Nitrous oxide may provide temporary relief to veterans suffering from PTSD

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For military veterans suffering from post-traumatic stress disorder (PTSD), symptoms such as anxiety, anger and depression can have a devastating impact on their health, daily routine, relationships and overall quality of life.

A new pilot study by the University of Chicago Medicine and the Stanford University School of Medicine team from the VA Palo Alto Health Care System (principal investigators Carolyn Rodriguez, MD, and David Clark, MD, PhD) provides an early glimpse of how some of these veterans may benefit from one simple, inexpensive treatment involving nitrous oxide, commonly known as laughing gas.

Effective treatments for PTSD are limited,” said anesthesiologist Peter Nagele, MD, chair of the Department of Anesthesia & Critical Care at UChicago Medicine and co-author of the paper. “While small in scale, this study shows the early promise of using nitrous oxide to quickly relieve symptoms of PTSD.”

The findings, based on a study of three military veterans suffering from PTSD and published June 30 in the Journal of Clinical Psychiatry, could lead to improved treatments for a psychiatric disorder that has affected thousands of current and former members of the U.S. military.

For this new study, three veterans with PTSD were asked to inhale a single one-hour dose of 50% nitrous oxide and 50% oxygen through a face mask.

Within hours after breathing nitrous oxide, two of the patients reported a marked improvement in their PTSD symptoms.

This improvement lasted one week for one of the patients, while the other patient’s symptoms gradually returned over the week.

The third patient reported an improvement two hours after his treatment but went back to experiencing symptoms the next day.

“Like many other treatments, nitrous oxide appears to be effective for some patients but not for others,” explained Nagele, who is himself a veteran of the Austrian Army and grateful to have identified an opportunity to help other veterans.

“Often drugs work only on a subset of patients, while others do not respond. It’s our role to determine who may benefit from this treatment, and who won’t.”

Nagele is a pioneer in the field of using nitrous oxide to treat depression. Most commonly known for its use by dentists, nitrous oxide is a low-cost, easy-to-use medication. Although some patients may experience side effects like nausea or vomiting while receiving nitrous oxide, the reactions are temporary.

Exactly how and why nitrous oxide relieves symptoms of depression in some people has yet to be fully understood. Most traditional antidepressants work through a brain chemical called serotonin.

Nitrous oxide, like ketamine, an anesthetic that recently received FDA-approval in a nasal spray form to treat major depression, works through a different mechanism, by blocking N-methyl-D-aspartate (NMDA) receptors.

A 2015 landmark study by Nagele found that two-thirds of patients with treatment-resistant depression experienced an improvement in symptoms after receiving nitrous oxide.

For his next study, Nagele is researching the ideal dose of nitrous oxide to treat intractable depression.

Study participants with treatment-resistant depression received different doses of nitrous oxide so that Nagele and his team could compare each dose’s effectiveness and side effects. The study is being funded by the Brain & Behavior Research Foundation.

“Does nitrous oxide help veterans with post traumatic stress disorder” was funded by the VA Office of Research and Development Clinical Science Research & Development Service.


Classified as an anxiety disorder, post-traumatic stress disorder (PTSD) is characterized by hyperarousal, avoidance, and various amnesic symptoms caused by exposure to a severe traumatic event (APA 1994) (Table 1).

By definition PTSD occurs in the aftermath of exposure to trauma, but there is growing awareness of the importance of multiple exposures to trauma in predicting the onset and severity of this disorder (Brewin 2001; Maes et al 2001).

Nevertheless, the more severe the initial trauma and the more intense the acute stress symptoms, the higher is the risk for developing PTSD (Gore and Richards 2002).

Table 1 – Main symptoms of PTSD

  • Reexperiencing
  • Invasive memories of the trauma
  • Frequent nightmares
  • Flashbacks
  • Psychological and physiological reactivity to internal/external cues resembling the trauma

Avoidance

  • Avoiding thoughts, conversations, feelings, places, activities, and people related to the event
  • Inability to recall an important aspect of the trauma
  • Loss of interest in external world and detachment from others
  • Difficulty feeling and expressing positive emotion
  • Lack of desire to deal with the future

Hyperarousal

  • Anxiety and hypervigilance
  • Problems with sleeping
  • Difficulty in concentrating and studying
  • Irritability with angry outbursts Constant feeling of alertness and exaggerated startle response

Data adapted from APA (1994).

Abbreviations: PTSD, post-traumatic stress disorder.

