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 ac tivity in the mouse brain, the mechanism underlying the psychological stres s-induced change in the activity, and the effects of anxiolytic and anxioge nic drugs on the activity in psychologically-stressed animals. Psychologica l stress exposure using a communication box paradigm for 2-16 h significant ly 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 TEARS content lasted for 30 min after the str ess exposure, while no significant increase of the TEARS content was observ ed in the liver or serum. Trolox (67.6 mg/kg, i.p.), an antioxidant drug, b ut 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-one (1-5 mg/kg, i.p. ), significantly suppressed the effect of psychological stress. The non-sel ective nitric oxide (NO) synthase (NOS) inhibitor NG-nitro-L-arginine methy l ester (L-NAME, 10-100 mg/kg, i.p.) and the selective neuronal NOS inhibit or 7-nitroindazole (25 and 50 mg/kg, i.p.), but not the inducible NOS inhib itor aminoguanidine (1-100 mg/kg, i.p.), dose dependently suppressed the ps ychological 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) rece ptor agonist diazepam (0.05-0.5 mg/kg, i.p.), the 5-HT1A receptor agonists (+/-)-8-hydroxy-di-propylaminotetralin and buspirone (0.1-1 mg/kg, i.p.), b ut not the 5-HT3 receptor agonist MDL72222, dose-dependently suppressed the psychological stress-induced enhancement of brain lipid peroxidation. In c ontrast, the administration of anxiogenic drugs, FG7142 (an inverse BZD ago nist: 1-10 mg/kg, i.p.) and 1-(3-chlorophenyl)piperazine (a mixed 5-HT2A/2B /2C agonist: 0.1-1 mg/kg, i.p.), potentiated it. The effects of diazepam an d 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 productio n of NO, and that drugs with a BZD or 5-HT1A receptor agonist profile have a protective effect on oxidative brain membrane damage induced by psycholog ical stress. (C) 1999 Elsevier Science B.V. All rights reserved.