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Vol. 61, Issue 5, 1222-1234, May 2002
Department of Pharmacology and Experimental Therapeutics (M.D.S.,
M.A., E.F.R.P., A.M., E.X.A.) and Department of Neurosurgery (H.M.E.),
University of Maryland School of Medicine, Baltimore, Maryland;
Departmento de Farmacologia Básica e Clínica, Instituto
de Ciênicas Biomédicas (Y.A., E.X.A.) and Instituto de
Biofísica Carlos Chagas Filho (M.D.S.), Centro de
Ciências da Saúde, Universidade Federal do Rio de Janeiro,
Rio de Janeiro, Brazil; and Institute of Physiological Chemistry and
Pathobiochemistry, Johannes-Gutenberg University Medical School,
Duesbergweg, Mainz, Germany (A.M.)
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 µM galantamine, acting as
a nicotinic APL, increased 
-aminobutyric acid (GABA) release
triggered by 10 µM acetylcholine (ACh). Likewise, 1 µM 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-
-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 µM, 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.
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