The most characteristic features of PTSD are pneumonic in nature (APA 1994) and include amnesia, flashbacks, fragmentation of memories (Elzinga and Bremner 2002), and an abnormal startle response; the latter reflecting an inability to properly integrate memories (van der Kolk 1994).

In lieu of the evidence for degeneration of the hippocampus in patients with PTSD, a dysfunctional hippocampus may represent the anatomic basis for the fragmentation of memory.

Although glucocorticoids have received the greatest attention with regards to the possible mechanisms involved in hippocampal shrinkage (McEwen 1999; Sapolsky 2000b), their role, as well as other molecules involved in cellular resilience, requires more stringent evaluation.

Recent preclinical studies have found that stress exerts significant effects on nitric oxide synthase (NOS) activity, while clinical trials have emphasized the role of gamma-amino butyric acid (GABA)-glutamate balance as a putative neurobiological target in the treatment of PTSD.

This paper reviews the role of GABA and glutamate in stress, especially the preclinical evidence for involvement of the nitric oxide (NO)-pathway in PTSD, and studies that have addressed these issues using time-dependent sensitization – a putative animal model of PTSD.

From this point of view, we address their role as protagonists of neuronal degeneration and atrophy evident in neuroimaging studies of patients with PTSD, and how this may unfold into new avenues of treatment.

Anatomy and neurobiology of PTSD
Brain areas accepted as critical in mediating the stress response are the hippocampus and prefrontal cortex. These areas are in turn affected by the stress response. Imaging studies in PTSD patients have demonstrated volume reductions in the hippocampus (Bremner 1999; Elzinga and Bremner 2002), while structural changes, as well as functional deficits have also been observed in the medial prefrontal cortex in PTSD (Bremner 2002; Elzinga and Bremner 2002).

Proper functioning of the hippocampus is necessary for explicit or declarative memory. Damage to the hippocampus resulting from stress not only causes problems in dealing with memories relating to past stressful experiences, but also impairs new learning (Bremner 1999; Elzinga and Bremner 2002).

The prefrontal cortex, on the other hand, plays an important role in the process of fear conditioning, specifically with regard to extinction of conditioned fear responses (Le Doux 1998; Hamann 2001).

In this regard, the medial prefrontal cortical areas modulate fear responding through inhibitory connections with the amygdala (Le Doux 1998), which in turn plays a crucial role in fear conditioning (Akirav et al 2001).

Recent studies suggest that structural abnormalities in PTSD may reflect either pre-trauma vulnerability or a consequence of trauma exposure (Gilbertson et al 2002). Furthermore, while increased plasma cortisol levels occur immediately after or during stress (Yehuda et al 1990), clinical studies of cortisol in PTSD have met with mixed results.

Thus, investigators have documented plasma cortisol as unchanged (Baker et al 1999), elevated (Liberzon et al 1999), and suppressed (Yehuda et al 2000). Given these diverse results, the causal role for glucocorticoids in hippocampal neurodegeneration and cognitive decline in patients with PTSD remains unclear.

A key issue in the pathogenesis of PTSD seems to be within associative learning and other behavioral processes mediated by the hippocampus. These processes involve the glutamate N-methyl-D-aspartate (NMDA) receptors (Heresco-Levy and Javitt 1998) and the NO signaling pathway (O’Dell et al 1994; McLeod et al 2001).

Moreover, the synaptic localization of NOS and the soluble guanylyl cyclase (McLeod et al 2001) facilitates the functioning of NO as a retrograde messenger – and thereby serves as a possible modulator of long-term potentiation (LTP) (Burette et al 2002).

LTP represents a form of synaptic learning that is known to exist in the hippocampus, striatum, and neocortex, and has been proposed as a cellular model for some forms of learning and memory. LTP describes a prolonged increase in the size of the postsynaptic response to a presynaptic stimulus of given strength.

Activation of NMDA receptors are obligatory for the induction of the type of LTP that occurs in the hippocampus CA1 region. These events are initiated by Ca2+ flow through open, unblocked NMDA channels that lead to alterations in the strength of interneuronal synaptic connectivity (Bliss and Collingridge 1993; Bloom 2001).

In the hippocampus, LTP is most evident in the dentate gyrus granule cells where glutamate activation of both AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and NMDA receptors (Vallance and Collier 1994) are required.

It is interesting that prolonged loss of consciousness following terrifying events appears to protect against the development of PTSD (Adler 1993). Although coma is not yet fully understood, it may involve disruption of glutamatergic pathways (O’Brien and Nutt 1998).

