Comparison of three muscarinic agonists injected into the medial pontine reticular formation of rats to enhance REM sleep

To gain insight into the subtypes of muscarinic receptors mediating the long lasting increase in REM sleep following microinjection of muscarinic agonists into the medial pontine reticular formation of the rat, multiple 60 nl injections were made utilizing three different muscarinic agonists. All agonists, in a concentration range of 10^-6 to 10^-2 Molar, increased REM sleep in a dose-related manner with an inverted "U" relationship. The order of potency to increase REM sleep was McN-A-343> oxotremorine-M=carbachol. Based on each agonist's subtype-selective potency in functional assays, oxotremorine-M is the most potent agonist at every subtype. It was therefore concluded that the observed order of potency is not consistent with activation of a single muscarinic receptor. Inasmuch as McN-A-343 acts as a weak, partial agonist and the other ligands full agonists at m3 receptors, we hypothesize that activation of m3 receptors by oxotremorine-M and carbachol antagonizes REM sleep increases and results in their lowered potency. This hypothesis is consistent with preliminary evidence demonstrating that injecting a relatively selective m3 antagonist, p-F-HHSiD, can increase the REM-inducing potency of a low and formerly ineffective dose of oxotremorine-M. An m3 muscarinic receptor mechanism in the pons antagonistic to increasing REM sleep, present in the rat but absent in the cat, may underlie some of the species differences observed in the cholinergic induction of REM sleep.