Variability in nicotine conditioned place preference and stress‐induced reinstatement in mice: Effects of sex, initial chamber preference, and guanfacine

Abstract

Relapse to smoking occurs at higher rates in women compared with men, especially when triggered by stress. Studies suggest that sex‐specific interactions between nicotine reward and stress contribute to these sex differences. Accordingly, novel treatment options targeting stress pathways, such as guanfacine, an α2‐adrenergic receptor agonist, may provide sex‐sensitive therapeutic effects. Preclinical studies are critical for elucidating neurobiological mechanisms of stress‐induced relapse and potential therapies, but rodent models of nicotine addiction are often hindered by large behavioral variability. In this study, we used nicotine conditioned place preference to investigate stress‐induced reinstatement of nicotine preference in male and female mice, and the effects of guanfacine on this behavior. Our results showed that overall, nicotine induced significant place preference acquisition and swim stress‐induced reinstatement in both male and female mice, but with different nicotine dose‐response patterns. In addition, we explored the variability in nicotine‐dependent behaviors with median split analyses and found that initial chamber preference in each sex differentially accounted for variability in stress‐induced reinstatement. In groups that showed significant stress‐induced reinstatement, pretreatment with guanfacine attenuated this behavior. Finally, we evaluated neuronal activation by Arc immunoreactivity in the infralimbic cortex, prelimbic cortex, anterior insula, basolateral amygdala, lateral central amygdala and nucleus accumbens core and shell. Guanfacine induced sex‐dependent changes in Arc immunoreactivity in the infralimbic cortex and anterior insula. This study demonstrates sex‐dependent relationships between initial chamber preference and stress‐induced reinstatement of nicotine conditioned place preference, and the effects of guanfacine on both behavior and neurobiological mechanisms.

Sex Differences in the Ventral Tegmental Area and Nucleus Accumbens Proteome at Baseline and Following Nicotine Exposure

“…The VTA or NAc shell proteomes were examined after subchronic nicotine administration and after withdrawal from chronic nicotine administration as shown by the workflow depicted in Figure 1. Sub-chronic nicotine was administered at doses and on a schedule that induces CPP in C3H/HeJ mice (Lee et al, 2020). Chronic nicotine was administered to C57BL/6J mice through drinking water for 21 days, followed by 24 h of normal drinking water administration prior to tissue collection, at which point mice can exhibit signs of withdrawal (Jackson and Imad Damaj, 2013;Damaj et al, 2003).…”

“…Different doses of nicotine were used to produce similar levels of nicotine reward in male and female mice, accounting for sex differences in nicotine response and sensitivity, including pharmacokinetic differences in nicotine absorption and metabolism (Kota et al, 2007(Kota et al, , 2008Lenoir et al, 2015;Pogun and Yararbas, 2009). We have previously demonstrated that the specific doses used in this study produce CPP in C3H/HeJ mice (Lee et al, 2020). The nicotine group received alternating injections of nicotine and saline on days 5-10, while the control group received saline on all days while alternating chambers on days 5-10.…”

“…Sub-chronic nicotine administration was used in the setting of conditioned place preference (CPP) training. Due to the variability in effective CPP conditioning paradigms, we used C3H/HeJ mice and a training schedule which has successfully produced CPP in both male and female mice in our hands (Lee et al, 2020) to ensure the behavioral relevance of the nicotine administration paradigm. Briefly, mice were handled for 3 days, with gentle stroking of the back and scruff of the neck on the first day, light scruffing of the neck on the second day, and then scruff while pressing syringe (without needles) to back of neck on the third day to simulate a subcutaneous (s.c.) injection.…”

Green Apple e-Cigarette Flavorant Farnesene Triggers Reward-Related Behavior by Promoting High-Sensitivity nAChRs in the Ventral Tegmental Area

“…In the pre-test stage, mice were placed in the central chamber and given 20 min of free access to all chambers. Drug-naive mice that spent .65% of their time in one of the two conditioning chambers were removed from the study and the remaining mice were counter-balanced, similar to previously published methods (Neugebauer et al, 2011;Einstein et al, 2013;Lee et al, 2020). Eight males and five females were excluded.…”

Sex differences in mechanisms of disease

“…Stress can also lead to reinstatement of drug‐seeking behavior, an effect observed equally in male and female mice. However, Lee et al show that the ability of the drug guanfacine to prevent stress‐induced reinstatement of nicotine‐seeking behavior in a conditioned place preference test depends on a novel interaction between sex and individual animals' preferred test chamber at baseline, suggesting a role for sex‐dependent context processing in the likelihood of substance abuse treatments being successful. Other aspects of addiction—such as substance type, age of initiation, and abuse trajectories—have clear sex and gender differences, suggesting a need for sex‐specific evaluation of addiction mechanisms.…”