Vol. 303, Issue 1, 99-103, October 2002

Muscarinic Agonist-Mediated Increases in Serum Corticosterone Levels Are Abolished in M₂ Muscarinic Acetylcholine Receptor Knockout Mice

S. K. Hemrick-Luecke, F. P. Bymaster, D. C. Evans, J. Wess and C. C. Felder

Neuroscience Division, Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana (S.K.H.-L., F.P.B., D.C.E., C.C.F.); and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (J.W.)

Muscarinic acetylcholine receptors (M₁-M₅) regulate many key functions in the central and peripheral nervous system. Due to the lack of receptor subtype-selective ligands, however, the physiological roles of individual muscarinic receptor subtypes remain to be determined. In this study, we examined the effects of the muscarinic M₂/M₄ receptor-preferring agonist [5R-(exo)]-6-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane (BuTAC) on serum corticosterone levels in M₂ and M₄ receptor single knockout (KO) and M_2,4 receptor double KO mice. Responses were compared with those obtained with the corresponding wild-type (WT) mice. BuTAC (0.03-0.3 mg/kg s.c.) dose dependently and significantly increased serum corticosterone concentrations in WT mice to 5-fold or greater levels compared with vehicle controls. In muscarinic M₂ and M_2,4 KO mice, however, BuTAC had no significant effect on corticosterone concentrations at doses of 0.1, 0.3, and 1 mg/kg s.c. In both WT and muscarinic M₄ KO mice increases in serum corticosterone concentrations induced by BuTAC (0.1 and 0.3 mg/kg) were not significantly different and were blocked by scopolamine. In summary, the muscarinic M_2,4-preferring agonist BuTAC had no effect on corticosterone levels in mice lacking functional muscarinic M₂ receptors. These data suggest that the muscarinic M₂ receptor subtype mediates muscarinic agonist-induced activation of the hypothalamic-pituitary-adrenocortical axis in mice.