No evidence of a role of the β4 subunit of the nicotinic acetylcholine receptor in alcohol-related behaviors

Kamens, Helen M.; Silva, Constanza; McCarthy, Riley Delaney; Cox, Ryan J.; Ehringer, Marissa A.

doi:10.1186/s13104-017-2470-7

Cited by 7 publications

(6 citation statements)

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“…To determine the nAChRs that underlie varenicline's reduction of ethanol consumption, researchers turned to genetically modified animals. Deletion of the α7, β2, and β4 nAChR subunits did not block the effect of varenicline on ethanol consumption suggesting that these receptor subunits are not involved (Kamens et al, 2010a; Kamens et al, 2017b; Patkar et al, 2016). In contrast, work in genetically modified animals that both increased sensitivity of the α4 subunit and knocked it out demonstrated that this subunit was necessary and sufficient for varenicline-induced reduction of ethanol consumption in adult mice (Hendrickson et al, 2011).…”

Section: Discussionmentioning

confidence: 97%

“…We have previously reported that varenicline increases ethanol-induced sedation in adult mice (Kamens et al, 2010b) and human clinical studies have reported enhanced ratings of alcohol sedation (Fucito et al, 2011). Research in knockout animal models has provided evidence that a number of nicotinic receptor subunits are involved in the sedative effects of ethanol – these include α5, α6, and α7 (Bowers et al, 2005; Kamens et al, 2012; Santos et al, 2013), but not β4 (Kamens et al, 2017b). It is possible that changes in expression and function of nAChRs throughout development (Azam et al, 2007; Doura et al, 2008; Kota et al, 2007) underlie the differences observed between adolescent and adult animals.…”

Section: Discussionmentioning

confidence: 99%

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Varenicline modulates ethanol and saccharin consumption in adolescent male and female C57BL/6J mice

Kamens

Silva

Peck

et al. 2018

Brain Research Bulletin

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Adolescence is a critical period in brain development that coincides with the initiation of alcohol use. Nicotinic acetylcholine receptors (nAChR) have been shown to modulate ethanol behaviors in adult humans and in animal models; however, the role of these receptors in adolescent ethanol behaviors has not been explored. Throughout adolescence, nAChR expression undergoes large-scale developmental changes which may alter behavioral responses to ethanol. Here we examined the effect of varenicline, a nAChR partial agonist, on ethanol consumption, ataxia, sedation, and metabolism in adolescent male and female C57BL/6J mice. The effect of varenicline on ethanol consumption was tested through the Drinking-in-the-Dark (DID) paradigm that models binge-like ethanol consumption. To ensure that results were specific for ethanol, we also tested the effect of varenicline on saccharin consumption. Additionally, varenicline was administered 30min prior to an acute injection of ethanol before being tested for ataxia on the balance beam, sedation using the loss of righting reflex, or ethanol metabolism. Varenicline dose dependently decreased ethanol consumption, but also influenced saccharin intake. Varenicline showed no significant effect on ethanol metabolism, ataxia, or sedation. Unlike its effects in adult animals, varenicline is able to reduce ethanol consumption without increasing the ataxic and sedative effects of ethanol. This work suggests that the neurobiological mechanisms of ethanol behaviors may change across the lifespan and highlights the need for more research on the role of nAChRs in ethanol behaviors throughout development.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Varenicline modulates ethanol and saccharin consumption in adolescent male and female C57BL/6J mice

Kamens

Silva

Peck

et al. 2018

Brain Research Bulletin

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“…However, in contrast to stimulants and opioids, to which adult female rodents are hyper-sensitive (e.g., [6,58,88]), the data pertaining to sex differences in alcohol-induced changes in loco-motor hyperactivity are mixed and vary as a function of species and strain (e.g., [32,53,60,75,76,94]; c.f., [19]). This being said, females tend not to differ from males with respect to behavioral measures of ethanol motor-incoordination and/or intoxication and while the severity of ethanol-induced intoxication varies considerably with strain in mice, the absence of malefemale differences in intoxication is consistent across different mouse strains (e.g., [9,10,24,25,59,75,76,103]).…”

Section: Subject Factor Interactions In the Locomotor Stimulatory Effmentioning

confidence: 93%

Complex interactions between the subject factors of biological sex and prior histories of binge-drinking and unpredictable stress influence behavioral sensitivity to alcohol and alcohol intake

