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The Journal of Neuroscience, January 15, 2000, 20(2):783-790
The M1 Muscarinic Agonist CI-1017 Facilitates Trace Eyeblink Conditioning in Aging Rabbits and Increases the Excitability of CA1 Pyramidal Neurons
Craig Weiss1, Alison R. Preston1, M. Matthew Oh1, Roy D. Schwarz2, Devin Welty2, and John F. Disterhoft1 1 Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611, and 2 Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105
The M1 muscarinic agonist CI-1017 was administered intravenously to aging rabbits on a daily basis before and during hippocampally dependent trace eyeblink conditioning sessions. Circulating levels of CI-1017 were significantly related to the drug dose. The drug was found to significantly increase the rate and amount of learning in a dose-dependent manner with no significant effects on the amplitude, area, or latency of conditioned responses. There was no evidence of pseudoconditioning at the highest drug concentration, and the minimally effective dose produced only mild and temporary hypersalivation as a side effect. CI-1017 (10 µM) was also found to increase the excitability of CA1 pyramidal neurons recorded from hippocampal slices from young and aging naive rabbits as measured by changes in spike-frequency adaptation and the postburst afterhyperpolarization. These biophysical changes were reversed with either atropine (1 µM) or pirenzepine (1 µM). These results suggest that M1 agonists ameliorate age-related learning and memory impairments at least in part by reducing the afterhyperpolarization and spike-frequency adaptation of hippocampal pyramidal neurons and that M1 agonists may be an effective therapy for reducing the cognitive deficits that accompany normal aging and/or Alzheimer's disease.
Key words: acetylcholine; afterhyperpolarization; Alzheimer's disease; cholinesterase; hippocampus; learning
Copyright © 2000 Society for Neuroscience 0270-6474/00/202783-08$05.00/0
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