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Investigating the role of the NO-cGMP pathway in an animal model of posttraumatic stress disorder (PTSD) / Tanya Bothma

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder characterised by
hypothalamic-pituitary-adrenal (HPA)-axis abnormalities, hyperarousal, anxiety,
flashbacks of trauma memories and avoidance. Increasing evidence is now
accumulating that the disorder is also associated with shrinkage of the hippocampus
and cognitive dysfunction that may have its origin in stress-induced excitotoxicity.
Animal studies have indeed highlighted a potential role of the excitotoxic glutamatenitric
oxide (NO) pathway in the stress response. Since PTSD appears to be an
illness that progresses and worsens over time after an initial severe traumatic event,
this study has used an animal model that emphasises repeated trauma to investigate
the effect of stress on hippocampal NO synthase (NOS) activity, the release of the
nitrogen oxide metabolites of NO (NOx), and also the evoked release of cGMP.
Furthermore, the modulation and dependency of these responses on glutamate, NO
and cGMP activity using drugs selective for these targets, will also be investigated.
Rats (n=10/group) were exposed to repeated stress together with saline or drug
administration immediately after the stress procedure and continuing for one week
post-stress. The animals were then sacrificed for assay of hippocampal NOS activity,
NO, and cGMP accumulation. Animals received either the glutamate-NMDA receptor
antagonist, memantine (MEM;5mg/kg ip/d), the neuronal NOS selective inhibitor, 7-
nitroindazole monosodium salt (7-NINA;20mg/kg ip/d), the cGMP-specific PDE
inhibitor, sildenafil (SIL;10mg/kg ip/d) or the NFkb antagonist, pyrollidine
dithiocarbamate (PDTC;70mg/kg ip/d). The latter inhibits the nuclear transcription
factor, NFkb, responsible for inducing the expression of iNOS, while it also appears
to mediate the glutamatergic actions on NOS expression,
Stress significantly increased hippocampal NOS activity, as well as significantly
increased hippocampal cGMP and NO, levels. These increases were blocked by pretreatment
with either PDTC or 7-NINA, while memantine was without effect. Sildenafil
significantly augmented stress induced NO, accumulation, as well as cGMP.
although the latter failed to reach significance. 7-NINA and memantine significantly
blocked the increase in cGMP evoked by time-dependent sensitisation (TDS)-stress,
with PDTC attenuating this response, but not significantly. Additionally, administration
of each drug separately for seven days without exposure to stress, did not evoke
significant changes in NOx levels, compared to the control group. However,
significant increases in cGMP levels, compared to the control group, were found with
all four drugs.
Repeated trauma therefore activates the NO-cGMP pathway, possibly involving
actions on both nNOS and iNOS. The NMDA receptor appears less involved after
chronic repeated stress, and may have limited therapeutic implications. Sub-cellular
NO-modulation, however, may represent an important therapeutic strategy in
preventing the effects of severe stress and in treating PTSD. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

Identiferoai:union.ndltd.org:NWUBOLOKA1/oai:dspace.nwu.ac.za:10394/477
Date January 2004
CreatorsBothma, Tanya
PublisherNorth-West University
Source SetsNorth-West University
Detected LanguageEnglish
TypeThesis

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