The nicotinic receptor drug sazetidine-A reduces alcohol consumption in mice without affecting concurrent nicotine consumption

Abstract

Alcohol and nicotine addiction are frequently co-morbid. The nicotinic acetylcholine receptors (nAChRs) are critical for both alcohol and nicotine addiction mechanisms, since nAChR drugs that reduce nicotine consumption have been shown to also reduce alcohol consumption. Sazetidine-A, a pre-clinical nAChR drug with agonist and desensitizing effects at α4β2 and α7 nAChRs, has been reported to reduce alcohol consumption and nicotine self-administration in rats when administered at high doses. However, this effect has not been replicated in mice. In this study, we examined the effect of sazetidine-A on alcohol and nicotine consumption in male and female mice utilizing voluntary oral consumption procedures previously developed in our lab. We found that sazetidine-A (1 mg/kg, i.p) reduced overnight alcohol consumption, but did not affect nicotine consumption when presented either alone or concurrently with alcohol. Sazetidine-A did not reduce water or saccharin consumption at any dose tested. In a chronic co-consumption experiment in which either alcohol or nicotine was re-introduced after one week of forced abstinence, sazetidine-A attenuated post-abstinence consumption of alcohol but not nicotine. Sazetidine-A also significantly reduced alcohol consumption in an acute, binge drinking-in-the-dark procedure. Finally, we tested the effect of sazetidine-A on alcohol withdrawal, and found that sazetidine-A significantly reduced handling-induced convulsions during alcohol withdrawal. Collectively, these data suggest a novel role for the nAChR targets of sazetidine-A in specifically mediating alcohol consumption, separate from the involvement of nAChRs in mediating nicotine consumption. Delineation of this pathway may provide insight into novel therapies for the treatment of alcohol use disorders.

Enhancement of alcohol aversion by the nicotinic acetylcholine receptor drug sazetidine-A

“…We previously showed that systemic sazetidine-A reduced binge DID alcohol consumption in both male and female C57BL/6J mice. 19 Since a major nAChR subtype that is activated and desensitized by sazetidine-A is the α4β2 nAChR, we sought to determine whether the α4 nAChR subunit was important for the actions of sazetidine-A. We tested the effect of systemic sazetidine-A in mice that lack the α 4 nAChR subunit in the DID procedure.…”

“…Pharmacological manipulation of nAChRs has been shown to reduce alcohol consumption in animal models, as mecamylamine, varenicline and sazetidine-A reduce alcohol consumption in rodents despite their different mechanisms of actions and nAChR subtype targets. [7][8][9]19 Varenicline is best known as a partial agonist at α 4β2 receptors, but in vitro studies show that it is also a partial agonist at α 3* and α 6* receptors and a full agonist at α 7 receptors. 16,[25][26][27] In vitro studies show that sazetidine-A is an agonist at α 4β2, α 3β4*, α 6* and α 7 nAChRs, 15-18 thus sazetidine-A and varenicline act on similar nAChR subtypes but with differing potencies.…”

“…Binge alcohol consumption in female α 4 wild-type and knock-out mice Female mice were used since our previous work showed that sazetidine-A reduces binge consumption in both male and female C57BL/6J mice and female mice consume more alcohol than male . 19 For the binge drinking-in-the-dark (DID) procedure, mice were habituated to three i.p. injections of saline (10µL/g) one week prior to the experiment.…”

“…[15][16][17][18] We previously reported an alcohol-specific effect of sazetidine-A in mice; a peripheral injection reduced 24-hour continuous and binge drinking-in-the-dark (DID) alcohol consumption in both male and female C57BL/6J mice without affecting the consumption of water, saccharin, or nicotine. 19 Here, we investigated the behavioral mechanism by which sazetidine-A reduces alcohol consumption. We report that sazetidine-A enhances the expression of alcohol aversion without affecting the expression or acquisition of alcohol reward.…”

Flavor-specific enhancement of electronic cigarette liquid consumption and preference in mice

“…Two-bottle choice consumption was performed in a similar manner as our prior work (O'Rourke et al, 2016;Touchette et al, 2018;DeBaker et al, 2019). For each group, the mice were singly housed and presented with one bottle of tap water and one bottle of drug formulation diluted in tap water (either nicotine alone, fruit-flavored nicotine-containing e-liquid, tobacco-flavored nicotine-containing e-liquid, nicotine-free fruit-flavored e-liquid, or nicotine-free tobacco-flavored e-liquid).…”