Models to assess the addictive-like properties of
nicotine in mice are limited. Therefore, we aimed to characterize and validate an addiction index by using an oral
nicotine free-choice paradigm in mice. Adult C57BL/6J, DBA/2J, or genetically modified mice carrying deletions for
nicotinic acetylcholine receptor (nAChR) subunits, (n = 8-10/sex/group) were given a choice of water or
nicotine (10-960 μg/ml)
solution using a two-bottle free-choice (2BC) paradigm. In general, oral
nicotine intake and preference were higher in female mice compared to males. Absence of
nicotine led to withdrawal, and intermittent access resulted in an escalation in consumption and greater
nicotine withdrawal than continuous exposure. Additionally, oral
nicotine consumption increased nucleus accumbens
tyrosine hydroxylase levels. While β2 and α6 KO mice showed a significant decrease in
nicotine intake, deletion of α5 nAChRs increased
nicotine consumption at high concentrations. Deletion of the α7 subunit altered the observed sex difference in
nicotine consumption, with females consuming less than males. The α4β2 partial agonist
varenicline decreased oral
nicotine consumption. Although addition of
quinine to the
nicotine solution lowered
nicotine intake, mice primed with
nicotine did not lower their intake after
quinine addition.
Nicotine deprivation followed by re-exposure showed increased
nicotine consumption, and DBA/2J mice consumed less
nicotine compared to C57BL/6J. We validated the mouse 2BC paradigm to study
nicotine's addictive-like properties including
nicotine intake, preference, withdrawal, and escalation of
nicotine consumption during
binge drinking or after reinstatement of a deprivation period.