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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Amantadine Inhibits Nicotinic Acetylcholine Receptor Function in Hippocampal Neurons

Hiroaki Matsubayashi, Karen L. Swanson and Edson X. Albuquerque
Journal of Pharmacology and Experimental Therapeutics May 1997, 281 (2) 834-844;
Hiroaki Matsubayashi
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Karen L. Swanson
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Edson X. Albuquerque
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Abstract

The effects of amantadine on nicotinic acetylcholine receptors (nAChRs) of hippocampal neurons were studied by recording three types of acetylcholine (ACh)-evoked currents, using the whole-cell patch-clamp technique. The rapidly desensitizing type IA nicotinic current, which is α-bungarotoxin-sensitive and is mediated by nAChRs bearing α7 subunits, was inhibited by application of amantadine to neurons for 10 min (IC50 = 6.5 μM), but the potency of ACh (EC50 = 0.27 mM) was not affected by the drug. Amantadine (30–50 μM) attenuated the peak current amplitude in a voltage-dependent manner, with greater effect at negative than at positive membrane potentials. In contrast, the decay phase of the currents was shortened in a voltage-independent manner. When amantadine was coapplied briefly with ACh, the drug was markedly less potent (IC50 = 130 μM). Thus, the noncompetitive effects of amantadine on the type IA nicotinic current are complex, involving actions on the closed and desensitized states of the α7 nAChR. The slowly desensitizing, α-bungarotoxin-insensitive nicotinic currents of type II, which is inhibited by dihydro-β-erythroidine and is mediated by α4β2 nAChRs, and of type III, which is inhibited by mecamylamine and is mediated by α3β4 nAChRs, were also sensitive to inhibition by amantadine. The peak amplitude of type II current was reduced only slightly by 10 μM amantadine coapplied with ACh, but the decay-time constant and amplitude of the sustained current were markedly reduced. Type III current was also inhibited when amantadine was briefly coapplied with ACh. In contrast to its effects on nicotinic currents, amantadine at 10 μM did not affect currents evoked byN-methyl-d-aspartate plus glycine, γ-aminobutyric acid, glycine or kainate. Thus, on cultured hippocampal neurons, amantadine preferentially inhibits nicotinic currents.

Footnotes

  • Send reprint requests to: Dr. Edson X. Albuquerque, Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201.

  • ↵1 A preliminary report of this study appeared previously (Matsubayashi and Albuquerque, 1995). This study was supported by National Institute of Neurological Diseases and Stroke Grant NS25296 and grants from Financiadora de Estudos e Projetos (FINEP) and Conselho Nacional de Desenvolvimento Científico e Technológico (CNPq) (Brazil).

  • Abbreviations:
    ACh
    acetylcholine
    ATP-RS
    ATP-regenerating solution
    α-BGT
    α-bungarotoxin
    DHβE
    dihydro-β-erythroidine
    EPC
    endplate current
    GABA
    γ-aminobutyric acid
    HEPES
    4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
    MLA
    methyllycaconitine
    nAChR
    nicotinic acetylcholine receptor
    NMDA
    N-methyl-d-aspartate
    • Received November 18, 1996.
    • Accepted January 27, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 2
1 May 1997
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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Amantadine Inhibits Nicotinic Acetylcholine Receptor Function in Hippocampal Neurons

Hiroaki Matsubayashi, Karen L. Swanson and Edson X. Albuquerque
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 834-844;

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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Amantadine Inhibits Nicotinic Acetylcholine Receptor Function in Hippocampal Neurons

Hiroaki Matsubayashi, Karen L. Swanson and Edson X. Albuquerque
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 834-844;
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