Psychological stress-induced enhancement of brain lipid peroxidation via nitric oxide systems and its modulation by anxiolytic and anxiogenic drugs in mice.

We investigated the effect of psychological stress on lipid peroxidation activity in the mouse brain, the mechanism underlying the psychological stress-induced change in the activity, and the effects of anxiolytic and anxiogenic drugs on the activity in psychologically-stressed animals. Psychological stress exposure using a communication box paradigm for 2-16 h significantly increased the content of thiobarbituric acid reactive substance (TBARS), an index of lipid peroxidation activity, in the brain, and the effect was maximal after peaked by a 4-h stress exposure. In the animals stressed for over 4 h, the increased brain TBARS content lasted for 30 min after the stress exposure, while no significant increase of the TBARS content was observed in the liver or serum. Trolox (67.6 mg/kg, i.p.), an antioxidant drug, but not monoamine oxidase inhibitors, clorgyline (2.5-5 mg/kg, i.p.) or 5-(4-benzylphenyl)-3-(2-cyanoethyl)-(3H)-1,3,4-oxadiazol-2-o ne (1-5 mg/kg, i.p.), significantly suppressed the effect of psychological stress. The non-selective nitric oxide (NO) synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10-100 mg/kg, i.p.) and the selective neuronal NOS inhibitor 7-nitroindazole (25 and 50 mg/kg, i.p.), but not the inducible NOS inhibitor aminoguanidine (1-100 mg/kg, i.p.), dose dependently suppressed the psychological stress-induced enhancement of lipid peroxidation in the brain. L-Arginine (300 mg/kg, i.p.), a substrate of NOS, antagonized the effect of L-NAME. Measurements of NO metabolites revealed a significant increase of NO production in the brains of stressed mice. The benzodiazepine (BZD) receptor agonist diazepam (0.05-0.5 mg/kg, i.p.), the 5-HT(1A) receptor agonists (+/-)-8-hydroxy-di-propylaminotetralin and buspirone (0.1-1 mg/kg, i. p.), but not the 5-HT(3) receptor agonist MDL72222, dose-dependently suppressed the psychological stress-induced enhancement of brain lipid peroxidation. In contrast, the administration of anxiogenic drugs, FG7142 (an inverse BZD agonist: 1-10 mg/kg, i.p.) and 1-(3-chlorophenyl)piperazine (a mixed 5-HT(2A/2B/2C) agonist: 0.1-1 mg/kg, i.p.), potentiated it. The effects of diazepam and FG7142 were abolished by the BZD receptor antagonist flumazenil (10 mg/kg, i.p.). These results indicate that psychological stress causes oxidative damage to the brain lipid via enhancing constitutive NOS-mediated production of NO, and that drugs with a BZD or 5-HT(1A) receptor agonist profile have a protective effect on oxidative brain membrane damage induced by psychological stress.