Related Experiment Videos
Reduced density of NMDA receptors and increased sensitivity to dizocilpine-induced learning impairment in aged rats
D K Ingram1, P Garofalo, E L Spangler
1Molecular Physiology and Genetics Section, Nathan W. Shock Laboratories, National Institute on Aging, Baltimore, MD 21224.
Abstract:
About 20 min prior to training in a shock-motivated 14-unit T-maze, young (3-4 months) and aged (24-25 months) male Fischer-344 rats were given s.c. injections of either saline or dizocilpine (MK-801, 0.02 or 0.04 mg/kg), a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. The aged rats showed a dose-dependent impairment in maze performance. Deficiencies were manifested as increases in errors, in runtime from start to goal, and in the number and duration of shocks received. In contrast, young rats exhibited no detrimental effects of dizocilpine on maze performance. Analysis of [3H]glutamate binding in these rats revealed a marked age-related decline in NMDA receptor binding in hippocampus. A significant correlation was observed between errors in the maze and hippocampal [3H]-glutamate binding, but the correlation was positive, i.e., rats that made the most errors had the highest level of NMDA receptor binding. Thus, compared to young rats, aged rats were more sensitive to the behavioral effects of NMDA receptor antagonism and they showed a hippocampal loss of [3H]glutamate in binding, which may be related to the increased sensitivity to dizocilpine. The positive correlation between poor maze performance and NMDA receptor binding suggests that the behaviors assessed involve complex interactions between NMDA receptors and other neuronal systems in the hippocampus.
Insights
Aged rats showed impaired maze performance after NMDA receptor antagonist dizocilpine, unlike young rats. This suggests age-related changes in NMDA receptors may increase sensitivity to such drugs.
Area of Science:
- Neuroscience
- Gerontology
- Pharmacology
Background:
- Aging is associated with cognitive decline and altered neurotransmitter systems.
- N-methyl-D-aspartate (NMDA) receptors are crucial for learning and memory.
- Age-related changes in NMDA receptor function may contribute to cognitive deficits.
Purpose of the Study:
- To investigate the effects of NMDA receptor antagonism on spatial learning and memory in young and aged rats.
- To examine age-related changes in hippocampal NMDA receptor binding.
- To explore the relationship between NMDA receptor binding and behavioral performance.
Main Methods:
- Young and aged male Fischer-344 rats were trained on a shock-motivated T-maze.
- Rats received subcutaneous injections of saline or dizocilpine (MK-801), an NMDA receptor antagonist.
- Hippocampal [3H]glutamate binding was analyzed.
Main Results:
- Aged rats exhibited dose-dependent impairments in maze performance, including increased errors and longer runtimes.
- Young rats showed no detrimental effects of dizocilpine on maze performance.
- Aged rats displayed a marked age-related decline in hippocampal NMDA receptor binding.
- A positive correlation was found between maze errors and hippocampal NMDA receptor binding.
Conclusions:
- Aged rats are more sensitive to the behavioral effects of NMDA receptor antagonism than young rats.
- Age-related decline in hippocampal NMDA receptor binding may contribute to increased sensitivity to dizocilpine.
- The findings suggest complex interactions between NMDA receptors and other neuronal systems in the hippocampus during aging.