EFFECTS OF TACRINE ON BRAIN MUSCARINIC-RECEPTOR-MEDIATED 2ND-MESSENGER SIGNALS

The purpose of this study was to investigate the effects of 9-amino-1, 2,3,4-tetrahydroacridine (THA; Tacrine(R)) on muscarinic-receptor-link ed second-messenger systems in rat brain and to determine the selectiv ity and mechanisms of these effects. Both competitive and noncompetiti ve antagonism was revealed in saturation radioligand binding studies p erformed in cortical and striatal tissue, depending on THA concentrati on. 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 bot h responses were blocked in the same concentration range (4-60 mumol/l ), noncompetitive antagonism of PI hydrolysis occurred at THA concentr ations greater than 10 mumol/l while competitive antagonism was displa yed for the cAMP response at concentrations of THA up to 40 mumol/l. T HA was equally effective at inhibiting PI hydrolysis stimulated by his tamine, phenylephrine or oxotremorine-M, when these agonists were empl oyed in concentrations equal to their EC50s for the response. THA did not antagonize PI hydrolysis mediated by the quisqualate receptor at a ny agonist concentration used. Furthermore, THA blocked carbachol- but not morphine-induced inhibition of forskolin-stimulated cAMP formatio n in the striatum.