Similarly, central nervous system (CNS) suppressants such as ethanol and benzodiazepines exert some of their effect by suppressing glutamatergic function, these frequently being abused by patients with PTSD, possibly assisting in preventing the reemergence of previously established memories (Collingridge and Bliss 1995).

The activation of neuronal NO synthase (nNOS) and other Ca2+ -dependant enzymes may account for many of the beneficial as well as deleterious affects associated with NMDA receptor activation, including neuronal development (Garthwaite 1991), learning, and memory (Iga et al 1993), but also cell death and neurodegeneration (Dawson VL and Dawson TM 1995).

Role of sensitization and kindling in PTSD
Models such as fear conditioning and kindling have been central to our understanding of fear circuitry, particularly through the processing of fear-relevant information between the amygdala, locus coeruleus, hippocampus, and thalamus.

The association between stressful life events and the onset and chronicity of psychiatric illness dates back to Kraepelin (1921) who proposed that in depression, the illness may become increasingly autonomous and less reliant on environmental adversity. This mechanism may hold for most psychiatric illnesses that are characterized by a progressive worsening over time.

The kindling phenomena was first described by Goddard et al (1969) who noted that repeated subthreshold electrical stimulation leads to full-blown seizures. After sufficient repetition the seizures begin to occur spontaneously.

The kindling hypothesis therefore has particular relevance for viewing how synapses react to environmental stressors, and represents one way to integrate a range of data describing the neurophysiology and neurochemistry of the onset, long-term development, and treatment responsiveness of PTSD.

The primary neural substrate of kindling involves glutamate and NMDA receptor activation, with inhibitory GABA pathways exerting essentially a permissive role on the kindling action of glutamate (Post and Weiss 1998).

This evidence not only emphasizes the involvement of excitatory glutamatergic and inhibitory GABA’ergic pathways in the neuropathology of PTSD (Chambers et al 1999; Vaiva et al 2004), but also the process of sensitization and kindling in the neuro-development of the disorder.

How may glucocorticoids be involved in the biobehavioral pathology of PTSD?
Exposure to an acute stressful event leads to a profound release of glucocorticoids from the adrenal cortex (Bremner 1999). Important to note is that glucocorticoids have bidirectional effects on memory function.

While hippocampal damage is associated with exposure to excessive levels of glucocorticoids (Bremner et al 1999), too low levels of glucocorticoids are also detrimental for normal hippocampal function (de Kloet et al 1999).

Repeated administration of corticosterone decreases 5-HT1A-mediated inhibition of the hippocampus (Karten et al 1999) through a process that occurs at the level of protein synthesis (Bijak et al 2001), resulting in reduced 5-HT1A receptor expression (Montgomery et al 2001).

Consequently, stress-induced corticosterone release immediately after stress will make the hippocampus more vulnerable to the laying down of long-term emotion-driven memories.

In both PTSD and TDS stress, increased sensitivity of hippocampal glucocorticoid receptors (Yehuda 1998) and release of glutamate may heighten the vulnerability of the hippocampus to atrophy, even in the absence of higher cortisol levels (Sapolsky 2000b).

Indeed, marked changes in glutamate NMDA receptors have been observed following TDS stress (Harvey et al 2004). Furthermore, high levels of corticosterone induce a rapid and non-genomic prolongation of NMDA receptor-mediated Ca2+ elevation in cultured rat hippocampal neurons (Takahashi et al 2002), while stress-mediated changes in hippocampal spine densities are NMDA receptor dependent (Shors et al 2004). These effects will further compromise hippocampal function, resulting in decreased spatial memory performance and reduced hippocampal volume as noted in PTSD patients.

Dysfunctional glucocorticoid-glutamate activity, described above, will lay the foundation for an impaired ability of neurons to survive coincident insults, particularly worsening neurotoxicity evoked by adverse conditions such as seizures, hypoxia-ischemia, metabolic poisons, hypoglycemia, oxidative stress, and exposure to excessive glucocorticoids (Sapolsky 2000b).

The profound effect of glucocorticoids on hippocampal volume is clearly illustrated in patients with Cushing’s disorder, with smaller hippocampal volumes being reported in these patients (Starkman et al 1992).

Although the hippocampus normally regulates glucocorticoid release through inhibitory effects on the HPA axis (Bremner 1999; Bremner et al 1999), hippocampal damage would result in disruption of this negative feedback loop, increasing the exposure of the hippocampus to glucocorticoid toxicity (Sapolsky 2000a, 2000b).

