Role of α5* nicotinic acetylcholine receptors in the effects of acute and chronic nicotine treatment on brain reward function in mice

Fowler, Christie D.; Tuesta, Luis M.; Kenny, Paul J.

doi:10.1007/s00213-013-3235-1

Cited by 71 publications

(72 citation statements)

References 58 publications

(86 reference statements)

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“…These observations have several interesting parallels to studies of α5 function in rodents, most notably the essential role of α5 in mediating the aversive effects of nicotine (Bailey et al, 2010;Fowler et al, 2011;Frahm et al, 2011;Jackson et al, 2010). The attenuated aversive response to nicotine might reduce the reward-inhibiting and increase the reward-enhancing potential of the drug (Fowler et al, 2011;Fowler et al, 2013). The lower ratings of aversive effects for A carriers in the nicotine condition relative to the saline condition may relate, partly, to an alleviation of nicotine withdrawal, as shown by the change in BQSU and MNWS scores following nicotine infusion.…”

Section: Discussionmentioning

confidence: 88%

“…rs16969968 encodes an amino-acid substitution in CHRNA5 that might mediate some of these risk effects, and several lines of evidence support this hypothesis. A proposed risk mechanism, based largely on animal models, suggests that the CHRNA5 risk allele increases the heaviness of smoking by attenuating the aversive response to nicotine (Bailey et al, 2010;Bierut et al, 2008;Fowler et al, 2011;Fowler et al, 2013;Frahm et al, 2011;Jackson et al, 2010;Kuryatov et al, 2011;Saccone et al, 2010;Saccone et al, 2007;Tobacco and Genetics Consortium, 2010). However, this mechanism has not been directly examined in human studies.…”

Section: Discussionmentioning

confidence: 99%

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A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans

Jensen

DeVito

Herman

et al. 2015

Neuropsychopharmacol

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Genome-wide association studies have implicated the CHRNA5-CHRNA3-CHRNB4 gene cluster in risk for heavy smoking and several smoking-related disorders. The heavy smoking risk allele might reduce the aversive effects of nicotine, but this hypothesis has not been tested in humans. We evaluated the effects of a candidate causal variant in CHRNA5, rs16969968, on the acute response to nicotine in European American (EA) and African American (AA) smokers (n=192; 50% AA; 73% male). Following overnight abstinence from nicotine, participants completed a protocol that included an intravenous (IV) dose of saline and two escalating IV doses of nicotine. The outcomes evaluated were the aversive, pleasurable, and stimulatory ratings of nicotine's effects, cardiovascular reactivity to nicotine, withdrawal severity, and cognitive performance before and after the nicotine administration session. The heavy smoking risk allele (rs16969968*A; frequency=28% (EA) and 6% (AA)) was associated with lower ratings of aversive effects (P<5 × 10(-8)) with marked specificity. This effect was evident in EA and AA subjects analyzed as separate groups and was most robust at the highest nicotine dose. Rs16969968*A was also associated with greater improvement on a measure of cognitive control (Stroop Task) following nicotine administration. These findings support differential aversive response to nicotine as one likely mechanism for the association of CHRNA5-CHRNA3-CHRNB4 with heavy smoking.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans

Jensen

DeVito

Herman

et al. 2015

Neuropsychopharmacol

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“…Fowler et al, 8,34 observed that α5 − / − mice exhibit an increase in IVSA for high nicotine doses, but no modifications at low doses, and found no strong evidence for a role in reward. They proposed that α5*-nAChRs in the mHb trigger an inhibitory motivational signal limiting nicotine intake of high nicotine doses.…”

Section: Discussionmentioning

confidence: 96%

Nicotine consumption is regulated by a human polymorphism in dopamine neurons

et al. 2013

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Smoking is the most important preventable cause of morbidity and mortality worldwide. Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer. Several polymorphisms in the CHRNA3-CHRNA5-CHRNB4 cluster coding for the nicotinic acetylcholine receptor (nAChR) α3, α5 and β4 subunits were implicated. In mouse models, we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). We first investigated the reinforcing effects of nicotine in drug-naive α5(-/-) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation. We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA, in general, or in DA neurons exclusively. Our results establish a crucial role for α5*-nAChRs in DAergic neurons. These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement. Finally, we demonstrate that a single-nucleotide polymorphism, the non-synonymous α5 variant rs16969968, frequent in many human populations, exhibits a partial loss of function of the protein in vivo. This leads to increased nicotine consumption in the self-administration paradigm. We thus define a critical link between a human predisposition marker, its expression in DA neurons and nicotine intake.

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“…A related approach was used to study the role of a5 nAChRs in the effects of nicotine on ICSS under a discrete-trial current-intensity procedure (Fowler et al, 2013). WT mice and a5 nAChR subunit knockout mice (a5ko) did not differ with regard to baseline ICSS.…”

Section: A Statesmentioning

confidence: 99%