Repeated nicotine vapor inhalation induces behavioral sensitization in male and female C57BL/6 mice

Abstract

Electronic cigarette use has significantly increased over the past decade. However, there is limited preclinical research on the behavioral and abuse-related effects of nicotine vapor inhalation in rodents. The present study evaluates the effects of repeated nicotine vapor inhalation in male and female mice using a nicotine behavioral sensitization model. Male and female C57BL/6 mice were administered vaporized nicotine (0–10.0 mg/ml) or the positive control of intraperitoneally administered nicotine (0.5 mg/kg) once daily for 5 days, and locomotor activity was assessed. Body temperatures were measured before and after nicotine vapor inhalation to assess hypothermia. Nicotine vapor inhalation (1.0–3.0 mg/ml) produced a dose-dependent behavioral sensitization effect and produced hypothermia in male and female mice. Nicotine (0.5 mg/kg) also produced significant behavioral sensitization. No sex differences were found for nicotine behavioral sensitization with either route of administration. Pretreatment with the nonselective nicotinic antagonist mecamylamine blocked the behavioral sensitization produced by 1.0 mg/ml of nicotine vapor inhalation. These results established that nicotine vapor inhalation produces behavioral sensitization in an inverted U-shaped curve that is similar to the effects of injected nicotine across several behavioral models. Additionally, pretreatment with mecamylamine demonstrated that nicotinic receptor activation was responsible for the behavioral sensitization produced by nicotine vapor inhalation and was not a conditioned response to the vapor. The methods used in the present study provide an additional behavioral approach for evaluating the behavioral effects of repeated nicotine vapor inhalation that allows the manipulation of several variables, including e-liquid oil blend, e-liquid flavors, puff duration, etc.

Acute and chronic effects by nicotine on striatal neurotransmission and synaptic plasticity in the female rat brain

“…Repeated exposure to nicotine produced a robust behavioral sensitization, which is in agreement with previous studies ( Benwell and Balfour, 1992 ; Ericson et al, 2010 ; Hamilton et al, 2014 ; Morud et al, 2016 ; Honeycutt et al, 2020 ). Behavioral sensitization to repeated psychostimulant administration has been proposed to reflect many of the neurochemical changes that are characteristic for drug addiction ( Robinson and Berridge, 1993 ; Steketee and Kalivas, 2011 ), and is in this regard a well-established model to outline behavioral transformations elicited by drugs of abuse.…”

Hyperactivity Induced By Vapor Inhalation of Nicotine in Male and Female Rats

“…We have shown that the inhalation of nicotine vapor increases spontaneous locomotor activity and decreases body temperature in male Sprague-Dawley rats, while reductions in activity were observed after nicotine injection (0.4, 0.8 mg/kg, s.c.) (Javadi-Paydar et al 2019a; Javadi-Paydar et al 2019b), similar effects have been reported in mice (Honeycutt et al 2020). Increased activity was found after 15 or 30 minutes of nicotine inhalation (30 mg/mL in the propylene glycol vehicle) in the male rats, lasted only ∼15-30 minutes after vapor exposure and were blocked by pre-inhalation administration of the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (Javadi-Paydar et al 2019b).…”

“…This is likely because mecamylamine itself reduced body temperature in the absence of nicotine here and in prior studies (Hetzler and Bauer 2013). The additive effect on lowering body temperature has also been reported in mice treated with mecamylamine prior to nicotine vapor inhalation (Honeycutt et al 2020).…”

“…Sometimes the contribution of rat sex has been examined (Frie et al 2023; Gutierrez et al 2024b; Lallai et al 2021) but in other cases not (Alkhlaif and Shelton 2023; Javadi-Paydar et al 2019a; Javadi-Paydar et al 2019b; Roeder et al 2023). In some studies, no locomotor effects of nicotine were observed after the first exposure but a sensitized response appeared after repeated dosing, an effect which may be sex-dependent (Honeycutt et al 2020; Lallai et al 2021). Additional work confirmed the locomotor stimulant effect of nicotine inhalation in mice (Echeveste Sanchez et al 2022; Shao et al 2019; Zhu et al 2021), although suppressed activity after nicotine inhalation has also been reported (Lefever et al 2017).…”

Melanin-concentrating hormone receptor antagonism differentially attenuates nicotine experience-dependent locomotor behavior in female and male rats

“…Importantly, varying patterns of nicotine-induced locomotion can become more prevalent once sex as a biological variable is considered. For example, many studies report increased behavioral activation over time in females when compared to males (Booze et al, 1999; Hamilton et al, 2014), but others report similar behavior between sexes (Ericson et al, 2010; Honeycutt et al, 2020). Further, locomotor activation reaches a maximum at moderate doses of nicotine, and high doses of nicotine induces low locomotion for both sexes (Elliott et al, 2004).…”