Faculty Affiliations and Disclosures
Dr. Nair is chief of Child and Youth Services at Burrell Behavioral Health in Springfield, Missouri, and adjunct associate professor in the Department of Psychiatry at the University of Missouri–Columbia. Dr. Ajit is staff psychiatrist at the Community Counseling Center in Ashtabula, Ohio.
Disclosure: The authors do not have an affiliation with or financial interest in any organization that might pose a conflict of interest.
Submitted for publication: July 9, 2007; Accepted for publication: June 16, 2008.
Please direct all correspondence to: Sarbjot Singh Ajit, MD, Community Counseling Center, 2801 “C” Ct., Ashtabula, OH 44004; Tel: 440-998-4210; E-mail: firstname.lastname@example.org.
Antiglutamatergic agents, such as lamotrigine, have been used successfully for the treatment of posttraumatic stress disorder (PTSD). They could be potentially acting through the stabilization of the corticotropin-releasing factor (CRF) systems. Glutamate mediates CRF release in various brain regions involved in the pathophysiology of PTSD, antiglutamatergic agents could stabilize the CRF system and, thereby, improve the symptom complex of PTSD (reexperiencing, hyperarousal, and avoidance). The role of glutamate and CRF in PTSD and other anxiety disorders are still being elucidated. However, it is clear that the glutamatergic systems play a role in the pathophysiology of PTSD.
The main symptom cluster of posttraumatic stress disorder (PTSD) includes reexperiencing, autonomic hyperarousal, and avoidance following exposure to trauma.1 These behavioral manifestations of PTSD occur as a result of neurotransmitter/hormonal mechanisms and neuroplasticity in the fear circuit in addition to other factors, such as genetic differences. Several studies4 point to the involvement of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD pathophysiology. Variations in cortisol level have been noted in PTSD patients,2,3 which have included low circulating cortisol levels in veterans with PTSD compared with controls. In a 24-hour circadian study, Yehuda and colleagues5 reported significantly lower plasma cortisol levels particularly in the early morning and late evening hours in combat veterans with PTSD compared to depressed patients and normal controls. Dysregulation at the HPA axis could explain the reported variations in cortisol in PTSD.
The fear circuit has been implicated in PTSD. With the advent of imaging technology parts of the brain involved in fear conditioning can be probed in real time providing a window to the changes in the areas of the brain involved in PTSD pathology. Studies utilizing fear conditioning and extinction paradigms in PTSD patients and control groups6-8 have shown that the PTSD patients have delayed learning of fear extinction. Fear conditioning and extinction occur as a result of plasticity at different points in the fear circuit.9-11 Neuroplastic changes at the synaptic level of the fear circuit may play a role in PTSD pathophysiology.9
Medications from different classes have been used clinically in the pharmacological treatment of PTSD. More recently, lamotrigine, an antiglutamatergic agent, has been reported to be effective in treating PTSD associated symptoms as described in a double-blind study where the lamotrigine-treated group had reported significant improvement of symptoms, such as avoidance, flashbacks (reexperiencing the trauma), and numbing, compared with placebo. Furthermore, lamotrigine has been shown efficacious in treating PTSD without comorbid bipolar disorder, largely in combat veterans.13
The aforementioned observations, especially the observed effectiveness of an antiglutamatergic agent in alleviating the symptoms of PTSD, suggest that the glutamatergic system could play a role in the pathophysiology of PTSD through both the fear circuit and the HPA axis.
In this article, the possible mechanisms by which agents acting on the glutamatergic system can lead to improvement in symptoms of hyperarousal, reexperiencing, and avoidance observed in PTSD will be discussed. The role of corticotropin-releasing factor (CRF) in the regulation of the HPA axis will be described, followed by the role of glutamate in modulating the CRF system in various brain regions involved in the pathophysiology of PTSD, thereby linking the glutamate-CRF system to the main behavioral manifestations of PTSD (hyperarousal, avoidance, and reexperiencing). In this manner, an association between the glutamatergic system and the PTSD symptom triad will be established.
