Increase in extracellular acetylcholine level by sigma ligands in rat frontal cortex.

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)