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.

Ion channels gated by acetylcholine and serotonin: structures, biology, and drug discovery

“…Importantly, ACh is released from presynaptic neurons and binds to the nAChRs that modulate the flow of ions across the cell membrane similarly to all cell-surface ligand-gated ion channels ( Figure 2 ). In the nervous system, cholinergic stimulation mediated through nAChRs controls pathways such as transmitter release and cell sensitivity, which can influence physiological activity including sleep, anxiety, pain processing and cognitive functions 30 , 31 , 32 , 33 . A net influx of cations through the associated channel pore depolarizes the cell membrane and increases neuronal excitability.…”

Natural genetic variability of the neuronal nicotinic acetylcholine receptor subunit genes in mice: Consequences and confounds

“…Similarly, the behavioral and physiological effects of nicotine, the major psychoactive component in tobacco, are influenced by genetic factors in mice (for an excellent review see (Marks, 2013)). For example, Marks et al (1989) demonstrated that there is a 2 to 6-fold difference in ED 50 values for a battery of tests for nicotine sensitivity across 19 inbred strains.…”

“…Extensive work has been done on the effects of nicotine in mice engineered to possess knockout or knockin alleles of most nAChR subunit genes (Picciotto, et al, 2001;Drenan and Lester, 2012;Marks, 2013). Although generally ignored, the natural nAChR variants described in this review potentially could impact the effect of an engineered mutation on nicotine sensitivity.…”

Drug-dependent behaviors and nicotinic acetylcholine receptor expressions in Caenorhabditis elegans following chronic nicotine exposure

“…nAChRs are expressed at the synapse of nerve and muscle cells and are responsible for mediating excitatory synaptic transmission at the neuromuscular junctions and in the nervous system (Jones & Sattelle, 2003). One mechanism of the development of drug-dependence behaviors is that the activation of nAChRs on dopaminergic neurons by the endogenous ligand acetylcholine (ACh) or exogenous agonists, such as nicotine, stimulates dopamine release, mediating rewarding effects of nicotine (Cahir et al , 2011; Marks, 2013). Nicotine administration results in behavioral stimulation after acute exposure, behavioral and physiological tolerance after chronic exposure, and dependence/withdrawal symptoms upon nicotine removal (Feng et al, 2006; Mineur & Picciotto, 2008).…”