Injected into the Medial Pontine Reticular Formation of Rats to Enhance REM Sleep

pontine reticular formation of the rat is capable of inducing long-lasting increases in REM sleep (Bourgin et al., 1995; Marks and Birabil, 1998). These effects are blocked by a previous injection of the non-selective, muscarinic antagonist atropine supporting mediation by muscarinic receptors (Bourgin et al., 1995; Marks and Birabil, 1998). Five different muscarinic receptor subtypes have been cloned and identified, m1-m5 (reviewed in Hulme et al., 1990). Cells in the pontine reticular formation of the rat contain mRNAcoding for the m2, m3 and m4 subtypes of muscarinic receptors (Buckley et al., 1988; Vilaró et al., 1992; Sugaya et al., 1997). The m2 subtype appears to be the most abundant in the region, but m1-m4 receptor proteins, as revealed by immunohistochemistry, are found in the reticular formation of a variety of species (Levey et al., 1991, 1994; Rye et al., 1995; Ray et al., 1999). The muscarinic receptor subtypes mediating effects on sleep/wake behavior in this region of brain are currently unknown. Several approaches have been applied to the investigation of receptor subtype in the induction of REM sleep in the cat (ValazquezMoctezuma et al., 1989; Baghdoyan et al., 1994, 1998; Shuman et al., 1995; Baghdoyan, 1997; Sakai and Onoe, 1997; Baghdoyan and Lydic, 1999), but a paucity of data exist in the model of this phenomenon in rat (Imeri et al., 1994; Baghdoyan, 1997; Ray et al., 1999). In that the different receptor subtypes couple to different effector mechanisms and have differential anatomical distributions (Caulfield, 1993), a knowledge of receptor subtypes mediating muscarinicinduction of REM sleep will be helpful in the identification of brainstem mechanisms subserving this sleep state. Many muscarinic receptor ligands exhibit a concentrationdependent selectivity with respect to their actions at different receptor subtypes (reviewed in Caulfield, 1993; Hulme et al., 1990). Comparison of efficacy among different ligands can be a useful tool to identify the role of different receptors. We now report on the dose-response relationship for inducing elevations in REM sleep by three muscarinic agonists microinjected into the medial pontine reticular formation of the rat. The results are consistent with mediation by multiple muscarinic receptor subtypes in interaction and appear at variance with results obtained in the cat.