Blockade of hippocampal M1 muscarinic receptors impairs working memory performance of rats.

In order to clarify the roles of hippocampal M1 and M2 muscarinic receptors in working and reference memory performance of rats, the effects of intrahippocampal injections of selective antagonists at both receptors on this behavior were examined with a three-panel runway task. In the working memory task, the M1 muscarinic receptor antagonist pirenzepine, injected bilaterally at 0.32 and 1.0 microgram/side into the dorsal hippocampus, significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points). This effect of intrahippocampal pirenzepine (1.0 microgram/side) on working memory was attenuated by concurrent injection of 10 micrograms/side AF102B, the selective M1 muscarinic receptor agonist. Intrahippocampal injection of the M2 muscarinic receptor antagonist methoctramine at doses up to 1.0 microgram/side had no significant effect on the number of working memory errors. Intrahippocampal methoctramine injection at 3.2 micrograms/side produced a significant increase in working memory errors, an effect that was reversed by concurrent injection of 10 micrograms/side AF102B. Concurrent injection of 0.32 microgram/side methoctramine significantly reduced the increase in working memory errors induced by intrahippocampal pirenzepine (1.0 microgram/side). In the reference memory task, neither pirenzepine nor methoctramine affected the number of errors when injected into the hippocampus at doses up to 1.0 and 3.2 micrograms/side, respectively. These results suggest that processes mediated by M1 muscarinic receptors in the hippocampus are involved in working memory, but not in reference memory, and that blockade of hippocampal M2 muscarinic receptors ameliorates working memory deficits produced by M1 muscarinic blockade, possibly by increasing acetylcholine release.