Introduction A wide variety of nicotine concentrations and formulations are available to users of electronic nicotine delivery systems (ENDS). This is increasingly true when considering the many flavors available with ENDS products. To date, there have been few preclinical investigations into the impact of nicotine doses, with and without flavors, on vaping-related behaviors. This present study evaluated how nicotine concentrations relevant to tank-based and pod-based ENDS, with and without flavors, impact reinforcement-related behavior in a mouse model. Methods Adult male and female C57/BL6J mice were used in vapor-inhalation self-administration assays. Mice were assigned e-liquids containing 6 mg/mL or 60 mg/mL nicotine. Additional mice were assigned these nicotine doses with green apple or menthol flavorants. Mice were trained on fixed-ratio 1 (FR1) for ten, two-hour sessions, then five sessions at FR3, three progressive ratio (PR) sessions, and two FR3 sessions. Results We observed male mice exhibited higher reinforcement-related behavior to menthol-flavored 6 mg/mL nicotine when compared to female mice. Males were only observed to have a menthol-induced enhancement of self-administration at 6 mg/mL nicotine and not 60 mg/mL nicotine. However, female mice exhibited significant menthol-induced increases in reinforcement-related behaviors with 60 mg/mL nicotine. Conclusions These data provide evidence that males and females exhibit different dose sensitivities to nicotine. These sex-dependent differences in nicotine sensitivity also indicate that flavor-induced enhancement in nicotine intake is dependent on the different doses for each sex. IMPLICATIONS There has been much discussion recently regarding the impact of flavors on vaping-related behavior. Our current study may support prior investigations that suggest flavors enhance the palatability of nicotine-containing products. However, this current study provides evidence that males and females exhibit different sensitivities to nicotine.

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ID 20494 Poster Board 335For years, prior research has established the scientific premise that the ventral tegmental area (VTA) and the medial habenula (MHb) mediate aspects of nicotine reward, reinforcement, aversion, and intake. To examine how both the VTA and MHb are involved in nicotine reinforcement-related behavior, we used genetically modified mice (males and females) that express fluorescent nAChRs in a mouse model of vapor self-administration. Mice were trained to acquire self-administration on a FR1 and FR3 schedule using nicotine with or without flavors (menthol or green apple). Green apple and menthol enhanced nicotine vapor self-administration in both male and female mice but in a sex-dependent manner (males at 6 mg/mL nicotine and females at 60 mg/mL nicotine). Following vapor self-administration, brain slices containing the VTA and MHb were prepared to examine self-administration-induced changes in baseline firing and intrinsic excitability. To examine intrinsic excitability, we used a current-step protocol to determine rheobase (current necessary to elicit an action potential) and maximum spikes during current steps. We correlated FR3 active nose pokes (mean of 5 FR3 sessions) to electrophysiological measures to examine how neuronal excitability in the VTA and MHb was linked to reinforcement-related behaviors. We observed that intrinsic excitability of VTA dopamine neurons did not correlate to FR3 active nose pokes; but it did correlate to active and inactive nose poke distinction. We observed that the intrinsic excitability of medial MHb neurons correlated inversely to FR3 active nose pokes (high FR3 nose pokes, lower intrinsic excitability). Correlations were consistent between unflavored or flavored nicotine assignments; but menthol and green apple exhibited greater changes in intrinsic excitability of neurons. These data suggest that the MHb may be critical for the magnitude of nicotine intake while VTA dopamine neurons may regulate the learning-related behavior associated with nicotine intake.

Adolescence is characterized as a period of increased social behavior, risk taking, and novelty seeking, partly due to ongoing maturation in critical brain areas and the hypothalamic-pituitary-adrenal (HPA) negative-feedback system. During this period there is heightened vulnerability to stress that can drive neuro-immune-endocrine remodeling, resulting in the emergence of maladaptive behaviors that increase susceptibility to alcohol and substance abuse. Here we used a rat model to investigate the impact of chronic adolescent unpredictable stress on a battery of behavioral measures to assess anxiety, novelty seeking, risk taking, depression, and voluntary ethanol consumption while determining whether the PPARγ agonist rosiglitazone can attenuate these effects. Adolescent female rats that experienced stress showed increased risk taking behavior and novelty seeking behavior with no change in ethanol consumption. The administration of rosiglitazone during stress induction attenuated stress-induced cortisol elevation, normalized risk taking behavior in a model anxiety, and attenuated novelty seeking in a task-specific manner. Depressive-like behavior was not impacted by adolescent unpredictable stress or the administration of rosiglitazone. The results from this study demonstrate that exposure to unpredictable stress during adolescence increases the prevalence of maladaptive behaviors that are known to increase susceptibility to alcohol and substance abuse, and that rosiglitazone may be an effective therapeutic to attenuate the emergence of select risk taking and novelty seeking behaviors in females.