Muscarinic acetylcholine receptors (M 1 -M 5 ) 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 M 2 /M 4 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 M 2 and M 4 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 M 2 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 M 4 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 M 2 receptors. These data suggest that the muscarinic M 2 receptor subtype mediates muscarinic agonist-induced activation of the hypothalamic-pituitary-adrenocortical axis in mice.There are five muscarinic acetylcholine receptor subtypes, designated M 1 , M 2 , M 3 , M 4 , and M 5 , widely expressed in the central nervous system and in the periphery. Muscarinic receptors modulate the activity of many neurotransmitter systems in the brain, play a key role in memory and learning, and regulate a great number of sensory, motor, and autonomic processes. Moreover, central cholinergic receptor dysfunction has been suggested to be involved in the pathophysiology of schizophrenia (Haroutunian et al

In dogs gastric secretion induced by tetragastrin and pancreatic secretion induced by secretin and/or cholecystokinin were inhibited by somatostatin at doses of 0.06-1 microgram X kg-1 X h-1 and 0.06-1 microgram X kg-1 X 0.5 h-1, respectively. Inhibition was a linear function of the logarithm of dose. Basal and 2-deoxy-D-glucose-induced gastric acid secretion was also significantly inhibited by low doses of somatostatin. Results in this study differ from those reported previously by clarifying the action of somatostatin as follows. 1) The inhibitory effect of somatostatin on pancreatic protein secretion was significantly greater than that on water and bicarbonate production. Somatostatin was more effective on cholecystokinin- than secretin-induced pancreatic secretion. 2) Although gastric mucosal blood flow (MBF) was affected by somatostatin, the reduction of MBF was not the primary mechanism responsible for its inhibitory action. 3) The low doses of somatostatin used in this study significantly inhibited gastric and pancreatic secretion without affecting the basal plasma concentrations of insulin, glucagon, growth hormone, gastrin, or secretin in the dogs, suggesting that the inhibitory action was not mediated by changes or reduction in plasma concentration of these hormones.

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Studies are increasingly using cholinergic parameters as biomarkers of early neurotoxicity, but few have characterized this system in ecologically relevant model organisms. In the present study, key neurochemicals in the cholinergic pathway were measured and analyzed from discrete parts of brain and blood from captive mink (Mustela vison). Similar to other mammals, the regional distribution of cholinergic parameters in the brain could be ranked from highest to lowest as: basal ganglia > occipital cortex > brain stem > cerebellum (F (3,192) = 172.1, p < 0.001). Higher variation in cholinergic parameters was found in the cerebellum (coefficient of variation = 34.9%), and the least variation was measured in the brain stem (19.7%). Variation was also assessed by calculating the difference between the lowest and highest measures among individual animals: choline acetyltransferase (1.6x fold difference), cholinesterase (2.0x), muscarinic receptor levels (2.4x), acetylcholine (3.7x), nicotinic receptor levels (3.9x), and choline transporter (5.0x). In blood samples, activity and inter-individual variation of cholinesterase was highest in whole blood and lowest in plasma and serum. By using captive mink of a common genetic source, age, gender, and rearing conditions, these data help establish normal levels, ranges, and variations of cholinergic biomarkers among brain regions, blood components, and individual animals. Such information may better enable the utility of cholinergic biomarkers in environmental assessments.