Chrna4 A529 knock-in mice exhibit altered nicotine sensitivity

Wilking, Jennifer A.; Hesterberg, Kirstin; Crouch, Eric L.; Homanics, Gregg E.; Stitzel, Jerry A.

doi:10.1097/fpc.0b013e3283369347

Cited by 20 publications

(29 citation statements)

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“…We measured voluntary nicotine self-administration by using a continuous-access, two-bottle choice paradigm, a widely used method to measure nicotine consumption and preference in mice (23)(24)(25). Prkce −/− and wild-type mice were given a choice between a bottle of 15 μg/mL nicotine with 2% saccharin and a bottle of tap water with 2% saccharin for 4 wk.…”

Section: Resultsmentioning

confidence: 99%

“…Voluntary nicotine was assessed with a two-bottle choice paradigm, a widely used method to measure consumption and preference in mice (23)(24)(25). Mice were individually housed and given 24-h access to a water bottle with 2% saccharin and a water bottle with 15 μg/mL nicotine and 2% saccharin for 31 d. Bottles were weighed every 2 d, and the positions of the bottles were reversed after each weighing.…”

Section: Methodsmentioning

confidence: 99%

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Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens

Lee

Messing

2011

Proc. Natl. Acad. Sci. U.S.A.

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Nicotine addiction and alcohol use disorders are very widespread and often occur together. Currently, there is no single drug approved for the simultaneous treatment of both conditions. Although these conditions share common genetic factors, the molecular mechanisms underlying their comorbidity are unknown. We have previously shown that mice lacking protein kinase C epsilon (PKCε) show decreased ethanol self-administration and reward as well as increased aversion to ethanol. Here we find that Prkce −/− mice self-administer less nicotine and show decreased conditioned place preference for nicotine compared with wild-type mice. In Prkce −/− mice, these behaviors are associated with reduced levels of α 6 and β 3 nicotinic receptor subunit mRNA in the ventral midbrain and striatum as well as a functional deficit in cholinergic modulation of dopamine release in nucleus accumbens. Our results indicate that PKCε regulates reward signaling through α 6 -containing nicotinic receptors and suggest that PKCε could be a target for the treatment of comorbid nicotine and alcohol addictions.T obacco addiction remains the leading cause of premature mortality in the world, and half of all tobacco users will die of tobacco-related disease (1). Nicotine is the primary, if not the only, compound that maintains addiction to tobacco (2), and smokers will adjust their level of cigarette smoking to maintain constant levels of plasma nicotine (3). Current approved pharmacotherapies for smoking cessation all target nicotinic acetylcholine receptors (nAChRs) and include nicotine-replacement therapy, bupropion (a nicotinic antagonist) (4), and varenicline (a partial nicotinic agonist) (5). Although this approach is effective in the short term, long-term abstinence rates are low, underscoring the need for the discovery of new drug targets and development of new treatments.It is striking that, among all drug addictions, alcohol and tobacco addictions are highly comorbid with more than 60% of smokers in the US reporting concurrent binge drinking or heavy use of alcohol (6). Likewise, the prevalence of smoking among those with alcohol use disorders has been reported to be as high as 88-96% (7, 8). In humans, a single exposure to alcohol can increase the urge to smoke and increase cigarette consumption (9, 10). Conversely, in rats, s.c. injections of nicotine can increase ethanol self-administration (11) and promote reinstatement for ethanol responding after extinction (11,12). In rats that selfadminister i.v. nicotine and oral alcohol, the extinction of alcohol responding is prolonged if nicotine remains available (13), suggesting that combined use of both substances may make it more difficult to successfully quit the use of nicotine or alcohol alone. Nicotine and alcohol addictions appear to share common genetic factors (14-16), but the molecular mechanisms underlying their comorbidity are unknown. Currently, no pharmaceutical agent has been approved to treat comorbid nicotine and alcohol addictions.The protein kinase C (PKC) family of serine/...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens

Lee

Messing

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…One of these naturally occurring mouse polymorphisms was found in the intracellular loop of the a4 subunit (a4A529T) (Stitzel et al, 2001). Expression of the a4A529 variant increases sensitivity to nicotine, eliminates nicotine conditioned place preference, and produces increased HS a4b2 nAChRs in the midbrain (Wilking et al, 2010). A smoking risk-associated nAChR polymorphism that occurs in the a5 nAChR subunit (Bierut et al, 2008) introduces an amino acid substitution in the intracellular loop of a5 (a5D397N; D398N for mouse sequence) and results in decreased function of a4b2 and a3b4 nAChRs (Bierut et al, 2008;Kuryatov et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Rare Human Nicotinic Acetylcholine Receptor α4 Subunit (CHRNA4) Variants Affect Expression and Function of High-Affinity Nicotinic Acetylcholine Receptors

McClure-Begley

Papke

Stone

et al. 2014

J Pharmacol Exp Ther

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Nicotine, the primary psychoactive component in tobacco smoke, produces its behavioral effects through interactions with neuronal nicotinic acetylcholine receptors (nAChRs). a4b2 nAChRs are the most abundant in mammalian brain, and converging evidence shows that this subtype mediates the rewarding and reinforcing effects of nicotine. A number of rare variants in the CHRNA4 gene that encode the a4 nAChR subunit have been identified in human subjects and appear to be underrepresented in a cohort of smokers. We compared three of these variants (a4R336C, a4P451L, and a4R487Q) to the common variant to determine their effects on a4b2 nAChR pharmacology. We examined [ 3 H]epibatidine binding, interacting proteins, and phosphorylation of the a4 nAChR subunit with liquid chromatography and tandem mass spectrometry (LC-MS/ MS) in HEK 293 cells and voltage-clamp electrophysiology in Xenopus laevis oocytes. We observed significant effects of the a4 variants on nAChR expression, subcellular distribution, and sensitivity to nicotine-induced receptor upregulation. Proteomic analysis of immunopurified a4b2 nAChRs incorporating the rare variants identified considerable differences in the intracellular interactomes due to these single amino acid substitutions. Electrophysiological characterization in X. laevis oocytes revealed alterations in the functional parameters of activation by nAChR agonists conferred by these a4 rare variants, as well as shifts in receptor function after incubation with nicotine. Taken together, these experiments suggest that genetic variation at CHRNA4 alters the assembly and expression of human a4b2 nAChRs, resulting in receptors that are more sensitive to nicotine exposure than those assembled with the common a4 variant. The changes in nAChR pharmacology could contribute to differences in responses to smoked nicotine in individuals harboring these rare variants.

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“…However, in a different study little effect of a global deletion of the α4 subunit was noted, but mice expressing the α4 S6’F gain of function mutation achieved conditioned place preference at lower nicotine doses than did wild-type mice [42]. Mice differing in the α4 A529T polymorphism differed significantly in nicotine conditioned place preference; mice expressing the T variant developed conditioned place preference, while those with the A variant did not [43]. Interestingly, DBA mice express the A variant and C57BL/6 express the T variant a result consistent with the difference in conditioned place preference reported for these inbred strains [39].…”

Section: Conditioned Place Preferencementioning

confidence: 99%

Genetic matters: Thirty years of progress using mouse models in nicotinic research

Marks

2013

Biochemical Pharmacology

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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.

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Chrna4 A529 knock-in mice exhibit altered nicotine sensitivity

Cited by 20 publications

References 45 publications

Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens

Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens

Rare Human Nicotinic Acetylcholine Receptor α4 Subunit (CHRNA4) Variants Affect Expression and Function of High-Affinity Nicotinic Acetylcholine Receptors

Genetic matters: Thirty years of progress using mouse models in nicotinic research

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