Nicotine Enhances the Hypnotic and Hypothermic Effects of Alcohol in the Mouse

Abstract

Background Ethanol and nicotine abuse are two leading causes of preventable mortality in the world, but little is known about the pharmacological mechanisms mediating co-abuse. Few studies have examined the interaction of the acute effects of ethanol and nicotine. Here, we examine the effects of nicotine administration on the duration of ethanol-induced loss of righting reflex (LORR) and characterize the nature of their pharmacological interactions in C57BL/6J mice. Methods We assessed the effects of ethanol and nicotine and the nature of their interaction in the LORR test using isobolographic analysis after acute injection in C57BL/6J male mice. Next, we examined the importance of receptor efficacy using nicotinic partial agonists varenicline and sazetidine. We evaluated the involvement of major nAChR subtypes using nicotinic antagonist mecamylamine and nicotinic α4 and α7 knockout mice. The selectivity of nicotine’s actions on ethanol-induced LORR was examined by testing nicotine’s effects on the hypnotic properties of ketamine and pentobarbital. We also assessed the development of tolerance after repeated nicotine exposure. Lastly, we assessed if the effects of nicotine on ethanol-induced LORR extends to hypothermia and ethanol intake in the Drinking in the Dark (DID) paradigm. Results We found that acute nicotine injection enhances ethanol’s hypnotic effects in a synergistic manner and that receptor efficacy plays an important role in this interaction. Furthermore, tolerance developed to the enhancement of ethanol’s hypnotic effects by nicotine after repeated exposure of the drug. α4* and α7 nAChRs seem to play an important role in nicotine-ethanol interaction in the LORR test. In addition, the magnitude of ethanol-induced LORR enhancement by nicotine was more pronounced in C57BL/6J than DBA/2J mice. Furthermore, acute nicotine enhanced ketamine and pentobarbital hypnotic effects in the mouse. Finally, nicotine enhanced ethanol-induced hypothermia but decreased ethanol intake in the DID test. Conclusion Our results demonstrate that nicotine synergistically enhances ethanol-induced LORR in the mouse.

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

“…When administered in vivo, a high dose of NS9283 (10 mg/kg) as well as subthreshold doses of NS9283 (2.5 mg/kg) plus varenicline (0.1 mg/kg) reduced ethanol consumption in mice to an extent similar to that reported previously for 2 mg/kg varenicline alone [28]. Although varenicline can increase ethanol-induced incoordination and LORR duration [15,29], we found that NS9283 alone, or in combination with 0.1 mg/kg varenicline did not alter these signs of ethanol intoxication. NS9283 appeared to accentuate the memory of ethanol's aversive properties, without altering memory of ethanol's rewarding effects.…”

“…Studies using pharmacological agents and knockout mice suggest that activating α4-containing nAChRs increases the hypnotic effect of ethanol [15,34]. However, we found that a NS9283 (10 mg/kg) alone did not induce CPP or CPA in C57BL/6J mice.…”

“…Varenicline can reduce ethanol drinking if administered at a high dose [28]. It may reduce ethanol intake, in part, because it enhances the intoxicating effects of ethanol [15,29]. Therefore, we investigated whether the combination of low-dose varenicline and NS9283 alters ethanol intoxication (Fig.…”

“…Both bind similar agonists [10], but show differences in agonist sensitivity, calcium permeability and rates of desensitization [11,12]. Pharmacological and genetic studies suggest that α4β2 nAChRs contribute to ethanol drinking and ethanol's sedative-hypnotic effects [13][14][15]. However, it is unknown if one or both of the stoichiometric forms are involved in these responses.…”

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

“…at a volume of 0.1 mL per 10 g of mouse mass for doses of 100 mg/kg and 30 mg/kg, respectively. The doses of alcohol (2 – 4g/kg) used in acute behavioral studies and conditioned place preference test were based on previously published studies (Alkana et al, 1992, Browman et al, 2000; Tanchuck-Nipper et al, 2015; Putman et al, 2016; Slater et al, 2016; Guildford et al, 2016).…”