Effects of tacrine on brain muscarinic-receptor-mediated second-messenger signals.
The purpose of this study was to investigate the effects of 9-amino-1,2,3,4-tetrahydroacridine (THA; Tacrine) on muscarinic-receptor-linked 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 mumol/l), non-competitive antagonism of PI hydrolysis occurred at THA concentrations greater than 10 mumol/l while competitive antagonism was displayed for the cAMP response at concentrations of THA up to 40 mumol/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.
Division of Neuroscience, Research in Psychiatry, University of Minnesota Medical School, Minneapolis 55455.
J S
JS
Kiefer-Day
E S
ES
Abdallah
C
C
Forray
N H
NH
Lee
O N
ON
Kim
E E
EE
el-Fakahany
D000818:Animals; D001921:Brain / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D007295:Inositol Phosphates / Q000096:biosynthesis; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects*; D015290:Second Messenger Systems / Q000187:drug effects*; D013619:Tacrine / Q000494:pharmacology*
D007295:Inositol Phosphates; D011976:Receptors, Muscarinic; D005576:Colforsin; D013619:Tacrine; D002217:Carbachol; D000242:Cyclic AMP