Pituitary-Adrenal Responses to Oxotremorine and Acute Stress in Male and Female M1 Muscarinic Receptor Knockout Mice: Comparisons to M2 Muscarinic Receptor Knockout Mice

Both within the brain and in the periphery, M1 muscarinic receptors function primarily as postsynaptic receptors and M2 muscarinic receptors function primarily as presynaptic autoreceptors. In addition to classical parasympathetic effectors, cholinergic stimulation of central muscarinic receptors influences the release of adrenocorticotrophic hormone (ACTH) and corticosterone. We previously reported that oxotremorine administration to male and female M2 receptor knockout and wild‐type mice increased ACTH to a significantly greater degree in knockout males compared to all other groups, and that M2 knockout mice of both sexes were significantly more responsive to the mild stress of saline injection than were wild‐type mice. These results accord with the primary function of M2 receptors as presynaptic autoreceptors. In the present study, we explored the role of the M1 receptor in pituitary–adrenal responses to oxotremorine and saline in male and female M1 knockout and wild‐type mice. Because these mice responded differently to the mild stress of saline injection than did the M2 knockout and wild‐type mice, we also determined hormone responses to restraint stress in both M1 and M2 knockout and wild‐type mice. Male and female M1 knockout and wild‐type mice were equally unresponsive to the stress of saline injection. Oxotremorine increased both ACTH and corticosterone in M1 wild‐type mice to a significantly greater degree than in knockout mice. In both M1 knockout and wild‐type animals, ACTH responses were greater in males compared to females, and corticosterone responses were greater in females compared to males. Hormone responses to restraint stress were increased in M2 knockout mice and decreased in M1 knockout mice compared to their wild‐type counterparts. These findings suggest that M1 and M2 muscarinic receptor subtypes differentially influence male and female pituitary–adrenal responses to cholinergic stimulation and stress. The decreased pituitary–adrenal sensitivity to oxotremorine and restraint stress noted in M1 knockout mice is consistent with M1 being primarily a postsynaptic receptor. Conversely, the increased pituitary–adrenal sensitivity to these challenges noted in M2 knockout mice is consistent with M2 being primarily a presynaptic autoreceptor.