Modulation of cholinergic transmission enhances excitability of hippocampal pyramidal neurons and ameliorates learning impairments in aging animals.
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.
Disterhoft
John F
JF
Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008, USA. jdisterhoft@northwestern.edu
Matthew Oh
M
M
D000375:Aging / Q000502:physiology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D007859:Learning Disabilities / Q000188:drug therapy*; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D009474:Neurons / Q000378:metabolism*; D010091:Oximes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D011712:Pyramidal Tracts / Q000187:drug effects* / Q000378:metabolism*; D011817:Rabbits; D011950:Receptors, Cholinergic / Q000187:drug effects* / Q000378:metabolism*; D014236:Trichlorfon / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002800:Cholinesterase Inhibitors; D018721:Muscarinic Agonists; D010091:Oximes; D011950:Receptors, Cholinergic; C096405:PD 142505-0028; D014236:Trichlorfon