Anti-stress effects of a GSK-3β inhibitor, AR-A014418, in immobilization stress of variable duration in mice.

Abstract

The present study was designed to explore the anti-stress role of AR-A014418, a selective glycogen synthase kinase-3β inhibitor (GSK-3β), on changes provoked by immobilization stress of varying duration. Acute stress of varying degree was induced by subjecting mice to immobilization stress of short duration (30 min) or long duration (120 min). Thereafter, these animals were exposed to the same stressor for 5 days to induce stress adaptation. The behavioral alterations were assessed using an actophotometer, a hole-board, and the open field and social interaction tests. The serum corticosterone levels were assessed as markers of the hypothalamic-pituitary-adrenal (HPA) axis activity. The levels of total GSK-3β and p-GSK-3β-S9 were determined in the prefrontal cortex. A single exposure to short or long immobilization stress produced behavioral and biochemical changes and the levels of p-GSK-3β-S9 decreased without affecting the total GSK-3β levels in the brain. However, repeated exposure to both short and long stress reversed the behavioral and biochemical changes along with the normalization of p-GSK-3β-S9 levels. The administration of AR-A014418, a selective GSK-3β inhibitor, diminished acute stress-induced behavioral and biochemical changes. Furthermore, AR-A014418 normalized acute stress-induced alterations in p-GSK-3β-S9 levels without changing total GSK-3β levels. Our study suggests that acute stress-induced decrease in p-GSK-3β-S9 levels in the brain contributes to the development of behavioral and biochemical alterations and the normalization of GSK-3β signaling may contribute to stress adaptive behavior in mice which have been subjected to repeated immobilization stress.