Genetic variation within the Chrna7 gene modulates nicotine reward‐like phenotypes in mice

Abstract

Mortality from tobacco smoking remains the leading cause of preventable death in the world, yet current cessation therapies are only modestly successful, suggesting new molecular targets are needed. Genetic analysis of gene expression and behavior identified Chrna7 as potentially modulating nicotine place conditioning in the BXD panel of inbred mice. We used gene targeting and pharmacological tools to confirm the role of Chrna7 in nicotine CPP. To identify molecular events downstream of Chrna7 that may modulate nicotine preference, we performed microarray analysis of α7 KO and WT nucleus accumbens tissue, followed by confirmation with quantitative PCR and immunoblotting. In the BXD panel, we found a putative cis eQTL for Chrna7 in nucleus accumbens that correlated inversely to nicotine CPP. We observed that gain-of-function α7 mice did not display nicotine preference at any dose tested, while conversely, α7 KO mice showed nicotine place preference at a dose below that routinely required to produce preference. In B6 mice, the α7 nAChR-selective agonist, PHA-543613, dose-dependently blocked nicotine CPP, which was restored using the α7 nAChR-selective antagonist, MLA. Our genomic studies implicated an mRNA co-expression network regulated by Chrna7 in nucleus accumbens. Mice lacking Chrna7 demonstrate increased insulin signaling in the nucleus accumbens, which may modulate nicotine place preference. Our studies provide novel targets for future work on development of more effective therapeutic approaches to counteract the rewarding properties of nicotine for smoking cessation.

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

“…The sum of these data strongly indicates that the naturally occurring variant in Chrna4 alters sensitivity to the effects of nicotine in mice. These findings also might indicate why nicotine CPP can be established in C57BL/6 mice, which possess the T529 allele of Chrna4 while it is difficult, if not impossible, to establish CPP in other strains, such as DBA/2, which possess the A529 allele of Chrna4 (Grabus, et al, 2006;Harenza, et al, 2014). …”

“…Miner and Collins (1989) reported similar results for nicotine-induced seizure sensitivity for the same 19 inbred strains. Genetic influences on the development of tolerance to nicotine (Marks, et al, 1986b;Marks, et al, 1991) nicotine oral self-selection (Robinson, et al, 1996;Li, et al, 2007), the effects of nicotine on open field activity (Marks, et al, 1986a) and conditioned place preference (Schechter, et al, 1995;Harenza, et al, 2014) have also been reported. Heritability estimates for some of these behaviors were obtained and found to range from 0.3 for nicotine-induced hypothermia (Marks, et al, 1984) to 0.63 for nicotine-induced seizure sensitivity (Miner, et al, 1984).…”

“…A recent study by Harenza (Harenza, et al, 2014) utilized recombinant inbred (RI) strains derived from the parent strains C57BL/6 and DBA/2 to assess the relationship between strain differences in α7 mRNA expression and nicotine place conditioning. This group reported that there was an inverse relationship between α7 mRNA expression in the striatum and prefrontal cortex of the RI strains and their corresponding place conditioning score.…”

Nicotinic Receptor Contributions to Smoking: Insights from Human Studies and Animal Models

“…Although early studies suggested that α7 nAChRs did not play a critical role in nicotine reinforcement or reward [83, 84], an accumulation of recent data suggest that low affinity α7 nAChRs work in opposition to β2*nAChRs, enhancing nicotine reinforcement and reward when α7 nAChRs are genetically or pharmacologically inhibited and reducing nicotine self-administration and nicotine CPP when α7 nAChRs are stimulated [105, 106]. Studies assessing methyllycaconitine (MLA) α7 nAChR antagonist effects on nicotine self-administration have returned mixed results [107, 108], perhaps because MLA has potency as an α6β2*nAChR antagonist [109].…”

“…Local infusion of a highly selective α7 antagonist peptide, α-conotoxin ArIB [V11L, V16D], into the NAc or ACC resulted in a nearly 3 fold increase in active lever pressing and breakpoints during a progressive ratio schedule of reinforcement suggesting that a loss of α7 nAChR function in these brain areas, such as that seen with schizophrenia, increases nicotine self-administration [105]. Nicotine-associated dopamine release is elevated in α7KO mice [110] which show leftward shifts in nicotine CPP [106] following systemic nicotine injection. By contrast, α7KO mice showed impaired oral nicotine self-administration during a 2 bottle choice but only after 40 days of exposure suggesting that α7 nAChRs may differentially regulate initiation and maintenance of nicotine self-administration in α7KO mice [83, 111].…”