The Hypothalamic-Pituitary-Adrenal Axis in Posttraumatic Stress Disorder
The HPA axis responds to a variety of psychogenic stressors leading to CRF release from CRF containing neurons in the hypothalamus. These neurons project to the hypothalamic median eminence. Immunohistochemical studies14 demonstrate that the majority of hypothalamic CRF containing neurons projecting to the median eminence are located in the paraventricular nucleus (PVN). Electrical stimulation of PVN leads to increase in CRF release and results in elevated plasma levels of adrenocorticotrophic hormone (ACTH).15 Similarly, inhibition of PVN by microinjection of lidocaine or muscimol (γ-aminobutyric acid [GABA] agonist) attenuated the stress-induced CRF and plasma ACTH elevation.16 Thus, PVN stimulation is the crucial point for HPA activation in stress.
A negative feedback mechanism regulates the plasma cortisol level. CRF action on the anterior pituitary results in ACTH release and, subsequently, ACTH stimulates cortisol release from the adrenal glands. Cortisol down-regulates CRF receptors through negative feedback, thereby, ultimately reducing cortisol levels.
Overall, the reports on the HPA axis disturbance in PTSD are mixed. Studies16-18 have implicated CRF and cortisol expression as predisposing factors in the pathogenesis of PTSD. Data from prospective studies16-18 suggest that individuals predisposed to develop PTSD after a traumatic event had an attenuated rise in their cortisol levels in the immediate aftermath of a traumatic event, with greater sympathetic arousal. Relatively low cortisol levels following a traumatic event may indicate an increased susceptibility to develop PTSD, and serve as a biological marker. Patients with chronic PTSD have chronically low cortisol levels. Immediately following a motor vehicle accident, subjects with low levels of cortisol had a higher incidence of subsequent PTSD compared with similar accident victims with normal cortisol levels.16-18 Cortisol levels were lower in rape victims who had suffered a previous assault than in those who were assaulted for the first time.17,18 Children of Holocaust survivors with PTSD, were at increased risk to develop PTSD following an exposure to a traumatic event. They typically had low cortisol levels. Children whose parents did not have PTSD were less likely to develop PTSD, and had normal cortisol levels. The children of Holocaust survivors with PTSD who had never experienced trauma had low cortisol levels, suggesting low cortisol expression may be due to HPA dysregulation predating the traumatic event.16
Role of Glutamate in Stress
The glutamatergic system plays a role in the stress response. Alteration in the expression of N-methyl-D-aspartate (NMDA) receptor subunit in the PVN has been described in animals following exposure to various types of stress with increased level of messenger ribonucleic acid coding for the NMDA receptor subunit NR1 in the PVN of rats after exposure to even a single immobilization stress.19 Enhancement of NMDA receptor binding in the hypothalamus 24 hours after immobilization has also been reported.20 Thus, stress affects glutamatergic system, as evidenced by increased NMDA receptor binding and expression.
These stress-induced changes in NMDA expression can be reproduced by exogenous administration of corticosterone in rats, indicating that stress could affect the glutamatergic system through the cortisol pathway. There is further evidence from reports21 describing that pre-treatment with the NMDA receptor antagonist dizocilpine significantly reduces ACTH secretion in response to immobilization stress. An increase of ~25% in c-Fos positive CRF neurons occurred with microinjection of glutamate into the PVN of anesthetized rats, which was accompanied by arousal shift in the electrocorticogram of these rats.22 This indicates that glutamate mediates the release of CRF in the PVN and plays a role in arousal. In conclusion, the glutamatergic and CRF systems modulates each other’s expression.
Glutamate mediates CRF release and studies21,23 in the PVN have shown that direct application of glutamate to PVN resulted in CRF release, a rise in ACTH, and an increase in corticosterone levels in rats. This effect of glutamate on CRF release is mediated through NMDA receptors and pretreatment with an NMDA receptor antagonist reduces corticosterone release.21,23 In another study,24 it was reported that incubation of rat hypothalamic slices with glutamate resulted in a dose-dependent increase in CRF release.