Quadir

Guzelian

Palmer

et al. 2019

Physiology & Behavior

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Alcohol use disorders, affective disorders and their comorbidity are sexually dimorphic in humans. However, it is difficult to disentangle the interactions between subject factors influencing alcohol sensitivity in studies of humans. Herein, we combined murine models of unpredictable, chronic, mild stress (UCMS) and voluntary binge-drinking to examine for sex differences in the interactions between prior histories of excessive ethanol-drinking and stress upon ethanol-induced changes in motor behavior and subsequent drinking. In Experiment 1, female mice were insensitive to the UCMS-induced increase in ethanol-induced locomotion and ethanol intake under continuous alcohol-access. Experiment 2 revealed interactions between ethanol dose and sex (females>males), binge-drinking history (water>ethanol), and UCMS history (UCMS>controls), with no additive effect of a sequential prior history of both binge drinking and UCMS observed. We also observed an interaction between UCMS history and sex for righting recovery. UCMS history potentiated subsequent binge-drinking in water controls of both sexes and in male binge-drinking mice. Conversely, a prior binge-drinking history increased subsequent ethanol intake in females only, irrespective of prior UCMS history. In Experiment 3, a concurrent history of binge-drinking and UCMS did not alter ethanol intake, nor did it influence the ethanol dose-locomotor response function, but it did augment alcohol-induced sedation and reduced subsequent alcohol intake over that produced by binge-drinking alone. Thus, the subject factors of biological sex, prior stressor history and prior binge-drinking history interact in complex ways in mice to impact sensitivity to alcohol's motor-stimulating, -incoordinating and intoxicating effects, as well as to influence subsequent heavy drinking.

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“…Finally, in addition to (α4) 3 (β2) 2 , NS9283 potentiates (α2) 3 (β2) 2 and (α2) 3 (β4) 2 nAChRs [18]. Although we cannot exclude the possibility that NS9283 reduced ethanol consumption by acting at these other subtypes, we note that expression of the α2 subunit is low in rodents [41] and studies of β4-null mice suggest that these receptors are not involved in ethanol drinking or intoxication [42,43].…”

Section: Ns9283 Limitationsmentioning

confidence: 68%

Promoting activity of (α4)3(β2)2 nicotinic cholinergic receptors reduces ethanol consumption

Wang

Blasio

Chapman

et al. 2019

Neuropsychopharmacol.

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There is increasing interest in developing drugs that act at α4β2 nicotinic acetylcholine receptors (nAChRs) to treat alcohol use disorder. The smoking cessation agent varenicline, a partial agonist of α4β2 nAChRs, reduces alcohol intake, but its use can be limited by side effects at high therapeutic doses. There are two stoichiometric forms of α4β2 nAChRs, (α4) 3 (β2) 2 and (α4) 2 (β2) 3. Here we investigated the hypothesis that NS9283, a positive allosteric modulator selective for the (α4) 3 (β2) 2 form, reduces ethanol consumption. NS9283 increased the potency of varenicline to activate and desensitize (α4) 3 (β2) 2 nAChRs in vitro without affecting other known targets of varenicline. In male and female C57BL/6J mice, NS9283 (10 mg/kg) reduced ethanol intake in a two-bottle choice, intermittent drinking procedure without affecting saccharin intake, ethanol-induced incoordination or ethanol-induced loss of the righting reflex. Subthreshold doses of NS9283 (2.5 mg/kg) plus varenicline (0.1 mg/kg) synergistically reduced ethanol intake in both sexes. Finally, despite having no aversive valence of its own, NS9283 enhanced ethanol-conditioned place aversion. We conclude that compounds targeting the (α4) 3 (β2) 2 subtype of nAChRs can reduce alcohol consumption, and when administered in combination with varenicline, may allow use of lower varenicline doses to decrease varenicline side effects.

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No evidence of a role of the β4 subunit of the nicotinic acetylcholine receptor in alcohol-related behaviors

Cited by 7 publications

References 50 publications

Varenicline modulates ethanol and saccharin consumption in adolescent male and female C57BL/6J mice

Varenicline modulates ethanol and saccharin consumption in adolescent male and female C57BL/6J mice

Complex interactions between the subject factors of biological sex and prior histories of binge-drinking and unpredictable stress influence behavioral sensitivity to alcohol and alcohol intake

Promoting activity of (α4)3(β2)2 nicotinic cholinergic receptors reduces ethanol consumption

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