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The Journal of Neuroscience, February 15, 2002, 22(4):1436-1442
Chronic Treatment with the Antidepressant Amitriptyline Prevents
Impairments in Water Maze Learning in Aging Rats
Joyce L. W.
Yau1,
June
Noble1,
Carina
Hibberd1,
Wayne B.
Rowe3,
Michael J.
Meaney3,
Richard G. M.
Morris2, and
Jonathan R.
Seckl1
1 Centre for the Study of the Ageing Brain, Molecular
Medicine Centre, Western General Hospital, Edinburgh EH4 2XU, United
Kingdom, 2 Centre for Neuroscience, University of
Edinburgh, Edinburgh EH8 9LE, United Kingdom, and
3 Developmental Neuroendocrinology Laboratory, Douglas
Hospital Research Center, McGill University, Montreal H3H IR4,
Canada
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.
Key words:
corticosterone; water maze; spatial learning; amitriptyline; anxiety; glucocorticoid
Copyright © 2002 Society for Neuroscience 0270-6474/02/2241436-07$05.00/0
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