Involvement of the NMDA receptor, NO-cyclic GMP and nuclear factor K-beta in an animal model of repeated trauma.
Post-traumatic stress disorder (PTSD) may be associated with shrinkage of the hippocampus, with glutamate release causally related to these events. Recent animal studies strongly implicate activation of the nitric oxide (NO)-cascade in anxiety and stress. Using an animal model of repeated trauma, the effect of stress was investigated on the hippocampal NO-cGMP signalling pathway, specifically the release of nitrogen oxides (NOx) and its modulation by NMDA receptor-, NO-, cGMP- and nuclear factor K-beta (NFK-beta)-selective drugs. Immediately after stress, rats received the glutamate NMDA receptor antagonist, memantine (MEM; 5 mg/kg i.p./d), the NO synthase inhibitor, 7-nitroindazole sodium salt (7-NINA; 20 mg/kg i.p./d), the cGMP-specific PDE inhibitor, sildenafil (SIL; 10 mg/kg i.p./d) or the NFkappa-beta antagonist, pyrollidine dithiocarbamate (PDTC; 70 mg/kg i.p./d), for 7 days. Stress significantly increased hippocampal NOx on day 7 post-stress, which was blocked by either 7-NINA or PDTC, while MEM was without effect. SIL, however, significantly augmented stress-induced NOx accumulation. Increased cGMP therefore acts as a protagonist in driving stress-related events, while both nNOS (neuronal NOS) and iNOS (inducible/immunological NOS) may represent a therapeutic target in preventing the effects of severe stress. The value of NMDA receptor antagonism, however, appears limited in this model.
Harvey
Brian H
BH
School of Pharmacy (Pharmacology), Faculty of Health Sciences, North-West University, Potchefstroom, South Africa 2520. fklbhh@puk.ac.za
Bothma
Tanya
T
Nel
Ané
A
Wegener
Gregers
G
Stein
Dan J
DJ
D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D007191:Indazoles / Q000627:therapeutic use; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D010879:Piperazines / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives / Q000627:therapeutic use; D011687:Purines; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D000068677:Sildenafil Citrate; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy / Q000209:etiology*; D013450:Sulfones; D013859:Thiocarbamates / Q000627:therapeutic use
D007191:Indazoles; D016328:NF-kappa B; D010879:Piperazines; D011687:Purines; D016194:Receptors, N-Methyl-D-Aspartate; D013450:Sulfones; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D009569:Nitric Oxide; D011392:Proline; D000068677:Sildenafil Citrate; D006152:Cyclic GMP; C080122:7-nitroindazole