Biphasic effect of tacrine on acetylcholine release in rat brain via M1 and M2 receptors.

Rat cortical synaptosomes preloaded with [3H]choline were superfused and stimulated with K+ in order to investigate the effect of the cholinesterase inhibitor tacrine on the in vitro release of acetylcholine (ACh). Tacrine was found to biphasically both increase (10(-6) and 5 x 10(-6) M) and decrease (10(-5)-10(-4) M) the release of ACh in a concentration-dependent manner. The facilitatory effect of tacrine was prevented by atropine and the M1 antagonist pirenzepine, whereas the inhibitory effect induced by tacrine was blocked by atropine and the M2 antagonist AF-DX 116. These results indicate that tacrine causes a biphasic effect on K+ stimulated ACh release in the brain via M1 and M2 muscarinic receptors. The tacrine induced enhancement of the ACh release occurs at clinical relevant tacrine concentrations and might therefore be of importance for the treatment outcome of Alzheimer's disease.