Changes in glutamate decarboxylase enzyme activity and tau-protein phosphorylation in the hippocampus of old rats exposed to chronic mild stress: Reversal with the neuronal nitric oxide synthase inhibitor 7-nitroindazole

Abstract

Effects of chronic stress are not completely understood. They may underlie depression and dementia. This study assessed the association between chronic stress, glutamate levels, tau-protein phosphorylation, and nitric-oxide in old rats exposed to chronic mild stress (CMS). Old (> 15 months) male Wistar rats were exposed to CMS. Comparison groups included old and young control rats, young CMS-exposed, and old CMS-exposed rats treated with the neuronal nitric-oxide synthase (nNOS) enzyme inhibitor, 7-nitroindazole (20 mg/kg/day i.p.). Hippocampal glutamate levels and glutamate decarboxylase (GAD) activity were determined and tau protein phosphorylation was assessed. Age was a significant ( p = 0.025) source of variation in glutamate level [811.71 ± 218.1, 665.9 ± 124.9 µmol/g tissue protein (M ± SD) in young and old control rats, respectively]. Old rats exposed to CMS were characterized by an increased risk to develop anhedonia. There was significant ( p = 0.035) decrease in GAD enzyme activity (− 60.06%) and increased tau protein hyperphosphorylation in old rats exposed to CMS compared to control. Administration of 7-nitroindazole to CMS-exposed old rats significantly ( p = 0.002) increased GAD activity, decreased glutamate levels (7.19 ± 3.19 vs. 763.9 ± 91 µmol/g tissue protein; p = 0.0005), and decreased phosphorylation of tau proteins compared to CMS exposed rats.