title: Genetic matters: thirty years of progress using mouse models in nicotinic research.
abstract: This research update summarizes thirty years of studies on genetic influences on responses to the acute or chronic administration of nicotine. Early studies established that various inbred mice are differentially sensitive to the effects of the drug. Classical genetic analyses confirmed that nicotine effects on locomotion, body temperature and seizures are heritable. A significant inverse correlation between the locomotor and hypothermic effects and the density of nicotine binding sites suggested that differential expression α4β2-neuronal nicotinic acetylcholine receptor (nAChR) mediated some of this genetic variability. Subsequent studies with α4 and β2 nAChR null (decreased sensitivity) and gain of function mutants (increased sensitivity) supports the role of the α4β2*nAChR subtype. However, null mutant mice still respond to nicotine, indicating that other nAChR subtypes also mediate these responses. Mice differing in initial sensitivity to nicotine also differ in tolerance development following chronic treatment: those mice that are initially more sensitive to nicotine develop tolerance at lower treatment doses than less sensitive mice, indicating that tolerance is an adaptive response to the effects of nicotine. In contrast, the sensitivity of mice to pre-pulse inhibition of acoustic startle response is correlated with the expression of α7-nAChR. While genetic variability in nAChR expression and function is an important factor contributing to differences in response to nicotine, the observations that altered activity of opioid, glutamate, and cannabinoid receptors among others also change nicotine sensitivity reinforces the proposal that the genetics of nicotine response is more complex than differences in nAChRs.
authors.affiliation: Institute for Behavioral Genetics and Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA. Electronic address: marksm@colorado.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology*; D014644:Genetic Variation; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*
chemical_list: D011978:Receptors, Nicotinic; D009538:Nicotine
keywords: Chrna; Chrnb; Knockout mice; LS; Mouse genetics; Mutations; Nicotine; Nicotinic acetylcholine receptors; SS; Short sleep mice; genes encoding α subunits of the nAChR; genes encoding β subunits of the nAChR; long sleep mice; nAChR; nicotinic acetylcholine receptor