However, abnormally low glucocorticoid levels are also associated with reduced hippocampal function (de Kloet et al 1999). For example, adrenalectomy results in a significant reduction in LTP, while exposure to stress results in a further reduction in LTP (Shors et al 1990).

The role of glucocorticoids in the neuropathology and development of PTSD can therefore not be underestimated. However, establishing its exact contribution is difficult considering the varied results obtained in clinical studies (Baker et al 1999; Liberzon, Abelson, et al 1999; Yehuda et al 2000).

Nevertheless, of particular interest is that the paradoxical and rather unexpected observation of reduced cortisol in PTSD is closely emulated by TDS stress in animals (Liberzon et al 1997; Liberzon, Lopez et al 1999; Harvey, Naciti, et al 2003). These data suggest that a decreased cortisol level is conducive to decreased memory performance (Harvey, Naciti, et al 2003).

The association between hypocortisolemia and neurodegeneration appears contradictory. However, despite the implications for glucocorticoid-induced hippocampal damage in stress and anxiety disorders, they may not be solely responsible for the hippocampal damage and subsequent memory deficits observed in PTSD.

Although the massive release of glucocorticoids during and immediately following exposure to trauma may result in hippocampal atrophy (Starkman et al 1992; Bremner 1999; Sapolsky 2000b), PTSD is a disorder that develops and worsens over time (Bremner 1999).

It is thus possible that massive glucocorticoid secretion due to acute trauma exposure is only the first step in a cascade of events leading to later neurodegeneration and hippocampal atrophy with subsequent memory deficits.

This cascade may involve kindling and sensitization as well as a host of molecular messengers, both neuroprotective and neurotoxic in nature, that will ultimately determine the progressive deterioration of neuronal function eventually culminating in the behavioral pathology typical of PTSD. Although various possible candidates could be discussed, for the purpose of this review we will maintain our focus on the glutamate-NO-pathway and the effects of TDS stress.

Glutamate-NMDA receptor pathway
Alterations of glutamatergic and NMDA receptor functions have been proposed to play a role in the etiology of PTSD in humans (van der Kolk 1994; Dawson VL and Dawson TM 1995; Chambers et al 1999).

The NMDA receptor is involved in the normal processes of memory encoding while overstimulation of the NMDA receptor leads to the formation of strongly ingrained emotional memories via excessive mobilization of free cytosolic Ca2+.

However, high levels of NMDA-Ca2+ activity are toxic to cells (McCaslin and Oh 1995) and, much like cortisol and memory described earlier, a delicate balance is needed for optimal neuronal function that does not hold any threat to neuronal survival.

Both stress and glucocorticoids have been found to increase glutamate concentrations in the hippocampal synapse, acknowledged as a prime mediator of glucocorticoid-induced neurotoxicity (Sapolsky 2000b).

The extreme neurotoxic potential of glutamate is well recognized in Alzheimer’s disease (Louzada et al 2004), schizophrenia (Heresco-Levy 1999), and possibly affective illnesses (Harvey 1996). One of the cardinal symptoms of Alzheimer’s disease is cognitive impairment and loss of mnemonic function, and has its origin in excessive glutamate activity (Dawson VL and Dawson TM 1995).

PTSD, similarly, is characterized by a loss of cognitive abilities with evidence for increased glutamatergic activity (Chambers et al 1999). In support of this, a recent pilot study by Heresco-Levy and colleagues (2002) report on the clinical evidence for efficacy of D-cycloserine, a partial agonist at the glycine regulatory site on the NMDA receptor, in the treatment of PTSD.

Stress and glucocorticoids not only increase glutamate concentrations in the hippocampus, but glucocorticoids also selectively increase glutamate accumulation in response to excitotoxic insults in this brain region (Sapolsky 2000a).

Thus, hippocampal damage resulting from the effects of increased levels of glucocorticoids due to trauma exposure will further elevate levels of glutamate, thus potentiating the neurotoxic process. It is therefore clear that, while increased levels of glucocorticoids may initiate hippocampal damage, it also activates other neurotoxic pathways that may drive neuronal damage over a protracted period after the traumatic event.

Recently, various animal studies have begun to tease out the role of glutamate during severe stress. For example, mice lacking a fully functional glutamate NMDA receptor are less sensitive to stress induced by the elevated plus-maze, light-dark box, and forced swimming tests (Miyamoto et al 2002).

