Document Detail

Modulation of cholinergic transmission enhances excitability of hippocampal pyramidal neurons and ameliorates learning impairments in aging animals.
MedLine Citation:
PMID:  14521865     Owner:  NLM     Status:  MEDLINE    
Four cholinesterase inhibitors have been approved by the US Food and Drug Administration for treating behavioral symptoms of Alzheimer's disease. Here we review our experiences with two cholinesterase inhibitors (metrifonate and galanthamine) and a muscarinic acetylcholine receptor agonist (CI-1017) in behavioral pharmacological and brain slice experiments in aging and young rabbits. Aging rabbits are impaired in their ability to acquire the hippocampus-dependent trace eyeblink conditioning task, as compared to young controls. A large proportion of aging animals cannot reach behavioral criterion in this task. Those that do learn, do so more slowly. In addition, the post-burst afterhyperpolarization and spike frequency accommodation is increased in hippocampal pyramidal neurons from aging animals, i.e., cellular excitability is reduced as compared to those from young animals. Metrifonate, galanthamine, and CI-1017 reduced the learning deficits observed in aging rabbits so that they learned almost as quickly as young controls. These cholinergic compounds also enhanced the postsynaptic excitability of hippocampal pyramidal neurons in vitro. Therefore, we propose that the amelioration of learning impairment with the cholinergic compounds may in part be due to the enhanced excitability of hippocampal pyramidal neurons. The potential relevance of our studies to further understanding the cellular and behavioral changes that occur with normal aging and Alzheimer's Disease is discussed.
John F Disterhoft; M Matthew Oh
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Neurobiology of learning and memory     Volume:  80     ISSN:  1074-7427     ISO Abbreviation:  Neurobiol Learn Mem     Publication Date:  2003 Nov 
Date Detail:
Created Date:  2003-10-02     Completed Date:  2004-03-29     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9508166     Medline TA:  Neurobiol Learn Mem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  223-33     Citation Subset:  IM    
Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008, USA.
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MeSH Terms
Aging / physiology*
Bicyclo Compounds, Heterocyclic / administration & dosage,  pharmacology*,  therapeutic use*
Cholinesterase Inhibitors / administration & dosage,  pharmacology*,  therapeutic use*
Hippocampus / drug effects*,  metabolism*
Learning Disorders / drug therapy*
Muscarinic Agonists / administration & dosage,  pharmacology*,  therapeutic use*
Neurons / metabolism*
Oximes / administration & dosage,  pharmacology*,  therapeutic use*
Pyramidal Tracts / drug effects*,  metabolism*
Receptors, Cholinergic / drug effects*,  metabolism*
Trichlorfon / administration & dosage,  pharmacology*,  therapeutic use*
Grant Support
Reg. No./Substance:
0/Bicyclo Compounds, Heterocyclic; 0/Cholinesterase Inhibitors; 0/Muscarinic Agonists; 0/Oximes; 0/Receptors, Cholinergic; 161774-09-0/PD 142505-0028; 52-68-6/Trichlorfon

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