Title

Effects of tacrine on brain muscarinic-receptor-mediated second-messenger signals

Document Type

Journal Article

Publication Date

1-1-1993

Journal

Pharmacology

Volume

47

Issue

2

DOI

10.1159/000139084

Keywords

9-Amino-1,2,3,4- tetrahydroacridine; Alzheimer’s disease; Cholinesterase inhibitor; Memory enhancer; Muscarinic receptor; Second messengers; Signal transduction; Tacrine®

Abstract

The purpose of this study was to investigate the effects of 9- amino-l,2,3,4-tetrahydroacridine(THA; Tacrine®) on musca- rinic-receptor-linkcd second-messenger systems in rat brain and to determine the selectivity and mechanisms of these effects. Both competitive and noncompetitive antagonism was revealed in saturation radioligand binding studies performed in cortical and striatal tissue, depending on THA concentration. Micromolar THA concentrations blocked muscarinic- receptor-mediated inhibition of cAMP formation and stimulation of phosphoinositide (PI) hydrolysis with poor selectivity between the two responses. While both responses were blocked in the same concentration range (4-60 μmol/l), noncompetitive antagonism of PI hydrolysis occurred at THA concentrations greater than 10 μmol/l while competitive antagonism was displayed for the cAMP response at concentrations of THA up to 40 μmol/l. THA was equally effective at inhibiting PI hydrolysis stimulated by histamine, phenylephrine or oxotremorine-M, when these agonists were employed in concentrations equal to their EC50S for the response. THA did not antagonize PI hydrolysis mediated by the quisqualate receptor at any agonist concentration used. Furthermore, THA blocked carbachol- but not morphine-induced inhibition of forskolin-stimulated cAMP formation in the striatum. © 1993 S. Karger AG, Basel.

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