Blockade of hippocampal M 1 muscarinic receptors impairs working memory performance of rats

Abstract

In order to clarify the roles of hippocampal M 1 and M 2 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 M 1 muscarinic receptor antagonist pirenzepine, injected bilaterally at 0.32 and 1.0 μg/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 μg/side) on working memory was attenuated by concurrent injection of 10 μg/side AF102B, the selective M 1 muscarinic receptor agonist. Intrahippocampal injection of the M 2 muscarinic receptor antagonist methoctramine at doses up to 1.0 μg/side had no significant effect on the number of working memory errors. Intrahippocampal methoctramine injection at 3.2 μg/side produced a significant increase in working memory errors, an effect that was reversed by concurrent injection of 10 μg/side AF102B. Concurrent injection of 0.32 μg/side methoctramine significantly reduced the increase in working memory errors induced by intrahippocampal pirenzepine (1.0 μg/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 μg/side, respectively. These results suggest that processes mediated by M 1 muscarinic receptors in the hippocampus are involved in working memory, but not in reference memory, and that blockade of hippocampal M 2 muscarinic receptors ameliorates working memory deficits produced by M 1 muscarinic blockade, possibly by increasing acetylcholine release.