Novel insights into M5 muscarinic acetylcholine receptor function by the use of gene targeting technology (original) (raw)
Until recently, little was known about the possible physiological functions of the M 5 muscarinic acetylcholine receptor subtype, the last member of the muscarinic receptor family (M 1 -M 5 ) to be cloned. To learn more about the potential physiological roles of this receptor subtype, we generated and analyzed M 5 receptor-deficient mice (M5 -/-mice). Strikingly, acetylcholine, a potent dilator of most vascular beds, virtually lost the ability to dilate cerebral arteries and arterioles in M5 -/-mice, suggesting that endothelial M 5 receptors mediate this activity in wild-type mice. This effect was specific for cerebral blood vessels, since acetylcholine-mediated dilation of extracerebral arteries remained fully intact in M5 -/-mice. In addition, in vitro neurotransmitter release experiments indicated that M 5 receptors located on dopaminergic nerve terminals play a role in facilitating muscarinic agonistinduced dopamine release in the striatum, consistent with the observation that the dopaminergic neurons innervating the striatum almost exclusively express the M 5 receptor subtype. We also found that the rewarding effects of morphine, the prototypical opiate analgesic, were substantially reduced in M5 -/-mice, as measured in the conditioned place preference paradigm. Furthermore, both the somatic and affective components of naloxoneinduced morphine withdrawal symptoms were significantly attenuated in M5 -/-mice. It is likely that these behavioral deficits are caused by the lack of mesolimbic M 5 receptors, activation of which is known to stimulate 0024-3205/$ -see front matter D (J. Wess). www.elsevier.com/locate/lifescie Life Sciences 74 (2003) 345 -353
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