A Human Polymorphism in CHRNA5 Is Linked to Relapse to Nicotine Seeking in Transgenic Rats

Forget, Benoît; Scholze, Petra; Langa, Francina; Morel, Carole; Pons, Stéphanie; Mondoloni, Sarah; Besson, Morgane; Cuttoli, Romain Durand-de; Hay, Y. Audrey; Tricoire, Ludovic; Lambolez, Bertrand; Mourot, Alexandre; Fauré, Philippe; Maskos, Uwe

doi:10.1016/j.cub.2018.08.044

“…It was confirmed by a recent study realized by Forget et al showing that transgenic rats expressing a human nicotinic receptor polymorphism selfadminister more nicotine at high doses and exhibit higher nicotine-induced reinstatement of nicotine seeking than wild type. This relapse is associated with reduced neuronal activity in the interpeduncular nucleus [51]. All these studies show the importance of the rs16969968, especially for early diagnosis of LC, and may provide potential targets for new therapies for smoking cessation interventions.…”

Section: Discussionmentioning

confidence: 80%

Association of TERT, OGG1, and CHRNA5 Polymorphisms and the Predisposition to Lung Cancer in Eastern Algeria

Mimouni

¹

,

Rouleau

²

,

Saulnier

³

et al. 2020

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Lung cancer remains the most common cancer in the world. The genetic polymorphisms (rs2853669 in TERT, rs1052133 in OGG1, and rs16969968 in CHRNA5 genes) were shown to be strongly associated with the risk of lung cancer. Our study's aim is to elucidate whether these polymorphisms predispose Eastern Algerian population to non-small-cell lung cancer (NSCLC). To date, no study has considered this association in the Algerian population. This study included 211 healthy individuals and 144 NSCLC cases. Genotyping was performed using TaqMan probes and Sanger sequencing, and the data were analyzed using multivariate logistic regression adjusted for covariates. The minor allele frequencies (MAFs) of TERT rs2853669, CHRNA5 rs16969968, and OGG1 rs1052133 polymorphisms in controls were C: 20%, A: 31%, and G: 29%, respectively. Of the three polymorphisms, none shows a significant association, but stratified analysis rs16969968 showed that persons carrying the AA genotype are significantly associated with adenocarcinoma risk (pAdj = 0:03, ORAdj = 2:55).Smokers with an AA allele have a larger risk of lung cancer than smokers with GG or GA genotype (pAdj = 0:03, ORAdj = 3:91), which is not the case of nonsmokers. Our study suggests that CHRNA5 rs16969968 polymorphism is associated with a significant increase of lung adenocarcinoma risk and with a nicotinic addiction.

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“…; Forget et al. ). Genome‐wide association studies have indicated that single‐nucleotide polymorphisms (SNPs) within genes encoding nAChR subunits can substantially affect nAChR‐mediated smoking behavior in humans.…”

Section: Introductionmentioning

confidence: 97%

The role of the nAChR subunits α 5, β 2, and β 4 on synaptic transmission in the mouse superior cervical ganglion

Simeone

¹

,

Karch

²

,

Ciuraszkiewicz

³

et al. 2019

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Our previous immunoprecipitation analysis of nicotinic acetylcholine receptors ( nAChR s) in the mouse superior cervical ganglion ( SCG ) revealed that approximately 55%, 24%, and 21% of receptors are comprised of α 3 β 4, α 3 β 4 α 5, and α 3 β 4 β 2 subunits, respectively. Moreover, mice lacking β 4 subunits do not express α 5‐containing receptors but still express a small number of α 3 β 2 receptors. Here, we investigated how synaptic transmission is affected in the SCG of α 5 β 4‐ KO and α 5 β 2‐ KO mice. Using an ex vivo SCG preparation, we stimulated the preganglionic cervical sympathetic trunk and measured compound action potentials ( CAP s) in the postganglionic internal carotid nerve. We found that CAP amplitude was unaffected in α 5 β 4‐ KO and α 5 β 2‐ KO ganglia, whereas the stimulation threshold for eliciting CAP s was significantly higher in α 5 β 4‐ KO ganglia. Moreover, intracellular recordings in SCG neurons revealed no difference in EPSP amplitude. We also found that the ganglionic blocking agent hexamethonium was the most potent in α 5 β 4‐ KO ganglia ( IC 50 : 22.1 μ mol/L), followed by α 5 β 2‐ KO ( IC 50 : 126.7 μ mol/L) and WT ganglia ( IC 50 : 389.2 μ mol/L). Based on these data, we estimated an IC 50 of 568.6 μ mol/L for a receptor population consisting solely of α 3 β 4 α 5 receptors; and we estimated that α 3 β 4 α 5 receptors comprise 72% of nAChR s expressed in the mouse SCG . Similarly, by measuring the effects of hexamethonium on AC h‐induced currents in cultured SCG neurons, we found that α 3 β ...

