Nitric oxide as inflammatory mediator in post-traumatic stress disorder (PTSD): evidence from an animal model

Abstract

Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that may develop after experiencing or witnessing a traumatic event. Recent clinical evidence has suggested the involvement of neurodegenerative pathology in the illness, particularly with brain imaging studies revealing a marked reduction in hippocampal volume. Of greater significance is that these anatomical changes appear to be positively correlated with the degree of cognitive deficit noted in these patients. Stress-induced increases in plasma cortisol have been implicated in this apparent atrophy. Although not definitive, clinical studies have observed a marked suppression of plasma cortisol in PTSD. The basis for hippocampal neurodegeneration and cognitive decline therefore remains unclear. Stress and glucocorticoids increase glutamate release, which is recognized as an important mediator of glucocorticoid-induced neurotoxicity. Recent preclinical studies have also noted that glutamate and nitric oxide (NO) play a causal role in anxiety-related behaviors. Because of the prominent role of NO in neuronal toxicity, cellular memory processes, and as a neuromodulator, nitrergic pathways may have an important role in stress-related hippocampal degenerative pathology and cognitive deficits seen in patients with PTSD. This paper reviews the preclinical evidence for involvement of the NO-pathway in PTSD, and emphasizes studies that have addressed these issues using time-dependent sensitization - a putative animal model of PTSD.

Keywords: GABA; NOS; PTSD; glucocorticoids; glutamate; nitric oxide; stress; time-dependent sensitization (TDS).

Figure 1

Role of nNOS in TDS stress. Immediately after an acute stress, NO is released via the action of adrenal glucocorticoids and the sequential release of glutamate in the hippocampus, activation of NMDA receptors, and the influx of Ca²⁺ leading to the activation of nNOS. 5HT released as a consequence of stress acts on 5HT2 receptors activating constitutive nNOS via the protein kinase C (PKC) pathway. NO then exerts various neuromodulatory effects (Prast and Phillippu 2001) as well as promotes the cellular processes of plasticity and memory either via itself, or by the synthesis of its second messenger, cGMP. However, NO prevents this cascade from progressing indefinitely by inhibiting its own synthesis (nNOS), inhibiting NMDA receptor function, promoting GABA release that further attenuates glutamate activity and by inhibiting the expression of iNOS. 5HT also inhibits guanylate cyclase-cGMP, thereby also effectively down-regulating the NO-pathway. Raised glucocorticoids inhibit cytokine release preventing any possible mobilization of iNOS. Shortly after the immediate response to a stressful event, glucorticoids then shut down the cortisol response by feedback inhibition of the HPA axis. Solid lines indicate activation; broken lines indicate inhibition. (Abbreviations are listed at the end of the paper.)

Figure 2

Role of iNOS in TDS stress. Under conditions of prolonged, recurrent stress, glucocorticoids fail to shut down the stress response leading to overt release of catecholamines and indolamines. In addition, a reactive hyperresponsiveness of the HPA axis ensues resulting in gross inhibition of glucorticoid release resulting in hypocortisolemia and disinhibition of cytokine expression. The result is an increased synthesis of IL-6 and subsequent expression of iNOS in local glia and astrocytes. The latter begins producing cell-toxic levels of NO for a protracted period, while an up-regulated state of the glucocorticoid receptor will increase susceptibility to cell toxic events, with profound consequences for the hippocampus. In an attempt to shut off excessive excitotoxic activity, NMDA receptors are down-regulated, leading to deficits in critical NMDA-driven cellular events such as neuroplasticity. Moreover, excessive NO inhibits GABA release thus destabilizing critical GABA glutamate balance. Activated iNOS in the CNS can also promote sympatho-adrenal outflow, complementing that already induced by raised CRF, thereby further increasing plasma catecholamines, worsening the state of hyperarousal already present. Solid lines indicate activation; broken lines indicate inhibition.

Figure 3

Neuroanatomy of memory and TDS stress. Acute moderate to high stress activates serotonergic neurons in the hippocampus to release 5HT. 5HT then activates postsynaptic 5HT_1A receptors that inhibit the process of hippocampal LTP, dependent on glutamate-NO mechanisms, and effectively suppress the encoding of excessive emotional memory. However, 5HT will also stimulate the release of corticotrophin (ACTH) from the hypothalamus, resulting in the secretion of glucocorticoids. Activation of the glucocorticoid receptor in the hippocampus inhibits the expression of 5HT_1A receptors, thereby preventing 5HT_1A receptors from inhibiting LTP-mediated hippocampal memory formation, while the subsequent release of glutamate evoked by glucocorticoids will further promote inappropriate memory consolidation. As the stressor increases in intensity, or becomes recurrent, the amygdala is activated, which further activates hypothalamic glucocorticoid release and reinforces hippocampal LTP via noradrenergic mechanisms, while the absence of adequate 5HT_1A-mediated suppression of hippocampal LTP, together with excessive glutamatergic activity, all combine to promote the consolidation of emotional-driven memories.