Multiple action of acetylcholine at a muscarinic receptor studied in the rat hippocampal slice.

Responses of hippocampal pyramidal cells to topical application of acetylcholine (ACh) were measured in the in vitro hippocampal slice preparation. ACh but not cyclic GMP produced a short-latency hyperpolarization associated with a decrease in input resistance. This was followed by a long-latency but long duration depolarization associated in some cells with an increase in input resistance. This change in resistance followed the depolarization and outlasted it by 5--20 min, until complete recovery. During the depolarization there was a reduction in magnitude of EPSPs produced by activation of the Schaffer collateral excitatory afferents. The reversal potential for the hyperpolarization was about -95 mV, and it was blocked by 4-aminopyridine. The depolarization, but not the hyperpolarization was markedly attenuated in slices maintained in low (25 degrees C) temperature. The responses to ACh were blocked by atropine but not by D-tubocurarine. The hyperpolarization as well as the depolarization were present in slices treated with tetrodotoxin (TTX)., but were reduced in slices superfused with a low Ca2+-high Mg2+ medium, and in slices treated with Mn2+ and Co2+ ions. It is suggested that ACh causes a fast increase in gK+, followed by a long-lasting energy-dependent depolarization associated with action potential discharges, a decrease in conductance and a suppression of EPSPs.