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“…␣5 subunits are nearly 10-fold more abundant in IPN than in any other brain area (Forget et al, 2018), and ␣5 knockout mice do not exhibit nicotine withdrawal (Salas et al, 2009) or attenuated nicotine self-administration of aversive doses of nicotine (Fowler et al, 2011). Rats expressing an ␣5 sequence variant associated with human nicotine dependence and lung cancer show more facile relapse to nicotine-seeking behavior as well as an inverse correlation between IPN neuronal activity and relapse behavior (Forget et al, 2018). These results support our data demonstrating sensitized neuronal and nAChR activity in the IPN following exposure to nicotine, and point to ␣5-containing nAChRs as a possible therapeutic target for smoking cessation (Picciotto and Kenny, 2013).…”

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confidence: 93%

“…IPN components, especially ␣5-containing nAChRs, are emerging as key mediators of nicotine dependence-associated behaviors. ␣5 subunits are nearly 10-fold more abundant in IPN than in any other brain area (Forget et al, 2018), and ␣5 knockout mice do not exhibit nicotine withdrawal (Salas et al, 2009) or attenuated nicotine self-administration of aversive doses of nicotine (Fowler et al, 2011). Rats expressing an ␣5 sequence variant associated with human nicotine dependence and lung cancer show more facile relapse to nicotine-seeking behavior as well as an inverse correlation between IPN neuronal activity and relapse behavior (Forget et al, 2018).…”

mentioning

confidence: 99%

Chronic Nicotine Exposure Alters the Neurophysiology of Habenulo-Interpeduncular Circuitry

Arvin

¹

,

Jin

²

,

Yan

³

et al. 2019

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Antagonism of nicotinic acetylcholine receptors (nAChRs) in the medial habenula (MHb) or interpeduncular nucleus (IPN) triggerswithdrawal-like behaviors in mice chronically exposed to nicotine, implying that nicotine dependence involves the sensitization of nicotinic signaling. Identification of receptor and/or neurophysiological mechanisms underlying this sensitization is important, as it could promote novel therapeutic strategies to reduce tobacco use. Using an approach involving photoactivatable nicotine, we previously demonstrated that chronic nicotine (cNIC) potently enhances nAChR function in dendrites of MHb neurons. However, whether cNIC modulates downstream components of the habenulo-interpeduncular (Hb-IP) circuit is unknown. In this study, cNIC-mediated changes to Hb-IP nAChR function were examined in mouse (male and female) brain slices using molecular, electrophysiological, and optical techniques. cNIC enhanced action potential firing and modified spike waveform characteristics in MHb neurons. Nicotine uncaging revealed nAChR functional enhancement by cNIC on proximal axonal membranes. Similarly, nAChR-driven glutamate release from MHb axons was enhanced by cNIC. In IPN, the target structure of MHb axons, neuronal morphology, and nAChR expression is complex, with stronger nAChR function in the rostral subnucleus [rostral IPN (IPR)]. As in MHb, cNIC induced strong upregulation of nAChR function in IPN neurons. This, coupled with cNIC-enhanced nicotine-stimulated glutamate release, was associated with stronger depolarization responses to brief (1 ms) nicotine uncaging adjacent to IPR neurons. Together, these results indicate that chronic exposure to nicotine dramatically alters nicotinic cholinergic signaling and cell excitability in Hb-IP circuits, a key pathway involved in nicotine dependence.This study uncovers several neuropharmacological alterations following chronic exposure to nicotine in a key brain circuit involved in nicotine dependence. These results suggest that smokers or regular users of electronic nicotine delivery systems (i.e., "e-cigarettes") likely undergo sensitization of cholinergic circuitry in the Hb-IP system. Reducing the activity of Hb-IP nAChRs, either volitionally during smoking cessation or inadvertently via receptor desensitization during nicotine intake, may be a key trigger of withdrawal in nicotine dependence. Escalation of nicotine intake in smokers, or tolerance, may involve stimulation of these sensitized cholinergic pathways. Smoking cessation therapeutics are only marginally effective, and by identifying cellular/ receptor mechanisms of nicotine dependence, our results take a step toward improved therapeutic approaches for this disorder. Arvin et al. • Habenulo-Interpeduncular Circuits Modified by Nicotine

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A Human Polymorphism in CHRNA5 Is Linked to Relapse to Nicotine Seeking in Transgenic Rats

Cited by 37 publications

References 59 publications

Association of TERT, OGG1, and CHRNA5 Polymorphisms and the Predisposition to Lung Cancer in Eastern Algeria

Association of TERT, OGG1, and CHRNA5 Polymorphisms and the Predisposition to Lung Cancer in Eastern Algeria

The role of the nAChR subunits α 5, β 2, and β 4 on synaptic transmission in the mouse superior cervical ganglion

Chronic Nicotine Exposure Alters the Neurophysiology of Habenulo-Interpeduncular Circuitry

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