Sex differences in the impact of electronic nicotine vapor on corticotropin-releasing factor receptor 1 neurons in the mouse ventral tegmental area

Abstract

Nicotine engages dopamine neurons in the ventral tegmental area (VTA) to encode reward and drive the development of nicotine addiction, however how nicotine selectively alters other VTA populations remains to be determined. Here, we used male and female CRF1-GFP mice and nicotine vapor exposure to examine the effects of nicotine in VTA corticotropin-releasing factor receptor 1 (CRF1) neurons. We use immunohistochemistry and electrophysiology to examine neuronal activity, excitability, and inhibitory signaling. We found that VTA CRF1 neurons are mainly dopaminergic and project to the nucleus accumbens (VTA-NAcCRF1 neurons). VTA-NAcCRF1 neurons show greater phasic inhibition in naive females and greater focal nicotine-induced increases in firing in naive males. Following acute nicotine vapor exposure, phasic inhibition was not altered, but focal nicotine-induced tonic inhibition was enhanced in females and diminished in males. Acute nicotine vapor exposure did not affect firing in VTA-NAcCRF1 neurons, but females showed lower baseline firing and higher focal nicotine-induced firing. Activity (cFos) was increased in the CRF1 dopaminergic VTA population in both sexes, but with greater increases in females. Following chronic nicotine vapor exposure, both sexes displayed reduced basal phasic inhibition and the sex difference in tonic inhibition following acute vapor exposure was no longer observed. Additionally, activity of the CRF1 dopaminergic VTA population was no longer elevated in either sex. These findings reveal sex- and exposure-dependent changes in mesolimbic VTA-NAc CRF1 neuronal activity, inhibitory signaling, and nicotine sensitivity following nicotine vapor exposure. These changes potentially contribute to nicotine-dependent behaviors and the intersection between stress, anxiety, and addiction.

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

“…While some initial studies of ENDS based nicotine exposure resorted to injecting e-cigarette vehicle/nicotine preparations into laboratory rodents (LeSage et al 2016), there has been progress in developing inhalation models for the delivery of several different drugs including cannabinoids (Freels et al 2020; Javadi-Paydar et al 2019a; Nguyen et al 2016b), methamphetamine and other psychomotor stimulants (Marusich et al 2016; Nguyen et al 2016a; Nguyen et al 2017), opioids, including fentanyl (McConnell et al 2021), heroin (Gutierrez et al 2021; Gutierrez et al 2022) and oxycodone (Nguyen et al 2019). Additional work has focused on developing and deploying rat and mouse models of nicotine vapor inhalation (Cooper et al 2021; Echeveste Sanchez et al 2022; Javadi-Paydar et al 2018; Lallai et al 2021; Montanari et al 2020; Roeder et al 2023; Smith et al 2020; Zhu et al 2023). Rodent locomotor behavior is an involuntary response to drugs which can be used as a relatively simple assay of drug potency and efficacy.…”