The effect of nicotine (1-10 microM) and tacrine (9-amino-1,2,3,4-tetrahydroacridine; THA) on stimulation evoked release of [3H]acetylcholine from the rat brain slice preparation preincubated with [3H]choline was investigated. In these preparations, nicotine enhanced while tacrine inhibited evoked [3H]acetylcholine release. These effects were blocked by (+)tubocurarine (1 microM) and atropine (0.1 microM) respectively. In the presence of idazoxan (0.3 microM) plus atropine (0.1 microM), nicotine (3 microM) continued to enhance evoked [3H]acetylcholine release while the inhibitory effect of tacrine (1 microM) on evoked [3H]acetylcholine release was reversed to an enhancement. Under these circumstances the effects of both nicotine and tacrine were blocked by (+)tubocurarine (1 microM). These findings demonstrate that tacrine can both inhibit or enhance [3H]acetylcholine release, most likely through its activity as a cholinesterase inhibitor. Under normal circumstances following tacrine the predominant effect of the elevated levels of acetylcholine will be activation of inhibitory presynaptic muscarine receptors on cholinergic nerves and an inhibition of evoked [3H]acetylcholine release. Under conditions where both presynaptic inhibitory muscarine and alpha 2-adrenoceptors are blocked, the elevated levels of acetylcholine produced by tacrine will lead to the activation of facilitatory presynaptic nicotine cholinoceptors on cholinergic nerves and an enhancement of evoked [3H]acetylcholine release.