Cholinergic dilation of cerebral blood vessels is abolished in M-5 muscarinic acetylcholine receptor knockout mice

The M-5 muscarinic receptor is the most recent member of the muscarinic ace tylcholine receptor family (M-1-M-5) to be cloned. At present, the physiolo gical relevance of this receptor subtype remains unknown, primarily because of its low expression levels and the lack of M-5 receptor-selective ligand s. To circumvent these difficulties, we used gene targeting technology to g enerate M-5 receptor-deficient mice (M5R(-/-) mice). M5R(-/-) mice did not differ from their wild-type littermates in various behavioral and pharmacol ogic tests. However, in vitro neurotransmitter release experiments showed t hat M-5 receptors play a role in facilitating muscarinic agonist-induced do pamine release in the striatum. Because M-5 receptor mRNA has been detected in several blood vessels, we also investigated whether the lack of M-5 rec eptors led to changes in vascular tone by using several in vivo and in vitr o vascular preparations. Strikingly, acetylcholine, a powerful dilator of m ost vascular beds, virtually lost the ability to dilate cerebral arteries a nd arterioles in M5R(-/-) mice. This effect was specific for cerebral blood vessels, because acetylcholine-mediated dilation of extracerebral arteries remained fully intact in M5R(-/-) mice. Our findings provide direct eviden ce that M-5 muscarinic receptors are physiologically relevant. Because it h as been suggested that impaired cholinergic dilation of cerebral blood vess els may play a role in the pathophysiology of Alzheimer's disease and focal cerebral ischemia, cerebrovascular M-5 receptors may represent an attracti ve therapeutic target.