92.
Troakes C. Ingram C. D. 2009 Anxiety Behaviour of the Male Rat on the Elevated Plus Maze: Associated Regional Increase in C-Fos mRNA Expression and Modulation by Early Maternal Separation. Stress.12 362 369 pii] 10.1080/10253890802506391. - 93.
Vinkers C. H. Bijlsma E. Y. Houtepen L. C. Westphal K. G. Veening J. G. Groenink L. Olivier B. 2010 Medial Amygdala Lesions Differentially Influence Stress Responsivity and Sensorimotor Gating in Rats. Physiol Behav.99 395 401 S0031-9384(09)00392-8 [pii] 10.1016/j.physbeh.2009.12.006. - 94.
Marschner A. Kalisch R. Vervliet B. Vansteenwegen D. Buchel C. 2008 Dissociable Roles for the Hippocampus and the Amygdala in Human Cued Versus Context Fear Conditioning. J Neurosci.28 9030 9036 pii] 10.1523/JNEUROSCI.1651-08.2008. - 95.
Onishi BK, Xavier GF 2010 Contextual, but Not Auditory, Fear Conditioning Is Disrupted by Neurotoxic Selective Lesion of the Basal Nucleus of Amygdala in Rats. Neurobiol Learn Mem.93 165 174 S1074-7427(09)00197-X [pii] 10.1016/j.nlm.2009.09.007. - 96.
Mc Donald A. J. Mascagni F. Guo L. 1996 Projections of the Medial and Lateral Prefrontal Cortices to the Amygdala: A Phaseolus Vulgaris Leucoagglutinin Study in the Rat. Neuroscience.71 55 75 pii]. - 97.
Vertes RP 2004 Differential Projections of the Infralimbic and Prelimbic Cortex in the Rat. Synapse.51 32 58 syn.10279. - 98.
Corcoran KA, Quirk GJ 2007 Recalling Safety: Cooperative Functions of the Ventromedial Prefrontal Cortex and the Hippocampus in Extinction. CNS Spectr.12 200 206 - 99.
Vidal-Gonzalez I. Vidal-Gonzalez B. Rauch S. L. Quirk G. J. 2006 Microstimulation Reveals Opposing Influences of Prelimbic and Infralimbic Cortex on the Expression of Conditioned Fear. Learn Mem.13 728 733 pii] 10.1101/lm.306106. - 100.
Sierra-Mercado D. Padilla-Coreano N. Quirk G. J. 2011 Dissociable Roles of Prelimbic and Infralimbic Cortices, Ventral Hippocampus, and Basolateral Amygdala in the Expression and Extinction of Conditioned Fear. Neuropsychopharmacology.36 529 538 npp2010184 [pii] 10.1038/npp.2010.184. - 101.
Li G. Amano T. Pare D. Nair S. S. 2011 Impact of Infralimbic Inputs on Intercalated Amygdala Neurons: A Biophysical Modeling Study. Learn Mem.18 226 240 lm.1938011 18/4/226 [pii]. - 102.
Milad M. R. Pitman R. K. Ellis C. B. Gold A. L. Shin L. M. Lasko N. B. MA Zeidan Handwerger. K. Orr S. P. Rauch S. L. 2009 Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder. Biol Psychiatry.66 1075 1082 S0006-3223(09)00896-8 [pii] 10.1016/j.biopsych.2009.06.026. - 103.
Rougemont-Bucking A. Linnman C. Zeffiro T. A. MA Zeidan-Milad Lebron. Rodriguez-Romaguera K. Rauch J. Pitman S. L. Milad R. K. M. R. 2011 Altered Processing of Contextual Information During Fear Extinction in PTSD: An fMRI Study. CNS Neurosci Ther.17 227 236 j.1755-5949.2010.00152.x CNS152 [pii]. - 104.
Kim MJ, Whalen PJ 2009 The Structural Integrity of an Amygdala-Prefrontal Pathway Predicts Trait Anxiety. J Neurosci.29 11614 11618 pii] 10.1523/JNEUROSCI.2335-09.2009. - 105.
Kim MJ, Gee DG, Loucks RA, Davis FC, Whalen PJ 2011 Anxiety Dissociates Dorsal and Ventral Medial Prefrontal Cortex Functional Connectivity with the Amygdala at Rest. Cereb Cortex.21 1667 1673 bhq237 [pii] 10.1093/cercor/bhq237. - 106.
Inoue T. Koyama T. Yamashita I. 1993 Effect of Conditioned Fear Stress on Serotonin Metabolism in the Rat Brain. Pharmacol Biochem Behav.44 371 374 A [pii]. - 107.
Yokoyama M. Suzuki E. Sato T. Maruta S. Watanabe S. Miyaoka H. 2005 Amygdalic Levels of Dopamine and Serotonin Rise Upon Exposure to Conditioned Fear Stress without Elevation of Glutamate. Neurosci Lett.379 37 41 S0304-3940(04)01584-8 [pii] 10.1016/j.neulet.2004.12.047. - 108.
Mo B. Feng N. Renner K. Forster G. 2008 Restraint Stress Increases Serotonin Release in the Central Nucleus of the Amygdala Via Activation of Corticotropin-Releasing Factor Receptors. Brain Res Bull.76 493 498 S0361-9230(08)00039-7 [pii] 10.1016/j.brainresbull.2008.02.011. - 109.
Zanoveli JM, Carvalho MC, Cunha JM, Brandão ML 2009 Extracellular Serotonin Level in the Basolateral Nucleus of the Amygdala and Dorsal Periaqueductal Gray under Unconditioned and Conditioned Fear States: An in Vivo Microdialysis Study. Brain Res.1294 106 115 S0006-8993(09)01537-6 [pii] 10.1016/j.brainres.2009.07.074. - 110.
BM Spannuth Hale. M. W. Evans A. K. Lukkes J. L. Campeau S. CA Lowry 2011 Investigation of a Central Nucleus of the Amygdala/Dorsal Raphe Nucleus Serotonergic Circuit Implicated in Fear-Potentiated Startle. Neuroscience.179 104 119 S0306-4522(11)00065-0 [pii] 10.1016/j.neuroscience.2011.01.042. - 111.
