The Rodent Electronic Nicotine Delivery System (RENDS): Behavior, physiology, and epigenetics

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Abstract Tobacco smoking is the number one preventable cause of death, causing a myriad of health problems. The primary compound responsible for tobacco use is nicotine. Although nicotine use had been on the decline, it is increasing recently with the rise of electronic nicotine delivery system (ENDS or e-cigarette) use, particularly in youth and young adults. Nicotine in ENDS can make young people more likely to use combusted tobacco cigarettes as well as use drugs of abuse, and cause persistent changes in brain development. Furthermore, women become dependent on nicotine more quickly and have a harder time quitting. Pre-clinical models are critical to examine the complex factors that can impact nicotine uptake and relapse. Current pre-clinical models of rodent electronic cigarette use have multiple limitations, however, including use of the whole-body exposure vapor chamber method, which coats the rodent in the e-liquid and nicotine solution and confounds measures of intake and physiological impact, and extended non-voluntary exposure to vapor while the chamber is cleared. With our Rodent ENDS (RENDS), rats can voluntarily access flavored vapor through a special nose port, thus exposing only the snout of the animal and only for the exact duration the rat chooses. Aim 1 will focus on acquisition and maintenance of RENDS use with young adult rats by examining 1) self-administration 2) cotinine (nicotine metabolite) blood levels and 3) somatic withdrawal across different nicotine doses. The involvement of A) epigenetic modifications during acquisition and maintenance will be preliminarily examined by systemic injection of the histone deacetylase (HDAC) inhibiter sodium butyrate (NaB), which impacts epigenetic processes. To isolate the roles of B) nicotine and fruit flavor, rats will self-administer a) nicotine salt without added flavor, b) fruit flavor without added nicotine, or c) nicotine salt + fruit flavor. Both male and female rats will be studied to examine the influence of C) biological sex. Aim 2 will focus on the cessation and relapse of RENDS use with young adult rats by examining 1) self- administration 2) cotinine blood levels and 3) somatic withdrawal during acquisition, extinction, and reinstatement by systemic injection of nicotine. We will investigate the involvement of A) epigenetic modifications during extinction and reinstatement (relapse) by nicotine and isolate the roles of B) nicotine and flavor and C) biological sex. We suggest that robust self-administration of flavored nicotine reflects nicotine's dual reinforcing actions: nicotine serves as a primary reward, and in addition, increases the reward value of the flavored vapor. We hypothesize that nicotine will serve as a reinforcer as well as reward enhancer in the RENDS. Furthermore, we expect to show that RENDS use results in meaningful cotinine levels, somatic withdrawal, and will be blocked by histone deacetylase inhibition (epigenetic modification). This R21 CEBRA proposal will validate the RENDS to increase the accessibility and scope of research into nicotine reinforcement in rodents as well as begin an investigation into the role of biological sex, fruit flavor, and epigenetic modification in the reinforcing effects of nicotine. These findings may ultimately influence the development of therapies, medications, and policies to prevent and treat ENDS addiction and thus improve human health. Our long-term goal is to elucidate and mitigate the role of epigenetics in nicotine taking and relapse.