Using the TDS model, Kahn and Liberzon (2004) describe the inhibitory effect of the glutamate receptor inhibitor, topiramate, on an exaggerated acoustic startle response induced by TDS stress.

Focusing more on the long-term sequelae of acute severe stress, we noted that TDS stress evokes a profound effect on glutamate receptors in the hippocampus of rats three weeks after stress exposure (Harvey et al 2004).

In the latter study, TDS stress induced a significant down-regulation of hippocampal NMDA receptors. Despite the indication that overstimulation of the NMDA receptor might explain the neurodegeneration observed in PTSD, preclinical studies have found that inhibition of glutamate reuptake, resulting in increased glutamate levels, leads to a decrease in NMDA receptor density (Cebers et al 1999). This is suggested as a possible neuroprotective mechanism to counteract NMDA receptor overstimulation (Naskar and Dreyer 2001).

Nitric oxide and its relevance to stress and PTSD
Nitric oxide (NO) pathway
Glutamatergic stimulation of NMDA receptors activates a number of enzymes including NOS, cyclooxygenases, proteases, lipases, and protein kinases by evoking a long-lasting (100 millisecond) Ca2+-ion influx.

In the presence of calmodulin, Ca2+ activates NOS, which converts the amino-acid L-arginine to Nω-hydroxy-L-arginine, which is further converted to NO and L-citrulline (Nathan 1992; Knowles and Moncada 1994). A small gaseous molecule (MW 30Da) with a biological half-life of minutes, NO is rapidly degraded to nitrites and nitrates. However, its great lipid solubility affords it the unique ability to move quickly within and between cells.

NOS exist in three different isoforms that are either constitutive or inducible (Table 2). The activity of the constitutive NOS depends on Ca2+ and calmodulin, whereas the inducible NOS is independent of Ca2+.

Endothelial eNOS is mainly located in the cell membrane, neuronal nNOS in neuronal cells, while inducible iNOS is located in macrophages and glial cells (Nathan 1992). All NOS isoforms are dependant on NADPH (β-nicotinamide adenine dinucleotide phosphate) and calmodulin.

In iNOS, calmodulin is present in a tightly bound form, such that iNOS produces NO in a sustained manner in the presence of adequate substrate (Marletta 1993). Calcium-calmodulin binds to the constitutive enzyme in a reversible manner, but binds irreversibly to the inducible enzyme, so that neurons and endothelial cells containing the constitutive enzyme produce receptor-regulated pulses of NO, while the inducible enzyme in macrophages and microglia produces sustained levels of NO in response to cytokines that are not regulated by receptors (McCaslin and Oh 1995).

Table 2

NOS isoforms

Neural
(n NOS, type 1)
Inducible
(iNOS, type 2)
Endothelial
(eNOS, type 3)
Cells first identified inNeuronsMacrophagesEndothelium
Other cells expressingMyocytesAstrocytesNeurons
AstrocytesMicroglia
Intracellular localizationSoluble or membrane boundSoluble or membrane boundLargely membrane bound
Ca2+ dependencyActivity depends on elevated Ca2+Activity is independent of elevated Ca2+Activity depends on elevated Ca2+
ExpressionConstitutive inducible under certain circumstances, eg, traumaInducibleConstitutive
Amounts of NO releasedSmall, pulsesLarge, continuousSmall, pulses
Proposed functionRegulationHost defenseRegulation
ActivatorsGlutamateLipopolysaccharideAcetylcholine
Noradrenaline

Data adapted from Yun et al (1997) and Moncada et al (1997).

Soluble guanylate cyclase represents the most important NO receptor in the brain (Dawson VL and Dawson TM 1995), with its activation by NO following glutamate-mediated activation of the NMDA receptor leading to an increase in the second messenger – cyclic guanosine monophosphate (cGMP) (Fedele et al 2001).

Important neuronal effects of cGMP include activation of G-kinase, activation or inhibition of phosphodiesterase and subsequent effects on cyclic adenosine monophosphate (cAMP), effects on ion channels and G-proteins, and neurotransmitter release (Harvey 1996; Prast and Philippu 2001).

All these actions exert a significant effect on neuronal function. The effects of cGMP are terminated by the phosphodiesterase (PDE) family, among which PDE 3 and PDE 5 are considered specific for cGMP (Soderling and Beavo 2000).


Source:
University of Chicago

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