Emoto H. Koga C. Ishii H. Yokoo H. Yoshida M. Tanaka M. 1993 A CRF Antagonist Attenuates Stress-Induced Increases in NA Turnover in Extended Brain Regions in Rats. Brain Res.627 171 176 C [pii]. - 112.
Dunn AJ 1988 Stress-Related Activation of Cerebral Dopaminergic Systems. Ann N Y Acad Sci.537 188 205 - 113.
Quirarte G. L. Galvez R. Roozendaal B. Mc Gaugh J. L. 1998 Norepinephrine Release in the Amygdala in Response to Footshock and Opioid Peptidergic Drugs. Brain Res.808 134 140 - 114.
Inglis F. M. Moghaddam B. 1999 Dopaminergic Innervation of the Amygdala Is Highly Responsive to Stress. J Neurochem.72 1088 1094 - 115.
Morilak D. A. Barrera G. Echevarria D. J. AS Garcia Hernandez. A. Ma Petre S. C. O. 2005 Role of Brain Norepinephrine in the Behavioral Response to Stress. Prog Neuropsychopharmacol Biol Psychiatry.29 1214 1224 S0278-5846(05)00270-8 [pii] 10.1016/j.pnpbp.2005.08.007. - 116.
Ma Morilak S. D. A. 2005 Norepinephrine Release in Medial Amygdala Facilitates Activation of the Hypothalamic-Pituitary-Adrenal Axis in Response to Acute Immobilisation Stress. J Neuroendocrinol.17 22 28 JNE1279 [pii] 10.1111/j.1365-2826.2005.01279.x. - 117.
Mitsushima D. Yamada K. Takase K. Funabashi T. Kimura F. 2006 Sex Differences in the Basolateral Amygdala: The Extracellular Levels of Serotonin and Dopamine, and Their Responses to Restraint Stress in Rats. Eur J Neurosci.24 3245 3254 EJN5214 [pii] 10.1111/j.1460-9568.2006.05214.x. - 118.
Mc Intyre C. K. Hatfield T. Mc Gaugh J. L. 2002 Amygdala Norepinephrine Levels after Training Predict Inhibitory Avoidance Retention Performance in Rats. Eur J Neurosci.16 1223 1226 - 119.
Carrasco GA, Van de Kar LD 2003 Neuroendocrine Pharmacology of Stress. Eur J Pharmacol.463 235 272 - 120.
Feltenstein MW, See RE. 2008 The Neurocircuitry of Addiction: An Overview. British Journal of Pharmacology154 261 274 - 121.
Butler PD, Weiss JM, Stout JC, Nemeroff CB 1990 Corticotropin-Releasing Factor Produces Fear-Enhancing and Behavioral Activating Effects Following Infusion into the Locus Coeruleus. J Neurosci.10 176 183 - 122.
Basso A. M. Spina M. Rivier J. Vale W. Koob G. F. 1999 Corticotropin-Releasing Factor Antagonist Attenuates the "Anxiogenic-Like" Effect in the Defensive Burying Paradigm but Not in the Elevated Plus-Maze Following Chronic Cocaine in Rats. Psychopharmacology (Berl).145 21 30 - 123.
Radulovic J. Ruhmann A. Liepold T. Spiess J. 1999 Modulation of Learning and Anxiety by Corticotropin-Releasing Factor (CRF) and Stress: Differential Roles of CRF Receptors 1 and 2. J Neurosci.19 5016 5025 - 124.
Kikusui T. Takeuchi Y. Mori Y. 2000 Involvement of Corticotropin-Releasing Factor in the Retrieval Process of Fear-Conditioned Ultrasonic Vocalization in Rats. Physiol Behav.71 323 328 - 125.
Takahashi LK 2001 Role of CRF(1) and CRF(2) Receptors in Fear and Anxiety. Neurosci Biobehav Rev.25 627 636 - 126.
Bale TL 2005 Sensitivity to Stress: Dysregulation of CRF Pathways and Disease Development. Horm Behav.48 1 10 - 127.
Lukkes J. Vuong S. Scholl J. Oliver H. Forster G. 2009 Corticotropin-Releasing Factor Receptor Antagonism within the Dorsal Raphe Nucleus Reduces Social Anxiety-Like Behavior after Early-Life Social Isolation. The Journal of Neuroscience.29 9955 9960 jneurosci.0854-09.2009. - 128.
Bledsoe AC, Oliver KM, Scholl JL, Forster GL 2011 Anxiety States Induced by Post-Weaning Social Isolation Are Mediated by CRF Receptors in the Dorsal Raphe Nucleus. Brain Res Bull.85 117 122 j.brainresbull.2011.03.003. - 129.
Risbrough VB, Stein MB 2006 Role of Corticotropin Releasing Factor in Anxiety Disorders: A Translational Research Perspective. Horm Behav.50 550 561 - 130.
Matsuzaki I. Takamatsu Y. Moroji T. 1989 The Effects of Intracerebroventricularly Injected Corticotropin-Releasing Factor (CRF) on the Central Nervous System: Behavioural and Biochemical Studies. Neuropeptides.13 147 155 - 131.
Amat J. Tamblyn J. P. Paul E. D. Bland S. T. Amat P. Foster A. C. Watkins L. R. Maier S. F. 2004 Microinjection of Urocortin 2 into the Dorsal Raphe Nucleus Activates Serotonergic Neurons and Increases Extracellular Serotonin in the Basolateral Amygdala. Neuroscience.129 509 519 S0306-4522(04)00718-3[pii] 10.1016/j.neuroscience.2004.07.052. - 132.
Forster G. L. Feng N. MJ Watt Korzan. W. J. Mouw N. J. Summers C. H. Renner K. J. 2006 Corticotropin-Releasing Factor in the Dorsal Raphe Elicits Temporally Distinct Serotonergic Responses in the Limbic System in Relation to Fear Behavior. Neuroscience.141 1047 1055 S0306-4522(06)00490-8 [pii] 10.1016/j.neuroscience.2006.04.006. - 133.
