title: The nicotinic allosteric potentiating ligand galantamine facilitates synaptic transmission in the mammalian central nervous system.
abstract: In this study, the patch-clamp technique was used to determine the effects of galantamine, a cholinesterase inhibitor and a nicotinic allosteric potentiating ligand (APL) used for treatment of Alzheimer's disease, on synaptic transmission in brain slices. In rat hippocampal and human cerebral cortical slices, 1 microM galantamine, acting as a nicotinic APL, increased gamma-aminobutyric acid (GABA) release triggered by 10 microM acetylcholine (ACh). Likewise, 1 microM galantamine, acting as an APL on presynaptically located nicotinic receptors (nAChRs) that are tonically active, potentiated glutamatergic or GABA-ergic transmission between Schaffer collaterals and CA1 neurons in rat hippocampal slices. The cholinesterase inhibitors rivastigmine, donepezil, and metrifonate, which are devoid of nicotinic APL action, did not affect synaptic transmission. Exogenous application of ACh indicated that high and low levels of nAChR activation in the Schaffer collaterals inhibit and facilitate, respectively, glutamate release onto CA1 neurons. The finding then that the nAChR antagonists methyllycaconitine and dihydro-beta-erythroidine facilitated glutamatergic transmission between Schaffer collaterals and CA1 neurons indicated that in a single hippocampal slice, the inhibitory action of strongly, tonically activated nAChRs in some glutamatergic fibers prevails over the facilitatory action of weakly, tonically activated nAChRs in other glutamatergic fibers synapsing onto a given neuron. Galantamine is known to sensitize nAChRs to activation by low, but not high agonist concentrations. Therefore, at 1 microM, galantamine is likely to increase facilitation of synaptic transmission by weakly, tonically activated nAChRs just enough to override inhibition by strongly, tonically activated nAChRs. In conclusion, the nicotinic APL action can be an important determinant of the therapeutic effectiveness of galantamine.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Máriton D
authors.initials: MD
authors.lastname: Santos
authors.forename: Manickavasagom
authors.initials: M
authors.lastname: Alkondon
authors.forename: Edna F R
authors.initials: EF
authors.lastname: Pereira
authors.forename: Yasco
authors.initials: Y
authors.lastname: Aracava
authors.forename: Howard M
authors.initials: HM
authors.lastname: Eisenberg
authors.forename: Alfred
authors.initials: A
authors.lastname: Maelicke
authors.forename: Edson X
authors.initials: EX
authors.lastname: Albuquerque
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects* / Q000502:physiology; D002802:Cholinesterases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005702:Galantamine / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011950:Receptors, Cholinergic / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D018697:Nootropic Agents; D011950:Receptors, Cholinergic; D017470:Receptors, Glutamate; D005702:Galantamine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D009538:Nicotine; D002802:Cholinesterases