Mounting evidence suggests that chronic stress can alter brain structure and function and promote the development of neuropsychiatric disorders, such as depression and
Alzheimer's disease. Although the results of several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown whether antagonists of a key stress regulator, the
corticotrophin releasing factor receptor 1 (CRF1), can prevent stress-induced anxiety and
memory deficits in animal models. In this study, we evaluated the potential benefits of two CRF1 antagonists,
R121919 and
antalarmin, for preventing stress-induced anxiety-related behavioral and
memory deficits and neurodegeneration in aged rats. We stressed rats using isolation-restraint for 3 months starting from the 18 months of age. Subsets of animals were administrated either
R121919 or
antalarmin through food chow for 3 months, followed by a series of behavioral, biochemical and morphological analyses. We found that stressed aged rats displayed
body weight losses and increased
corticosterone levels, as well as anxiety-related behaviors and
memory deficits. Additionally, chronic stress induced a loss of cortical dendritic spines and synapses. However,
R121919 and
antalarmin both prevented stress-induced behavioral changes including anxiety-related behaviors and
memory deficits and prevented synapse loss, perhaps through reversing HPA axis dysfunction. These results suggest that CRF1 antagonists may hold promise as a potential
therapy for preventing stress-induced anxiety and
memory deficits in aged individuals.