Scholl JL, Vuong SM, Forster GL 2010 Chronic Amphetamine Treatment Enhances Corticotropin-Releasing Factor-Induced Serotonin Release in the Amygdala. Eur J Pharmacol.644 80 87 S0014-2999(10)00705-3 [pii] 10.1016/j.ejphar.2010.07.008. - 134.
Gray TS 1993 Amygdaloid CRF Pathways. Role in Autonomic, Neuroendocrine, and Behavioral Responses to Stress. Ann N Y Acad Sci.697 53 60 - 135.
Day H. E. Greenwood B. N. Hammack S. E. Watkins L. R. Fleshner M. Maier S. F. Campeau S. 2004 Differential Expression of 5HT-1a, Alpha 1b Adrenergic, CRF-R1, and CFR-R2 Receptor mRNA in Serotonergic, Gamma-Aminobutyric Acidergic, and Catecholaminergic Cells of the Rat Dorsal Raphe Nucleus. J Comp Neurol.474 364 378 - 136.
Wang B. You Z. B. Rice K. C. Wise R. A. 2007 Stress-Induced Relapse to Cocaine Seeking: Roles for the CRF(2) Receptor and CRF-Binding Protein in the Ventral Tegmental Area of the Rat. Psychopharmacology (Berl).193 283 294 - 137.
Pringle RB, Mouw NJ, Lukkes JL, Forster GL 2008 Amphetamine Treatment Increases Corticotropin-Releasing Factor Receptors in the Dorsal Raphe Nucleus. Neurosci Res.62 62 65 - 138.
Reyes BA, Valentino RJ, Van Bockstaele EJ 2008 Stress-Induced Intracellular Trafficking of Corticotropin-Releasing Factor Receptors in Rat Locus Coeruleus Neurons. Endocrinology.149 122 130 - 139.
Wise R. A. Morales M. 2010 A Ventral Tegmental CRF-Glutamate-Dopamine Interaction in Addiction. Brain Res.1314 38 43 j.brainres.2009.09.101. - 140.
Tagliaferro P. Morales M. 2008 Synapses between Corticotropin-Releasing Factor-Containing Axon Terminals and Dopaminergic Neurons in the Ventral Tegmental Area Are Predominantly Glutamatergic. J Comp Neurol.506 616 626 cne.21576. - 141.
Pernar L. Curtis A. L. Vale W. W. Rivier J. E. Valentino R. J. 2004 Selective Activation of Corticotropin-Releasing Factor-2 Receptors on Neurochemically Identified Neurons in the Rat Dorsal Raphe Nucleus Reveals Dual Actions. J Neurosci.24 1305 1311 - 142.
Waselus M. Nazzaro C. Valentino R. J. Van Bockstaele E. J. 2009 Stress-Induced Redistribution of Corticotropin-Releasing Factor Receptor Subtypes in the Dorsal Raphe Nucleus. Biol Psychiatry.66 76 83 - 143.
Lukkes JL, Summers CH, Scholl JL, Renner KJ, Forster GL 2009 Early Life Social Isolation Alters Corticotropin-Releasing Factor Responses in Adult Rats. Neuroscience.158 845 855 - 144.
Boyson C. Miguel T. Quadros I. De Bold J. Miczek K. 2011 Prevention of Social Stress-Escalated Cocaine Self-Administration by CRF-R1 Antagonist in the Rat Vta. Psychopharmacology (Berl).1 13 s00213-011-2266-8. - 145.
Faria R. Magalhães A. Monteiro P. R. Gomes-Da-Silva J. Amélia Tavares. M. Summavielle T. 2006 MDMA in Adolescent Male Rats: Decreased Serotonin in the Amygdala and Behavioral Effects in the Elevated Plus-Maze Test. Ann N Y Acad Sci.1074 643 649 pii] 10.1196/annals.1369.062. - 146.
Niwa M. Matsumoto Y. Mouri A. Ozaki N. Nabeshima T. 2011 Vulnerability in Early Life to Changes in the Rearing Environment Plays a Crucial Role in the Aetiopathology of Psychiatric Disorders. Int J Neuropsychopharmacol.14 459 477 S1461145710001239 [pii] 10.1017/S1461145710001239. - 147.
Costall B. Jones B. J. ME Kelly Naylor. R. J. Oakley N. R. Onaivi E. S. Tyers M. B. 1989 The Effects of Ondansetron (Gr38032f) in Rats and Mice Treated Subchronically with Diazepam. Pharmacol Biochem Behav.34 769 778 - 148.
Cruz A. P. M. Pinheiro G. Alves S. H. Ferreira G. Mendes M. Faria L. et al. 2005 Behavioral effects of systemically administered MK-212 are prevented by ritanserin microinfusion into the basolateral amygdala of rats exposed to the elevated plus-maze. Psychopharmacology.182 345 54 - 149.
Zangrossi H. Graeff F. G. 1994 Behavioral effects of intraamygdala injections of GABA and 5-HT acting drugs in the elevated plus-maze. Braz. J Med Biol Res.27 2453 6 - 150.
Cornelio AM, Nunes-de-Souza RL 2007 Anxiogenic-Like Effects of MCPP Microinfusions into the Amygdala (but not Dorsal or Ventral Hippocampus) in Mice Exposed to Elevated Plus-Maze. Behav Brain Res.178 82 89 j.bbr.2006.12.003. - 151.
Higgins GA, Jones BJ, Oakley NR, Tyers MB 1991 Evidence that the Amygdala Is Involved in the Disinhibitory Effects of 5-HT3 Receptor Antagonists. Psychopharmacology (Berl).104 545 551 - 152.
Tomkins D. M. Costall B. ME Kelly 1990 Release of Suppressed Behavior of rat on the Elevated X-maze by 5-HT3 Receptor Antagonists injected into the Basolateral Amygdala. J Psychopharmacol.4 203 5 - 153.
Gonzalez L. E. Andrews N. File S. E. 1996 HT1a and Benzodiazepine Receptors in the Basolateral Amygdala Modulate Anxiety in the Social Interaction Test, but Not in the Elevated Plus-Maze. Brain Res.732 145 153 - 154.
