The β2 nicotinic acetylcholine receptor subunit differentially influences ethanol behavioral effects in the mouse

Dawson, Anton; Miles, Micheal F.; Damaj, M. Imad

doi:10.1016/j.alcohol.2012.12.004

Cited by 20 publications

(15 citation statements)

References 53 publications

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“…The deletion of β2-containing nAChRs modifies anxiolytic and withdrawal behaviors to alcohol (97,98), but has no effect on alcohol drinking behavior (98) or alcohol preference (99). Deletion of the α7 nAChR subunit results in significant reduction of alcohol intake in female mice as compared to wild-type mice, with no effect in males (100).…”

Section: Concurrent Use Of Nicotine and Alcoholmentioning

confidence: 99%

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse

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Lotfipour

Leslie

2016

The American Journal of Drug and Alcohol Abuse

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Concurrent use of tobacco and alcohol or psychostimulants represents a major public health concern, with use of one substance influencing consumption of the other. Co-abuse of these drugs leads to substantial negative health outcomes, reduced cessation, and high economic costs, but the underlying mechanisms are poorly understood. Epidemiological data suggest that tobacco use during adolescence plays a particularly significant role. Adolescence is a sensitive period of development marked by major neurobiological maturation of brain regions critical for reward processing, learning and memory, and executive function. Nicotine exposure during this time produces a unique and long-lasting vulnerability to subsequent substance use, likely via actions at cholinergic, dopaminergic, and serotonergic systems. In this review, we discuss recent clinical and preclinical data examining the genetic factors and mechanisms underlying co-use of nicotine and alcohol or cocaine and amphetamines. We evaluate the critical role of nicotinic acetylcholine receptors throughout, and emphasize the dearth of preclinical studies assessing concurrent drug exposure. We stress important age and sex differences in drug responses, and highlight a brief, low-dose nicotine exposure paradigm that may better model early use of tobacco products. The escalating use of e-cigarettes among youth necessitates a closer look at the consequences of early adolescent nicotine exposure on subsequent alcohol and drug abuse.

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Section: Concurrent Use Of Nicotine and Alcoholmentioning

confidence: 99%

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse

Cross

Lotfipour

Leslie

2016

The American Journal of Drug and Alcohol Abuse

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“…Our lab has previously highlighted the role of β2* nAChRs in the induction on LORR after ethanol treatment (Dawson et al, 2013). Given that ethanol has been shown to have distinct effects depending on the subunit composition of nAChRs (Cardoso et al, 1999; Borghese et al, 2003), we tested the latency and duration of ethanol-induced LORR after treatment with 3.8 g/kg ethanol in WT and α5 null mice.…”

Section: Resultsmentioning

confidence: 99%

Knockout of alpha 5 nicotinic acetylcholine receptors subunit alters ethanol-mediated behavioral effects and reward in mice

et al. 2018

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Evidence suggests that there is an association between polymorphisms in the α5 nicotinic acetylcholine receptor (nAChR) subunit and risk of developing alcohol dependence in humans. The α5 nAChR subunit has also recently been shown to modulate some of the acute response to ethanol in mice. The aim of the current study was to further characterize the role of α5-containing (α5*) nAChRs in acute ethanol responsive behaviors, ethanol consumption and ethanol preference in mice. We conducted a battery of tests in male α5 knockout (KO) mice for a range of ethanol-induced behaviors including hypothermia, hypnosis, and anxiolysis. We also investigated the effects of α5* nAChR on ethanol reward using the Conditioned Place Preference (CPP) assay. Further, we tested the effects of gene deletion on drinking behaviors using the voluntary ethanol consumption in a two-bottle choice assay and Drinking in the Dark (DID, with or without stress) paradigm. We found that deletion of the α5 nAChR subunit enhanced ethanol-induced hypothermia, hypnosis, and an anxiolytic-like response in comparison to wild-type controls. The α5 KO mice showed reduced CPP for ethanol, suggesting that the rewarding properties of ethanol are decreased in mutant mice. Interestingly, Chrna5 gene deletion had no effect on basal ethanol drinking behavior, or ethanol metabolism, but did decrease ethanol intake in the DID paradigm following restraint stress. Taken together, we provide new evidence that α5 nAChRs are involved in some but not all of the behavioral effects of ethanol. Our results highlight the importance of nAChRs as a possible target for the treatment of alcohol dependence.

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“…The computer simulation data further support the HS stoichiometry by (Figs 6 and 7 ) suggesting a preferential binding of lynx1 to the α4:α4 interface of the α4β2 nAChRs. We also saw that the β2*-selective nAChR antagonist DHβE was able to block nicotine’s antinociceptive effect in lynx1KO mice, which further suggests that lynx1 is able to modulate the α4β2 nAChR subtype, demonstrating the β2* nAChRs involvement in antinociception but not locomotion or thermal regulation [ 80 ] ( Fig 4 ).…”

Section: Discussionmentioning

confidence: 98%

Augmenting the antinociceptive effects of nicotinic acetylcholine receptor activity through lynx1 modulation

et al. 2018

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Neuronal nicotinic acetylcholine receptors (nAChRs) of the cholinergic system have been linked to antinociception, and therefore could be an alternative target for pain alleviation. nAChR activity has been shown to be regulated by the nicotinic modulator, lynx1, which forms stable complexes with nAChRs and has a negative allosteric action on their function. The objective in this study was to investigate the contribution of lynx1 to nicotine-mediated antinociception. Lynx1 contribution was investigated by mRNA expression analysis and electrophysiological responses to nicotine in the dorsal raphe nucleus (DRN), a part of the pain signaling pathway. In vivo antinociception was investigated in a test of nociception, the hot-plate analgesia assay with behavioral pharmacology. Lynx1/α4β2 nAChR interactions were investigated using molecular dynamics computational modeling. Nicotine evoked responses in serotonergic and GABAergic neurons in the DRN are augmented in slices lacking lynx1 (lynx1KO). The antinociceptive effect of nicotine and epibatidine is enhanced in lynx1KO mice and blocked by mecamylamine and DHβE. Computer simulations predict preferential binding affinity of lynx1 to the α:α interface that exists in the stoichiometry of the low sensitivity (α4)3(β2)2 nAChRs. Taken together, these data point to a role of lynx1 in mediating pain signaling in the DRN through preferential affinity to the low sensitivity α4β2 nAChRs. This study suggests that lynx1 is a possible alternative avenue for nociceptive modulation outside of opioid-based strategies.

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The β2 nicotinic acetylcholine receptor subunit differentially influences ethanol behavioral effects in the mouse

Cited by 20 publications

References 53 publications

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse

Knockout of alpha 5 nicotinic acetylcholine receptors subunit alters ethanol-mediated behavioral effects and reward in mice

Augmenting the antinociceptive effects of nicotinic acetylcholine receptor activity through lynx1 modulation

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