The direct effect of glutamate on CRF-releasing neurons is to increase CRF release and, subsequently, activate the stress-response hormone cascade. These hormones increase extracellular glutamate and NMDA expression, as previously described. Reduction in NMDA expression or the neutralization of glutamate increase by antiglutamatergic agents could potentially attenuate CRF release, leading to improvement in the symptoms of PTSD.
Posttraumatic Stress Disorder Symptoms
PTSD includes the symptoms of hyperarousal, avoidance, and reexperiencing following exposure to a severe traumatic experience. As mentioned earlier, CRF and other components of the HPA axis play a role in PTSD pathophysiology. The three core symptoms and the role of the glutamatergic system in the pathology of these will be discussed together with how antiglutamatergic agents, such as lamotrogine, may play a role in treating PTSD symptoms.
Hyperarousal is a state of alertness mediated by increased secretion of norepinephrine (NE) from locus coeruleus. Hyperarousal is an emotionally based response related to the sensing of danger and the need for quick reaction by the individual or the “fight or flight response.” The quick response involves the amygdala, a prominent limbic structure that links common experiences by placing an emotional valence on the individual experience. The amygdala receives excitatory glutamatergic innervations that activate the amygdala and contains GABAergic interneurons that modulate and inhibit glutamatergic excitability within the amygdala.25 This interaction between glutamatergic activation and GABAergic inhibition may be central to the neurobiology of PTSD.
In brief, amygdala is divided into the basolateral nuclear group and the central amygdaloid nucleus (CeN). The basolateral nuclear group receives input from throughout the brain. The temporal cortex relays information from higher-order auditory and visual processing to the basolateral nuclear group. The CeN is part of a cellular continuum that spans the entire forebrain to include the lateral bed nucleus of the stria terminalis25 activating several output centers, including the locus coeruleus.
The CeN contains a high density of CRF-containing cell bodies and CRF binding sites. This CRF system responds to stressors that have a large psychological component. Animal studies26-28 have suggested that CRF action in amygdala is dependent on NMDA receptors. Urocortin, a potent CRF receptor agonist, increased glutamatergic activation, resulting in persistent anxiety-like responses.
A pathway utilizing CRF from the CeN group has been shown to be important in activating the locus ceruleus with resultant release of NE and hyperarousal response. Direct infusion of CRF into the locus coeruleus leads to the increase of discharge rate and a change in the mode of discharge. There was an increase in tonic modes of locus coeruleus discharge compared with phasic tonic discharge. Tonic modes of locus coeruleus discharge favor scanning attention—associated with the hyperarousal state—rather than selective attentional functions in a non-anxious state.29
Activation of the locus coeruleus by CRF will increase NE release in the forebrain targets, resulting in cortical activation. Sensitization of the locus coeruleus-NE system has been reported in response to CRF activation associated with chronic stress.30 Patients with PTSD may have sensitized CRF receptors in the locus coeruleus, such that previously subthreshold stimuli now activate the locus coeruleus and release of NE, resulting in increased arousal and heightened attention. Sensitized CRF receptors may also result in patients with PTSD, responding inappropriately to stimuli that do not typically activate the locus coeruleus-NE system. Only stressors that cause CRF release in the locus coeruleus produce an exaggerated response.29
The noradrenergic hyper-reactivity seen in PTSD may relate to conditioned or sensitized responses to specific traumatic stimuli due to sensitization of CRF receptors in the locus coeruleus, resulting in heightened noradrenergic function observed in PTSD patients.29 Stimulation of the locus coeruleus-NE system occurs at the level of the locus coeruleus projections to the basal forebrain and in the interaction of the peripheral sympathetic system with the central NE system. The occurrence of clinically observed hyperarousal in PTSD as a result of activation of the noradrenergic system is supported in the literature.29,30 Higher urinary NE levels have been noted in combat veterans with PTSD compared to patients with schizophrenia or major depression.31
Combat veterans with PTSD exposed in laboratories to visual and auditory stimuli associated with combat showed signs of sympathetic autonomic arousal, such as higher resting pulses and pulse-rate increases, as well as higher systolic pressures, than similarly exposed combat veterans without PTSD, patients with generalized anxiety disorder, and normal volunteers.24 Reports also state that cerebrospinal level of CRF is high in patients with PTSD, supporting the possibility of increased CRF receptor activity.32-34
The glutamatergic system modulates the HPA axis by increasing of CRF release that would result in release of NE from locus coeruleus as a result of the direct action of CRF. In addition, as previously mentioned in this section, other indirect mechanisms acting through the amygdala also work with the glutamatergic system.32 Overall, there is evidence26 that antiglutamatergic agents would reduce anxiety-like response when acting in the amygdalar region. Antiglutamatergic agents could reduce hyperarousal in PTSD patients through the mechanism of decreased CRF release from the median eminence, reduce CRF at the locus coeruleus, and, thus, improve the symptoms of PTSD, as observed with lamotrigine use.
