Profound alteration in reward processing due to a human polymorphism in CHRNA5: a role in alcohol dependence and feeding behavior

Abstract

Human genetic variation in the nicotinic receptor gene cluster CHRNA5/A3/B4, in particular the nonsynonymous and frequent CHRNA5 variant rs16969968 (α5SNP), has an important consequence on smoking behavior in humans. A number of genetic association studies have additionally implicated the CHRNA5 gene in addictions to other drugs, and also body mass index (BMI). Here, we model the α5SNP, in a transgenic rat line, and establish its role in alcohol dependence, and feeding behavior. Rats expressing the α5SNP consume more alcohol, and exhibit increased relapse to alcohol seeking after abstinence. This high relapsing phenotype is reflected in altered activity in the insula, linked to interoception, as established using c-Fos immunostaining. Similarly, relapse to food seeking is increased in the transgenic group, while a nicotine treatment reduces relapse in both transgenic and control rats. These findings point to a general role of this human polymorphism in reward processing, and multiple addictions other than smoking. This could pave the way for the use of medication targeting the nicotinic receptor in the treatment of alcohol use and eating disorders, and comorbid conditions in smokers.

Genetic susceptibility to nicotine addiction: Advances and shortcomings in our understanding of the CHRNA5/A3/B4 gene cluster contribution

“…The 5 subunit is expressed in several brain areas important for addiction-like processes, including the ventral tegmental area (VTA), which is crucial for nicotine rewarding properties (Klink et al, 2001), but mostly in the IPN where it can combine with 42* or 34*nAChRs (Grady et al, 2009;Hsu et al, 2013). Alterations in nAChRs containing these subunits may impact the risk for NA by modifying the affinity for nicotine but also by altering the basal activity of the complex brain circuitry involved in addiction-like processes, as suggested by the implication of the CHRNA5-A3-B4 cluster in the abuse of other substances in addition to nicotine (Besson et al, 2019;Haller et al, 2014;Sherva et al, 2010).…”

Concatemers to re-investigate the role of α5 in α4β2 nicotinic receptors

“…In mice, α4 -/and β2 -/genotypes fail to self-administer nicotine, while α5 -/genotype displays a unique altered behavior towards nicotine, with partly reduced nicotine-related behaviors [2][3][4] and also towards ethanol, whose effects are partly enhanced [5], together with anxiety-related behaviors [6]. In rats, a recent study also highlighted a phenotype linked to nicotine and alcohol relapse processes [7,8]. In the brain, α5 incorporates in α3β4α5 and α4β2α5 nAChRs, and both nAChRs may contribute to these effects.…”

Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice

“…The images were then first processed with NDP View v2 software (Hamamatsu Photonics) to delimit the striatal region within each brain section and corresponding area (mm 2 ), and image exportation parameters were established for Sox9 and NeuN channels for the whole experimental image set to avoid any possible bias in posterior counting. The number of NeuN+ and Sox9+ nuclei in delimited striatal area of each brain section was automatically counted, using the spot detector module of ICY software (Institut Pasteur, Paris, France) to avoid experimenter bias 61 , and normalized by striatal area (mm 2 ) to compute cell density.…”