MA Vicente Zangrossi. H. 2011 Serotonin-2c Receptors in the Basolateral Nucleus of the Amygdala Mediate the Anxiogenic Effect of Acute Imipramine and Fluoxetine Administration. Int J Neuropsychopharmacol.1 12 S1461145711000873 [pii] 10.1017/S1461145711000873. - 155.
Duxon MS, Beckett SR, Baxter GS, Blackburn TP, Fone KCF. 1995 Intraamygdala Injection of the 5-HT2B Receptor Agonist BW-72386 Produces Anxiolysis on the Elevated Plus-Maze in the Rat. Br J Pharmacol 116,331 P331 - 156.
MS Duxon Kennett. G. A. Lightowler S. Blackburn T. P. Fone K. C. 1997 Activation of 5-HT2b Receptors in the Medial Amygdala Causes Anxiolysis in the Social Interaction Test in the Rat. Neuropharmacology.36 601 608 - 157.
Inoue T. Li X. B. Abekawa T. Kitaichi Y. Izumi T. Nakagawa S. Koyama T. 2004 Selective Serotonin Reuptake Inhibitor Reduces Conditioned Fear through Its Effect in the Amygdala. Eur J Pharmacol.497 311 316 S0014-2999(04)00702-2 [pii] 10.1016/j.ejphar.2004.06.061. - 158.
Leite-Panissi C. R. AA Ferrarese Terzian. A. L. Menescal-de-Oliveira L. 2006 Serotoninergic Activation of the Basolateral Amygdala and Modulation of Tonic Immobility in Guinea Pig. Brain Res Bull.69 356 364 S0361-9230(06)00051-7 [pii] 10.1016/j.brainresbull.2006.02.007. - 159.
Li X. Inoue T. Abekawa T. Weng S. Nakagawa S. Izumi T. Koyama T. 2006 Ht1a Receptor Agonist Affects Fear Conditioning through Stimulations of the Postsynaptic 5-Ht1a Receptors in the Hippocampus and Amygdala. Eur J Pharmacol.532 74 80 S0014-2999(05)01310-5 [pii] 10.1016/j.ejphar.2005.12.008. - 160.
Morrison KE, Cooper MA 2012 A Role for 5-Ht1a Receptors in the Basolateral Amygdala in the Development of Conditioned Defeat in Syrian Hamsters. Pharmacol Biochem Behav.100 592 600 S0091-3057(11)00312-1 [pii] 10.1016/j.pbb.2011.09.005. - 161.
Centonze D. Usiello A. Gubellini P. Pisani A. Borrelli E. Bernardi G. Calabresi P. 2002 Dopamine D2 Receptor-Mediated Inhibition of Dopaminergic Neurons in Mice Lacking D2l Receptors. Neuropsychopharmacology.27 723 726 - 162.
Rouge-Pont F. Usiello A. Benoit-Marand M. Gonon F. Piazza P. V. Borrelli E. 2002 Changes in Extracellular Dopamine Induced by Morphine and Cocaine: Crucial Control by D2 Receptors. J Neurosci.22 3293 3301 - 163.
Summavielle T. Magalhães A. Castro-Vale I. de Sousa L. MA Tavares 2002 Neonatal Exposure to Cocaine: Altered Dopamine Levels in the Amygdala and Behavioral Outcomes in the Developing Rat. Ann N Y Acad Sci.965 515 521 - 164.
Izumo N. Ishibashi Y. Ohba M. Morikawa T. Manabe T. 2012 Decreased Voluntary Activity and Amygdala Levels of Serotonin and Dopamine in Ovariectomized Rats. Behav Brain Res.227 1 6 S0166-4328(11)00764-9 [pii] 10.1016/j.bbr.2011.10.031. - 165.
Rezayof A. Hosseini S. S. Zarrindast M. R. 2009 Effects of Morphine on Rat Behaviour in the Elevated Plus Maze: The Role of Central Amygdala Dopamine Receptors. Behav Brain Res.202 171 178 S0166-4328(09)00193-4 [pii] 10.1016/j.bbr.2009.03.030. - 166.
de la Mora M. P. Gallegos-Cari A. Crespo-Ramirez M. Marcellino D. Hansson A. C. Fuxe K. 2012 Distribution of Dopamine D(2)-Like Receptors in the Rat Amygdala and Their Role in the Modulation of Unconditioned Fear and Anxiety. Neuroscience.201 252 266 S0306-4522(11)01238-3 [pii] 10.1016/j.neuroscience.2011.10.045. - 167.
Sullivan R. M. Duchesne A. Hussain D. Waldron J. Laplante F. 2009 Effects of Unilateral Amygdala Dopamine Depletion on Behaviour in the Elevated Plus Maze: Role of Sex, Hemisphere and Retesting. Behav Brain Res.205 115 122 S0166-4328(09)00440-9 [pii] 10.1016/j.bbr.2009.07.023. - 168.
Bananej M. Karimi-Sori A. Zarrindast M. R. Ahmadi S. 2011 D1 and D2 Dopaminergic Systems in the Rat Basolateral Amygdala Are Involved in Anxiogenic-Like Effects Induced by Histamine. J Psychopharmacol. 0269881111405556 [pii] 10.1177/0269881111405556. - 169.
de la Mora M. P. Cardenas-Cachon L. Vazquez-Garcia M. Crespo-Ramirez M. Jacobsen K. Hoistad M. Agnati L. Fuxe K. 2005 Anxiolytic Effects of Intra-Amygdaloid Injection of the D1 Antagonist SCH23390 in the Rat. Neurosci Lett.377 101 105 j.neulet.2004.11.079. - 170.
Greba Q. Gifkins A. Kokkinidis L. 2001 Inhibition of Amygdaloid Dopamine D2 Receptors Impairs Emotional Learning Measured with Fear-Potentiated Startle. Brain Res.899 218 226 S0006-8993(01)02243-0 [pii]. - 171.
Guarraci FA, Frohardt RJ, Kapp BS 1999 Amygdaloid D1 Dopamine Receptor Involvement in Pavlovian Fear Conditioning. Brain Res.827 28 40 S0006-8993(99)01291-3 [pii]. - 172.
