Journal article
Novel insights into M 5 muscarinic acetylcholine receptor function by the use of gene targeting technology
Life sciences (1973), Vol.74(2), pp.345-353
2003
DOI: 10.1016/j.lfs.2003.09.022
PMID: 14607263
Abstract
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 extra-cerebral 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 agonist-induced 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 naloxone-induced 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 dopamine release in the nucleus accumbens. These results convincingly demonstrate that the M
5 muscarinic receptor is involved in modulating several important pharmacological and behavioral functions. These findings may lead to novel therapeutic strategies for the treatment of drug addiction and certain cerebrovascular disorders.
Details
- Title: Subtitle
- Novel insights into M 5 muscarinic acetylcholine receptor function by the use of gene targeting technology
- Creators
- Masahisa Yamada - National Institute of Diabetes and Digestive and Kidney DiseasesAnthony S Basile - National Institute of Diabetes and Digestive and Kidney DiseasesIrina Fedorova - National Institute of Diabetes and Digestive and Kidney DiseasesWeilie Zhang - National Institute of Diabetes and Digestive and Kidney DiseasesAlokesh Duttaroy - National Institute of Diabetes and Digestive and Kidney DiseasesYinghong Cui - National Institute of Diabetes and Digestive and Kidney DiseasesKathryn G Lamping - University of IowaFrank M Faraci - University of IowaChu-Xia Deng - National Institute of Diabetes and Digestive and Kidney DiseasesJürgen Wess - National Institute of Diabetes and Digestive and Kidney Diseases
- Resource Type
- Journal article
- Publication Details
- Life sciences (1973), Vol.74(2), pp.345-353
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.lfs.2003.09.022
- PMID
- 14607263
- ISSN
- 0024-3205
- eISSN
- 1879-0631
- Language
- English
- Date published
- 2003
- Academic Unit
- Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984303741102771
Metrics
2 Record Views