Chronic treatment with the antidepressant amitriptyline prevents impairments in water maze learning in aging rats

Increasing evidence links chronically elevated glucocorticoid levels and cognitive impairments in a subpopulation of aged rodents and humans. Antidepressant drugs improve hypothalamic-pituitary-adrenal axis feedback regulation and reduce plasma glucocorticoid levels. Decreasing the cumulative lifetime exposure to glucocorticoid excess by long-term exposure to antidepressants may prevent the emergence of cognitive impairments in aged rats. To test this hypothesis, we treated middle-aged male Lister hooded rats (16 months) with amitriptyline until they were 24 months of age, and their cognitive function was assessed in the water maze. Performance in the spatial learning task declined significantly with aging (p < 0.01), with 33% of aged controls showing poorer (<2.5 SD) probe test performance than young controls. Amitriptyline treatment from midlife preserved water maze performance with aging (p < 0.01 compared with aged controls) and significantly (p < 0.01) reduced the proportion of poor performers (7%). Measures of anxiety-related behaviors in the elevated plus-maze were significantly (p < 0.05) decreased in the aged rats after amitriptyline. Furthermore, evening plasma corticosterone levels were reduced (30% decrease; p < 0.01 compared with aged controls) after 6 months of amitriptyline. These data suggest that long-term treatment with amitriptyline decreases the prevalence of cognitive impairment in aged rats and that this may, in part, be a consequence of reduced plasma corticosterone levels and reduced anxiety.