Guarraci FA, Frohardt RJ, Falls WA, Kapp BS 2000 The Effects of Intra-Amygdaloid Infusions of a D2 Dopamine Receptor Antagonist on Pavlovian Fear Conditioning. Behav Neurosci.114 647 651 - 173.
Selden NR, Everitt BJ, Jarrard LE, Robbins TW 1991 Complementary Roles for the Amygdala and Hippocampus in Aversive Conditioning to Explicit and Contextual Cues. Neuroscience.42 335 350 pii]. - 174.
Greba Q. Kokkinidis L. 2000 Peripheral and Intraamygdalar Administration of the Dopamine D1 Receptor Antagonist Sch 23390 Blocks Fear-Potentiated Startle but Not Shock Reactivity or the Shock Sensitization of Acoustic Startle. Behav Neurosci.114 262 272 - 175.
de Oliveira AR, Reimer AE, de Macedo CE, de Carvalho MC, Silva MA, Brandão ML 2011 Conditioned Fear Is Modulated by D2 Receptor Pathway Connecting the Ventral Tegmental Area and Basolateral Amygdala. Neurobiol Learn Mem.95 37 45 S1074-7427(10)00172-3 [pii] 10.1016/j.nlm.2010.10.005. - 176.
Cecchi M. Khoshbouei H. Morilak D. A. 2002 Modulatory Effects of Norepinephrine, Acting on Alpha 1 Receptors in the Central Nucleus of the Amygdala, on Behavioral and Neuroendocrine Responses to Acute Immobilization Stress. Neuropharmacology.43 1139 1147 S0028390802002927 [pii]. - 177.
Debiec J. Le Doux J. E. 2006 Noradrenergic Signaling in the Amygdala Contributes to the Reconsolidation of Fear Memory: Treatment Implications for PTSD. Ann N Y Acad Sci.1071 521 524 pii] 10.1196/annals.1364.056. - 178.
LaLumiere RT, Buen TV, McGaugh JL 2003 Post-Training Intra-Basolateral Amygdala Infusions of Norepinephrine Enhance Consolidation of Memory for Contextual Fear Conditioning. J Neurosci.23 6754 6758 pii]. - 179.
Lazzaro S. C. Hou M. Cunha C. Le Doux J. E. Cain C. K. 2010 Antagonism of Lateral Amygdala Alpha1-Adrenergic Receptors Facilitates Fear Conditioning and Long-Term Potentiation. Learn Mem.17 489 493 pii] 10.1101/lm.1918210. - 180.
Debiec J. Ledoux J. E. 2004 Disruption of Reconsolidation but Not Consolidation of Auditory Fear Conditioning by Noradrenergic Blockade in the Amygdala. Neuroscience.129 267 272 S0306-4522(04)00745-6 [pii] 10.1016/j.neuroscience.2004.08.018. - 181.
Roozendaal B. Hui G. K. Hui I. R. Berlau D. J. Mc Gaugh J. L. Weinberger N. M. 2006 Basolateral Amygdala Noradrenergic Activity Mediates Corticosterone-Induced Enhancement of Auditory Fear Conditioning. Neurobiol Learn Mem.86 249 255 S1074-7427(06)00032-3 [pii] 10.1016/j.nlm.2006.03.003. - 182.
Cloos-M J. Ferreira V. 2009 Current Use of Benzodiazepines in Anxiety Disorders. Curr Opin Psychiatry.22 90 95 - 183.
Ravindran LN, Stein MB 2010 The Pharmacologic Treatment of Anxiety Disorders: A Review of Progress. J Clin Psychiatry.71 839 854 - 184.
Brignell CM, Curran HV 2006 Drugs, Sweat and Fears: A Comparison of the Effects of Diazepam and Methylphenidate on Fear Conditioning. Psychopharmacol.186 504 516 s00213-006-0363-x. - 185.
Hellewell J. S. Guimaraes F. S. Wang M. Deakin J. F. 1999 Comparison of Buspirone with Diazepam and Fluvoxamine on Aversive Classical Conditioning in Humans. J Psychopharmacol.13 122 127 - 186.
Scaife J. C. Hou R. H. Samuels E. R. Baqui F. Langley R. W. Bradshaw C. M. Szabadi E. 2007 Diazepam-Induced Disruption of Classically-Conditioned Fear-Potentiation of Late-Latency Auditory Evoked Potentials Is Prevented by Flumazenil Given before, but Not after, CS/US Pairing. J Psychopharmacol.21 93 101 - 187.
Zangara A. Blair R. J. R. Curran H. V. 2002 A Comparison of the Effects of a Beta-Adrenergic Blocker and a Benzodiazepine Upon the Recognition of Human Facial Expressions. Psychopharmacology (Berl).163 36 41 - 188.
Brignell C. M. Rosenthal J. Curran H. V. 2007 Pharmacological Manipulations of Arousal and Memory for Emotional Material: Effects of a Single Dose of Methylphenidate or Lorazepam. J Psychopharmacol.21 673 683 - 189.
Buchanan T. W. MS Karafin Adolphs. R. 2003 Selective Effects of Triazolam on Memory for Emotional, Relative to Neutral, Stimuli: Differential Effects on Gist Versus Detail. Behav Neurosci.117 517 525 - 190.
Paulus M. P. Feinstein J. S. Castillo G. Simmons A. N. Stein M. B. 2005 Dose-Dependent Decrease of Activation in Bilateral Amygdala and Insula by Lorazepam During Emotion Processing. Arch Gen Psychiatry.62 282 288 - 191.
Del-Ben CM, Ferreira CA, Sanchez TA, Alves-Neto WC, Guapo VG, de Araujo DB, Graeff FG 2010 Effects of Diazepam on Bold Activation During the Processing of Aversive Faces. J Psychopharmacol. - 192.
Schunck T. Mathis A. Erb G. Namer I. J. Demazieres A. Luthringer R. 2010 Effects of Lorazepam on Brain Activity Pattern During an Anxiety Symptom Provocation Challenge. J Psychopharmacol.24 701 708 - 193.
Brantigan C. O. Brantigan T. A. Joseph N. 1979 The Effect of Beta Blockade on Stage Fright. A Controlled Study. Rocky Mt Med J.76 227 233 - 194.