Avoidance prevents behaviors that could result in an element of stress. Places and activities that could remind patients with PTSD of the traumatic events are actively avoided. Avoidance behavior can be related to the disengaging behavior described in clinical literature in PTSD.35 Differences in cortisol levels have been noted in PTSD patients with avoidance behavior in longitudinal studies35 indicating a disturbance of the HPA axis.
Longitudinal studies35 conducted in male Vietnam war veterans with PTSD, measuring their urinary cortisol levels at admission, mid-point, and discharge during 90-day hospitalization, which included intensive exposure therapy. Patients with PTSD with relatively high urinary cortisol levels at admission showed a significant drop in their cortisol levels at the midpoint of their hospitalizations. These patients were disengaged from their intensive exposure therapy and had relatively severe PTSD core symptoms, with poorer levels of social functioning compared with patients whose cortisol levels rose at the midpoint of their hospitalization. These patients were engaged in their intensive exposure therapy, had better social functioning, and less severe PTSD core symptoms than patients whose cortisol levels dropped in the midpoint of their hospitalization. Interestingly, the actively engaged patients who had high cortisol levels during the midpoint of their hospitalization had relatively low levels of urinary cortisol on admission.35
The relationship between low urinary cortisol level and avoidant and disengaged behavior extends to preoperative patients,35 when it was observed that individuals with higher cortisol levels the day before elective cardiothoracic surgery were more likely to be engaged in anticipatory preparation for their surgery than patients with low cortisol levels who were disengaged from the process.
Cortisol levels are mediated by the CRF and glutamate innervation. In a double-blind, placebo-controlled study,12,36 lamotrigine reportedly improved associated numbing and avoidance in PTSD patients. The initially higher levels of cortisol at admission in avoidant and disengaged PTSD patients in the longitudinal study by Mason and colleagues35 may result from alteration in the glutamatergic and CRF system. Antiglutamatergic agents may stabilize glutamatergic-CRF and, thereby, improve avoidance.
Reexperiencing involves emotional recall of traumatic events triggered by stimuli not necessarily related to the original traumatic experience. There is interplay of emotion and memory in this phenomenon. Amygdalae and hippocampi both play a role, with amygdala providing emotional valance to experiences and hippocampus playing a role in memory storage.9,10
The medial prefrontal cortex inhibits exaggerated emotional amygdalar response and plays a crucial role in extinction of fear responses. Hippocampus, on the other hand, is vital in the recalling of previously conditioned stimuli (explicit memories). These inputs are relayed to the basolateral nuclear group of the amygdala, which fire a particular neuronal pattern based on the emotional valence attached to the stimuli. Firing patterns from the basolateral nuclear group are modified according to the perceived threat, and, based on these firing patterns, CeN may be activated.
The amygdala is critical in fear conditioning and stress potentiation. Remarkably, while stress and cortisol elevation results in atrophy of hippocampal dendritic processes, extension of dendritic processes in the amygdala with stress has been reported.9 The amygdala has a higher threshold for calcium influx than other brain structures, such as the hippocampus and medial prefrontal cortex. The higher threshold may result in dendritic arborization of neurons in the amygdala and dendritic retraction in the hippocampus and medial prefrontal cortex. This excitatory response in the amygdala may prolong the excitatory and excitotoxic effects in the hippocampus and medial prefrontal cortex.
