| Summary: | Post-traumatic stress disorder (PTSD), an anxiety disorder, may develop after
experiencing or witnessing a severe traumatic event. Characteristic symptoms
include hyper arousal and amnesic symptoms, while volume reductions in the
hippocampus of these patients appear correlated with illness severity and the
degree of cognitive deficit. Stress-induced increases in plasma cortisol have been
implicated in this apparent atrophy of the hippocampus, although, clinical studies
have described a marked suppression of plasma cortisol in PTSD. Given this
hypocortisolemia, the basis for hippocampal neuro degeneration and cognitive
decline remains unclear.
While stress-related hippocampal structural changes have been linked to the
neurotoxic effects of glucocorticoids and glutamate. NMDA-NO pathways have
been found to play a causal role in anxiety-related behaviours.
Prior exposure to trauma is an important risk factor for PTSD. In most instances the
disorder becomes progressively worse over time, possibly with a delayed onset,
suggesting a role for sensitization. In this study a time-dependent sensitization
(TDS) model was used to induce PTSD-like sequelae in male Spraque-Dawley rats.
The TDS-model is based on exposure to acute stressors, with a reminder of the
trauma, in the form of re-exposure to one of the acute stressor, seven days later.
NOS-activity, NMDA receptor parameters (Bmax and Kd) and GABA levels in the
hippocampus of rats, as well as plasma corticosterone levels were determined 21
days after exposure to the TDS-model.
Increased levels of corticosterone were measured after exposure to acute stress,
but these levels were found to decrease below basal levels 21 days after the re-exposure,
thus mimicking glucocorticoid levels in patients with PTSD. These
findings may also imply that the increase in glucocorticoid levels after stress
exposure is only the initial step in a cascade of events leading to neuronal
damage in the hippocampus.
This study also found that stress-restress evoked a long-lasting increase in
hippocampal NOS activity that was accompanied by a reactive down-regulation
of hippocampal NMDA receptors and dysregulation of inhibitory GABA pathways.
Subsequently, animals were chronically treated with certain pharmacological
agents prior to exposure to the TDS-model to determine possible approaches for
inhibiting the induction of PTSD. Pre-treatment with fluoxetine, currently indicated
in the treatment of PTSD. and the nNOS inhibitor, 7-nitroindazole, had no effect on
the increased NOS activity measured 21 days afler exposure to the TDS-model.
Pre-treatment with the iNOS inhibitor, aminoguanidine, however, resulted in
inhibition of the observed increase in hippocampal NOS-activity, implicating a
possible role for the iNOS isoform in the etiology of PTSD.
Treatment with ketoconazole, an inhibitor of glucoccfticoid synthesis, resulted in
inhibition of the increase in NOS-activity observed after exposure to TDS-stress, thus
indicating a possible link between stress glucocorticoid-release and NO synthesis.
These perturbations may have importance in explaining the increasing evidence
for stress-related hippocampal degenerative pathology and cognitive deficits
seen in patients with PTSD. Uncovering and understanding the role of NO in PTSD
will hopefully lead to the development of selective therapeutic agents in disorders
like PTSD. as well as providing a better understanding of basic processes
underlying normal and pathological neuronal functions in PTSD. === Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2004.
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