Heiser J. F. Defrancisco D. 1976 The Treatment of Pathological Panic States with Propranolol. Am J Psychiatry.133 1389 1394 - 195.
Tyrer P. 1988 Current Status of Beta-Blocking Drugs in the Treatment of Anxiety Disorders. Drugs.36 773 783 - 196.
Bell J. 2008 Propranolol, Post-Traumatic Stress Disorder and Narrative Identity. J Med Ethics. 34, e23. 10.1136/jme.2008.024752. - 197.
Dębiec J. Bush D. E. A. Le Doux J. E. 2011 Noradrenergic Enhancement of Reconsolidation in the Amygdala Impairs Extinction of Conditioned Fear in Rats--a Possible Mechanism for the Persistence of Traumatic Memories in PTSD. Depress Anxiety.28 186 193 - 198.
Fletcher S. Creamer M. Forbes D. 2010 Preventing Post Traumatic Stress Disorder: Are Drugs the Answer? The Australian and New Zealand Journal of Psychiatry.44 1064 1071 - 199.
McGhee LL, Maani CV, Garza TH, Desocio PA, Gaylord KM, Black IH 2009 The Effect of Propranolol on Posttraumatic Stress Disorder in Burned Service Members. Journal of Burn Care & Research,30 92 97 - 200.
Stein M. B. Kerridge C. Dimsdale J. E. Hoyt D. B. 2007 Pharmacotherapy to Prevent Ptsd: Results from a Randomized Controlled Proof-of-Concept Trial in Physically Injured Patients. Journal of Traumatic Stress.20 923 932 - 201.
Hurlemann R. Walter H. Rehme A. K. Kukolja J. Santoro S. C. Schmidt C. Schnell K. Musshoff F. Keysers C. Maier W. Kendrick K. M. Onur O. A. 2010 Human Amygdala Reactivity Is Diminished by the Β-Noradrenergic Antagonist Propranolol. Psychological Medicine.40 1839 1848 - 202.
van Stegeren A. H. Goekoop R. Everaerd W. Scheltens P. Barkhof F. Kuijer J. P. A. Rombouts S. A. R. B. 2005 Noradrenaline Mediates Amygdala Activation in Men and Women During Encoding of Emotional Material. Neuroimage.24 898 909 - 203.
Kent JM, Coplan JD, Gorman JM 1998 Clinical Utility of the Selective Serotonin Reuptake Inhibitors in the Spectrum of Anxiety. Biol Psychiatry.44 812 824 - 204.
Browning M. Reid C. Cowen P. J. Goodwin G. M. Harmer C. J. 2007 A Single Dose of Citalopram Increases Fear Recognition in Healthy Subjects. J Psychopharmacol.21 684 690 - 205.
Grillon C. Levenson J. DS Pine 2007 A Single Dose of the Selective Serotonin Reuptake Inhibitor Citalopram Exacerbates Anxiety in Humans: A Fear-Potentiated Startle Study. Neuropsychopharmacology.32 225 231 - 206.
Harmer C. J. Bhagwagar Z. Perrett D. I. BA Völlm Cowen. P. J. Goodwin G. M. 2003 Acute Ssri Administration Affects the Processing of Social Cues in Healthy Volunteers. Neuropsychopharmacology.28 148 152 - 207.
Harmer CJ, Shelley NC, Cowen PJ, Goodwin GM 2004 Increased Positive Versus Negative Affective Perception and Memory in Healthy Volunteers Following Selective Serotonin and Norepinephrine Reuptake Inhibition. Am J Psychiatry.161 1256 1263 - 208.
Murphy S. E. Yiend J. Lester K. J. Cowen P. J. Harmer C. J. 2009 Short-Term Serotonergic but Not Noradrenergic Antidepressant Administration Reduces Attentional Vigilance to Threat in Healthy Volunteers. The International Journal of Neuropsychopharmacology.12 169 179 - 209.
Harmer CJ, Mackay CE, Reid CB, Cowen PJ, Goodwin GM 2006 Antidepressant Drug Treatment Modifies the Neural Processing of Nonconscious Threat Cues. Biol Psychiatry.59 816 820 - 210.
Anderson I. M. Del -Ben C. M. Mc Kie S. Richardson P. Williams S. R. Elliott R. Deakin J. F. W. 2007 Citalopram Modulation of Neuronal Responses to Aversive Face Emotions: A Functional MRI Study. Neuroreport.18 1351 1355 - 211.
Del -Ben C. M. Deakin J. F. W. Mc Kie S. Delvai N. A. Williams S. R. Elliott R. Dolan M. Anderson I. M. 2005 The Effect of Citalopram Pretreatment on Neuronal Responses to Neuropsychological Tasks in Normal Volunteers: An fMRI Study. Neuropsychopharmacology.30 1724 1734 - 212.
Cools R. Calder A. J. Lawrence A. D. Clark L. Bullmore E. Robbins T. W. 2005 Individual Differences in Threat Sensitivity Predict Serotonergic Modulation of Amygdala Response to Fearful Faces. Psychopharmacology (Berl).180 670 679 - 213.
MJ Attenburrow Williams. C. Odontiadis J. Reed A. Powell J. Cowen P. J. Harmer C. J. 2003 Acute Administration of Nutritionally Sourced Tryptophan Increases Fear Recognition. Psychopharmacology (Berl).169 104 107 s00213-003-1479-x. - 214.
Rhodes R. A. Murthy N. V. MA Dresner Selvaraj. S. Stavrakakis N. Babar S. Cowen P. J. Grasby P. M. 2007 Human 5-HT Transporter Availability Predicts Amygdala Reactivity in Vivo. The Journal of Neuroscience.27 9233 9237 - 215.
Niehoff DL, Kuhar MJ 1983 Benzodiazepine Receptors: Localization in Rat Amygdala. The Journal of Neuroscience.3 2091 2097 - 216.
Young WS, 3rd, Kuhar MJ 1980 Radiohistochemical Localization of Benzodiazepine Receptors in Rat Brain. J Pharmacol Exp Ther.212 337 346 - 217.
