C.G. and T.C.G. contributed equally to this work.
Staying awake – a genetic region that hinders α2 adrenergic receptor agonist-induced sleep
Article first published online: 27 MAR 2014
© 2014 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
European Journal of Neuroscience
Volume 40, Issue 1, pages 2311–2319, July 2014
How to Cite
Gelegen, C., Gent, T. C., Ferretti, V., Zhang, Z., Yustos, R., Lan, F., Yang, Q., Overington, D. W. U., Vyssotski, A. L., van Lith, H. A., Wisden, W. and Franks, N. P. (2014), Staying awake – a genetic region that hinders α2 adrenergic receptor agonist-induced sleep. European Journal of Neuroscience, 40: 2311–2319. doi: 10.1111/ejn.12570
- Issue published online: 6 JUL 2014
- Article first published online: 27 MAR 2014
- Manuscript Accepted: 24 FEB 2014
- Manuscript Revised: 21 FEB 2014
- Manuscript Received: 17 JAN 2014
- Medical Research Council. Grant Numbers: G0901892, G0800399
- Biotechnology and Biological Sciences Research Council. Grant Number: G021691
- Biological Sciences Research Council
- Wellcome Trust Vacation
- Chinese Society of Anesthesiology
- alpha2a adrenergic receptor;
How external stimuli prevent the onset of sleep has been little studied. This is usually considered to be a non-specific type of phenomenon. However, the hypnotic drug dexmedetomidine, an agonist at α2 adrenergic receptors, has unusual properties that make it useful for investigating this question. Dexmedetomidine is considered to produce an ‘arousable’ sleep-like state, so that patients or animals given dexmedetomidine become alert following modest stimulation. We hypothesized that it might be more difficult to make mice unconscious with dexmedetomidine if there was a sufficient external stimulus. Employing a motorized rotating cylinder, which provided a continuous and controlled arousal stimulus, we quantitatively measured the ability of such a stimulus to prevent dexmedetomidine loss of righting reflex in two inbred strains of mice (C57BL/6 and 129X1). We found that whereas the C57BL/6 strain required a strong stimulus to prevent dexmedetomidine-induced hypnosis, the 129X1 strain stayed awake even with minimal stimuli. Remarkably, this could be calibrated as a simple threshold trait, i.e. a binary ‘yes–no’ response, which after crossing the two mouse strains behaved as a dominant-like trait. We carried out a genome-wide linkage analysis on the F2 progeny to determine if the ability of a stimulus to prevent dexmedetomidine hypnosis could be mapped to one or more chromosomal regions. We identified a locus on chromosome 4 with an associated Logarithm of Odds score exceeding the pre-established threshold level. These results show that complex traits, such as the ability of a stimulus to reverse drug-induced hypnosis, may have precise genetic determinants.