The effects of sigma ligands on the central acetylcholine (ACh) systems in the rat frontal cortex were examined. By using brain microdialysis techniques, we showed that nonbenzomorphan sigma ligands, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine and 1,3-di(2-tolyl)guanidine (DTG) dose-dependently increased the extracellular ACh level in this area. Similarly, benzomorphan sigma ligands, (+/-)-pentazocine and (+)-N-allylnormetazocine [(+)-SKF-10,047] also increased the extracellular ACh level. The increase in extracellular ACh level elicited by (+)-SKF-10,047 was greater than that by (-)-SKF-10,047. Moreover, the (+)-SKF-10,047- and DTG-induced increase in the extracellular ACh level were reduced significantly by simultaneous administration of haloperidol, a putative sigma receptor antagonist, whereas the (+)-SKF-10,047-induced increase was unaffected by (+/-)-3-(2- carboxypiperazin-4-yl)-propyl-1-phosphonic acid, a competitive N-methyl-D-aspartate receptor channel antagonist. On the other hand, none of the sigma ligands tested in this study had any effects on acetylcholinesterase or choline acetyltransferase activity and sodium-dependent high affinity choline uptake site in the rat frontal cortex. Ranking of potency for increasing extracellular ACh level was in the following order: (+/-)-pentazocine > (+)-SKF-10,047 > (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine > DTG. This order was positively correlated with the order of binding potency for the (+)-[3H]SKF-10,047 binding site in the rat frontal cortex, but was not correlated with binding to the [3H]DTG, [3H]quinuclidinyl benzylate and [3H]AF-DX116 ([3H]11-[(2-[(dimethylamino)methyl]-1-piperidinyl)acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one) binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)