Hodges H. Green S. Glenn B. 1987 Evidence That the Amygdala Is Involved in Benzodiazepine and Serotonergic Effects on Punished Responding but Not on Discrimination. Psychopharmacology (Berl).92 491 504 - 218.
Nagy J. Zámbó K. Decsi L. 1979 Anti-Anxiety Action of Diazepam after Intra-Amygdaloid Application in the Rat. Neuropharmacology.18 573 576 - 219.
Petersen E. N. Braestrup C. Scheel-Krüger J. 1985 Evidence That the Anticonflict Effect of Midazolam in Amygdala Is Mediated by the Specific Benzodiazepine Receptors. Neurosci Lett.53 285 288 - 220.
Scheel-Krüger J. Petersen E. N. 1982 Anticonflict Effect of the Benzodiazepines Mediated by a Gabaergic Mechanism in the Amygdala. Eur J Pharmacol.82 115 116 - 221.
Shibata K. Kataoka Y. Gomita Y. Ueki S. 1982 Localization of the Site of the Anticonflict Action of Benzodiazepines in the Amygdaloid Nucleus of Rats. Brain Res.234 442 446 - 222.
Green S. Vale A. L. 1992 Role of Amygdaloid Nuclei in the Anxiolytic Effects of Benzodiazepines in Rats. Behavioural Pharmacology.3 261 264 - 223.
Pesold C. Treit D. 1995 The Central and Basolateral Amygdala Differentially Mediate the Anxiolytic Effects of Benzodiazepines. Brain Res.671 213 221 - 224.
Carvalho MC, Moreira CM, Zanoveli JM, Brandão ML 2012 Central, but Not Basolateral, Amygdala Involvement in the Anxiolytic-Like Effects of Midazolam in Rats in the Elevated Plus Maze. J Psychopharmacol.26 543 54 - 225.
Tomaz C. Dickinson-Anson H. Mc Gaugh J. L. 1992 Basolateral Amygdala Lesions Block Diazepam-Induced Anterograde Amnesia in an Inhibitory Avoidance Task. Proc Natl Acad Sci U S A.89 3615 3619 - 226.
Tomaz C. Dickinson-Anson H. Mc Gaugh J. L. MA Souza-Silva Viana. M. B. Graeff F. G. 1993 Localization in the Amygdala of the Amnestic Action of Diazepam on Emotional Memory. Behav Brain Res.58 99 105 - 227.
MA Silva Tomaz. C. 1995 Amnesia after Diazepam Infusion into Basolateral but Not Central Amygdala of Rattus Norvegicus. Neuropsychobiology.32 31 36 - 228.
Da Cunha. C. Roozendaal B. Vazdarjanova A. Mc Gaugh J. L. 1999 Microinfusions of Flumazenil into the Basolateral but Not the Central Nucleus of the Amygdala Enhance Memory Consolidation in Rats. Neurobiology of Learning and Memory.72 1 7 - 229.
Coles ME, Heimberg RG 2002 Memory Biases in the Anxiety Disorders: Current Status. Clin Psychol Rev.22 587 627 - 230.
Coles ME, Turk CL, Heimberg RG 2007 Memory Bias for Threat in Generalized Anxiety Disorder: The Potential Importance of Stimulus Relevance. Cognitive Behaviour Therapy.36 65 73 - 231.
Ferry B. Mc Gaugh J. L. 2000 Role of Amygdala Norepinephrine in Mediating Stress Hormone Regulation of Memory Storage. Acta Pharmacol Sin.21 481 493 - 232.
Ferry B. Roozendaal B. Mc Gaugh J. 1999 Role of Norepinephrine in Mediating Stress Hormone Regulation of Long-tern Memory Storage: A Critical Involvement of the Amygdala. Biol Psych.46 1140 1152 S0006322399001572 [pii]. - 233.
Berlau DJ, McGaugh JL 2006 Enhancement of Extinction Memory Consolidation: The Role of the Noradrenergic and Gabaergic Systems within the Basolateral Amygdala. Neurobiology of Learning and Memory.86 123 132 - 234.
Lin H-C, Tseng Y-C, Mao S-C, Chen P-S, Gean P-W 2011 Gabaa Receptor Endocytosis in the Basolateral Amygdala Is Critical to the Reinstatement of Fear Memory Measured by Fear-Potentiated Startle. The Journal of Neuroscience:.31 8851 8861 - 235.
Geracioti T. D. Jr Baker D. G. Ekhator N. N. West S. A. Hill K. K. Bruce A. B. Schmidt D. Rounds-Kugler B. Yehuda R. Keck P. E. Jr Kasckow J. W. 2001 CSF Norepinephrine Concentrations in Posttraumatic Stress Disorder. Am J Psychiatry.158 1227 1230 - 236.
Strawn JR, Geracioti TD, Jr. 2008 Noradrenergic Dysfunction and the Psychopharmacology of Posttraumatic Stress Disorder. Depress Anxiety.25 260 271 - 237.
Asnis G. M. Kohn S. R. Henderson M. Brown N. L. 2004 Ssris Versus Non-Ssris in Post-Traumatic Stress Disorder: An Update with Recommendations. Drugs.64 383 404 - 238.
Braun P. Greenberg D. Dasberg H. Lerer B. 1990 Core Symptoms of Posttraumatic Stress Disorder Unimproved by Alprazolam Treatment. J Clin Psychiatry.51 236 238 - 239.
Pitman R. K. Sanders K. M. Zusman R. M. Healy A. R. Cheema F. Lasko N. B. Cahill L. Orr S. P. 2002 Pilot Study of Secondary Prevention of Posttraumatic Stress Disorder with Propranolol. Biol Psychiatry.51 189 192 - 240.
Vaiva G. Ducrocq F. Jezequel K. Averland B. Lestavel P. Brunet A. Marmar C. R. 2003 Immediate Treatment with Propranolol Decreases Posttraumatic Stress Disorder Two Months after Trauma. Biol Psychiatry.54 947 949 - 241.
Adamec R. Muir C. Grimes M. Pearcey K. 2007 Involvement of Noradrenergic and Corticoid Receptors in the Consolidation of the Lasting Anxiogenic Effects of Predator Stress. Behav Brain Res.179 192 207 j.bbr.2007.02.001. - 242.