Decrease in hippocampal volume in cases of PTSD has been reported and replicated in imaging studies.37 The decrease in hippocampal volume could be as a result of repeated exposure to stress and glucocorticoids. Experiments in rats23 have shown that repeated exposure to stress or glucocorticoids results in retraction of hippocampal dendritic processes. The reported loss of rat apical dendritic branch points and decreased length of apical dendrites produces atrophy and regression in CA1 and CA3 cell fields of the hippocampus. This process reverses gradually with the cessation of stress or glucocorticoid exposure.
Patients with Cushing’s syndrome an endocrinal disorder characterized by elevation of glucocorticoid level have been shown to have a smaller hippocampi and impairment of hippocampal-dependent cognition, suggesting that elevated glucocorticoid level correlates with reduction in hippocampal volume.9,38 The reduction in hippocampi volume in Cushing’s syndrome is reversible following the stabilization in glucocorticoid levels.
Glucocorticoids released during stress stimulate the release of glutamate in CA3 pyramidal neurons in the rodent hippocampi. When the rodent adrenal glands were removed, there was a reduction in glucocorticoid levels in response to stress. This reduction in glucocorticoid level resulted in attenuation of the stress-induced outflow of glutamate in the hippocampus and the medial prefrontal cortex. Replacement of glucocorticoids exogenously reversed glutamates attenuation.23 Glutamate prolongs calcium influx in neuronal cells and is excitotoxic. The observed effects of glucocorticoids in various brain regions involved in the pathology of PTSD (hippocampus, amygdala, prefrontal cortex) may, therefore, lie in glucocorticoid modulation of glutamate release.
As the hippocampal function is disrupted due to atrophy of the dendritic process, explicit memories of traumatic experiences falter while the emotional intonation of the traumatic experience is exaggerated with the occurrence of dendritic extension in the amygdala. This results in memories being emotionally based rather than cognitively based, creating a cycle in which unconditioned stimuli, such as loud noises, elicit reexperiencing of traumatic events, such as flashbacks and hyperarousal.
Double-blind, placebo-controlled studies of lamotrigine12 have reported an improvement in the symptoms in the reexperiencing domain. The reported benefit could be a combination of direct effects, reduced CRF and cortisol, and the improvement as a result of reduced hyperarousal and noradrenergic tone through their antiglutamatergic mechanism. This reduction would lead to reduction in the intensity of the perceived triggers that lead to reexperiencing episodes.
The neurobiology of PTSD has several facets and the mechanisms include changes in HPA axis as well as the fear circuit. Treatment of the symptoms of PTSD has been a clinical challenge and the recent reports of efficacy of lamotrigine in improving the symptoms of PTSD lead us to attempt an explanation of the possible mechanisms behind this observation and link the observed behavior with the various mechanisms wherever possible.
The glutamatergic system plays a significant role in the pathogenesis of PTSD. Glutamate modulates the HPA axis by stimulating the release of CRF, a key components of the HPA axis. CRF release can lead to multiple down stream changes in the stress hormone cascade. Multiple studies have concluded that HPA axis dysregulation is a part of the pathology of PTSD. Reduction in CRF level can reduce locus coeruleus discharges and the resulting hyperarousal alter cortisol levels and potentially affect avoidance and reexperiencing. Agents acting on the glutamatergic system, such as lamotrigine, have been shown to be effective in treating core PTSD symptoms. Lamotrigine, an antiglutamatergic agent, may attenuate the excitotoxic effects of stress in various brain regions involved in PTSD and, thereby, may be neuroprotective.
In the future, more information on the mechanism of antiglutamatergic agents, such as lamotrigine, would add to the understanding of PTSD. The discussion was limited mainly to the HPA axis, the focus of this article and included the components of the fear circuit only when relevant. Pharmaceutical agents affecting the glutamatergic system add to the clinician’s ability to treat the symptoms of PTSD.
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