Date of Award

1-1-2006

Embargo Period

1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell and Molecular Pharmacology and Experimental Therapeutics

College

College of Graduate Studies

First Advisor

Lotta Graham

Second Advisor

Kumar Sambamurti

Third Advisor

Heather Bimonte-Nelson

Fourth Advisor

John Hildebrandt

Fifth Advisor

Jerry G. Webb

Sixth Advisor

David Kurtz

Abstract

Nicotine and Galantamine were studied for their pharmacological effects on age associated memory impairment (AAMI) and the neurotrophin system in the aged female F344 rat. Nicotine was found to have dose dependent effects on cognition in the 24 month old rat. A low dose of nicotine improved both working and reference memory (WM, RM) performance on the water radial arm maze and also improved the ability of aged rats to handle an increasing WM load. A high dose did not improve WM and caused deficits in RM, and high cotinine levels in these subjects correlated with worse performance. Nicotine treatment also reduced hippocampal nerve growth factor (NGF) levels in the aged rat, which were found to be elevated compared to young rats. Nicotine treatment had no impact on number of TrkA positive neurons in the basal forebrain and did not affect TrkA density in specific regions of the hippocampal formation. Our data indicate that nicotine may be an effective intervention for AAMI but that careful attention must be paid to dosing. In addition, nicotine appears to be beneficial in normalizing age-related changes in hippocampal NGF. Galantamine treatment did not improve memory or impact neurotrophin levels in 20 month old rats but did have subtle effects on use of a chaining strategy. Our findings regarding galantamine, as well as those in other laboratories, suggest that the low doses used were not adequate to significantly impact memory performance. We also found that while both 20 and 24 month old female rats were cognitively impaired compared to young rats, they also differed significantly from each other in terms of cognitive ability and neurotrophin expression. RM deficits were apparent as early as 20 months, but deficits in ability to handle an increasing WM load were more severe in the 24 month olds compared to the 20 month olds. Age related changes in NGF and BDNF were not apparent until 24 months of age. These findings suggest that AAMI is evident before changes in neurotrophin levels are apparent and that careful attention should be given to actual age studied in 'aging' studies.

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