Cohen H. Kaplan Z. Koresh O. MA Matar Geva. A. B. Zohar J. 2011 Early Post-Stressor Intervention with Propranolol Is Ineffective in Preventing Posttraumatic Stress Responses in an Animal Model for PTSD. European Neuropsychopharmacology.21 230 240 - 243.
Adamec R. E. Blundell J. Collins A. 2001 Neural Plasticity and Stress Induced Changes in Defense in the Rat. Neurosci Biobehav Rev.25 721 744 - 244.
Bodnoff S. R. Suranyi-Cadotte B. Quirion R. MJ Meaney 1989 A Comparison of the Effects of Diazepam Versus Several Typical and Atypical Anti-Depressant Drugs in an Animal Model of Anxiety. Psychopharmacology (Berl).97 277 279 - 245.
Griebel G. Moreau J. L. Jenck F. Misslin R. Martin J. R. 1994 Acute and Chronic Treatment with 5-HT Reuptake Inhibitors Differentially Modulate Emotional Responses in Anxiety Models in Rodents. Psychopharmacology (Berl).113 463 470 - 246.
Kurt M. Arik A. C. Celik S. 2000 The Effects of Sertraline and Fluoxetine on Anxiety in the Elevated Plus-Maze Test in Mice. Journal of Basic and Clinical Physiology and Pharmacology.11 173 180 - 247.
Dekeyne A. Denorme B. Monneyron S. MJ Millan 2000 Citalopram Reduces Social Interaction in Rats by Activation of Serotonin (5-HT)(2c) Receptors. Neuropharmacology.39 1114 1117 - 248.
Griebel G. 1995 Hydroxytryptamine-Interacting Drugs in Animal Models of Anxiety Disorders: More Than 30 Years of Research. Pharmacology & Therapeutics.65 319 395 - 249.
Campbell BM, Merchant KM 2003 Serotonin 2c Receptors within the Basolateral Amygdala Induce Acute Fear-Like Responses in an Open-Field Environment. Brain Res.993 1 9 - 250.
Christianson J. P. Ragole T. Amat J. Greenwood B. N. Strong P. V. Paul E. D. Fleshner M. Watkins L. R. Maier S. F. 2010 Hydroxytryptamine 2c Receptors in the Basolateral Amygdala Are Involved in the Expression of Anxiety after Uncontrollable Traumatic Stress. Biol Psychiatry.67 339 345 - 251.
MA Vicente Zangrossi. H. 2011 Serotonin-2c Receptors in the Basolateral Nucleus of the Amygdala Mediate the Anxiogenic Effect of Acute Imipramine and Fluoxetine Administration. The International Journal of Neuropsychopharmacology.1 12 - 252.
Burghardt NS, Bush DEA, McEwen BS, LeDoux JE 2007 Acute Selective Serotonin Reuptake Inhibitors Increase Conditioned Fear Expression: Blockade with a 5-HT(2c) Receptor Antagonist. Biol Psychiatry.62 1111 1118 - 253.
Bagdy G. Graf M. Anheuer Z. E. Modos E. A. Kantor S. 2001 Anxiety-Like Effects Induced by Acute Fluoxetine, Sertraline or M-CPP Treatment Are Reversed by Pretreatment with the 5-HT2c Receptor Antagonist Sb-242084 but not the 5-HT1a Receptor Antagonist Way-100635. Int J Neuropsychopharmacol.4 399 408 doi:10.1017/S1461145701002632. - 254.
Salchner P. Singewald N. 2006 HT Receptor Subtypes Involved in the Anxiogenic-Like Action and Associated Fos Response of Acute Fluoxetine Treatment in Rats. Psychopharmacology (Berl).185 282 288 - 255.
Hollander E. De Caria C. Gully R. Nitescu A. Suckow R. F. Gorman J. M. Klein D. F. Liebowitz M. R. 1991 Effects of Chronic Fluoxetine Treatment on Behavioral and Neuroendocrine Responses to Meta-Chlorophenylpiperazine in Obsessive-Compulsive Disorder. Psychiatry Res.36 1 17 - 256.
Zohar J. Insel T. R. Zohar-Kadouch R. C. Hill J. L. Murphy D. L. 1988 Serotonergic Responsivity in Obsessive-Compulsive Disorder. Effects of Chronic Clomipramine Treatment. Archives of General Psychiatry.45 167 172 - 257.
Kennedy A. J. Gibson E. L. O’Connell M. T. Curzon G. 1993 Effects of Housing, Restraint and Chronic Treatments with MCPP and Sertraline on Behavioural Responses to MCPP. Psychopharmacology (Berl).113 262 268 - 258.
Yamauchi M. Tatebayashi T. Nagase K. Kojima M. Imanishi T. 2004 Chronic Treatment with Fluvoxamine Desensitizes 5-HT2c Receptor-Mediated Hypolocomotion in Rats. Pharmacol Biochem Behav.78 683 689 - 259.
Seeman P. 2002 Atypical antipsychotics: mechanism of action. Can J Psychiatry,47 27 38 - 260.
de Boet T. 1996 The pharmacological profile of mirtazapine. J Clin Psychiatry.57 19 25 - 261.
Ravindran LN, Stein MB. 2010 The pharmacologic treatment of anxiety disorders: a review of progress. J Clin Psychiatry.71 839 54 - 262.
Rainer Q. Xia L. Guilloux J. P. Gabriel C. Mocaër E. Hen R. Enhamre E. Gardier A. M. David D. J. 2010 Beneficial Behavioural and Neurogenic effects of Agomelatine in a Model of Depression/Anxiety. Int J Neuropsychopharmacol.8 1 15 - 263.
Katzman MA. 2011 Aripiprazole: a clinical review of its use for the treatment of anxiety disorders and anxiety as a comorbidity in mental illness. J Affect Disord. 128, S11 20 - 264.
Kehne JH, Cain CK 2010 Therapeutic Utility of Non-Peptidic CRF1 Receptor Antagonists in Anxiety, Depression, and Stress-Related Disorders: Evidence from Animal Models. Pharmacology & Therapeutics.128 460 487 j.pharmthera.2010.08.011.