A Model of Combined Exposure to Nicotine and Tetrahydrocannabinol via Electronic Cigarettes in Pregnant Rats

Abstract

Nicotine and cannabis are two of the most commonly consumed licit and illicit drugs during pregnancy, often consumed together via e-cigarettes. Vaping is assumed to be a safer alternative than traditional routes of consumption, yet the potential consequences of prenatal e-cigarette exposure are largely unknown, particularly when these two drugs are co-consumed. In a novel co-exposure model, pregnant Sprague-Dawley rats received nicotine (36 mg/mL), tetrahydrocannabinol (THC) (100 mg/mL), the combination, or the vehicle via e-cigarettes daily from gestational days 5-20, mimicking the first and second human trimesters. Maternal blood samples were collected throughout pregnancy to measure drug and metabolite levels, and core body temperatures before and after exposure were also measured. Pregnant dams exposed to combined nicotine and THC had lower plasma nicotine and cotinine levels than those exposed to nicotine alone; similarly, the combined exposure group also had lower plasma THC and THC metabolite (THC-OH and THC-COOH) levels than those exposed to THC alone. Prenatal nicotine exposure gradually decreased initial core body temperatures each day, with chronic exposure, whereas exposure to THC decreased temperatures during the individual sessions. Despite these physiological effects, no changes were observed in food or water intake, weight gain, or basic litter outcomes. The use of this model can help elucidate the effects of co-exposure to THC and nicotine via e-cigarettes on both users and their offspring. Understanding the effects of co-use during pregnancy is critical for improving education for pregnant mothers about prenatal e-cigarette use and has important implications for public policy.

Keywords: THC; cannabis; co-exposure; e-cigarette; electronic cigarette; nicotine; poly-drug; prenatal.

FIGURE 1

Timeline of study events.

FIGURE 2

Neither maternal body weights (A) nor pregnancy weight gain (B) during gestation were significantly altered by prenatal exposure to nicotine, THC, or the combination via e-cigarettes.

FIGURE 3

At baseline, pregnant dams assigned to receive THC exposure had higher food intakes, however, no differences among groups were observed throughout the vapor inhalation period (A). During the last days of vapor inhalation, dams exposed to nicotine alone during pregnancy drank less water than dams exposed to THC, although no groups differed significantly from controls (B). *THC > no THC, p < 0.05. **Nicotine < Nicotine + THC and THC, p’s < 0.05.

FIGURE 4

Pregnant dams exposed to nicotine via e-cigarettes had lower initial daily temperatures across the vapor inhalation exposure period (A). At the beginning of drug exposure, dams exposed to THC had significantly higher initial daily temperatures, which declined to control levels by mid-pregnancy. Dams exposed to any nicotine maintained lower initial daily temperatures throughout the latter half of pregnancy (B). In contrast, pregnant dams exposed to THC via e-cigarettes had lower temperatures following vapor inhalation (C). Early in exposure, this effect was driven by the combined exposure group, but a main effect of THC remained throughout the rest of the exposure period (D). When compared against initial daily body temperatures, pregnant dams exposed to THC had a greater temperature change compared to all other groups (E). *Nicotine different than no Nicotine, p’s < 0.05. ^#THC only > all other groups, p < 0.01. **THC < no THC, p’s < 0.05. ***Nicotine + THC < all other groups, p’s < 0.001. +Nicotine only > Vehicle, p < 0.05. ^##THC only < Vehicle, p < 0.05.

FIGURE 5

The addition of THC significantly reduced plasma nicotine levels. This effect was seen consistently on GD 5 (A), 10 (B), and 15 (C). By GD 20, this effect was still present, but not as pronounced, as nicotine levels in the combined exposure group gradually increased throughout the vapor inhalation exposure period (D). *Nicotine + THC < Nicotine, p < 0.05.

FIGURE 6

Pregnant dams exposed to the combination of Nicotine + THC had lower plasma cotinine levels than those exposed to Nicotine alone on each day and time throughout the vapor inhalation procedure (A–D). *Nicotine + THC < Nicotine, p < 0.05.

FIGURE 7

Pregnant dams exposed to the combination of Nicotine + THC had lower plasma THC levels than those exposed to THC alone on gestational days 5 (A), 10 (B), and 15 (C). However, this effect was not seen by the last day of vapor inhalation (D), as plasma THC levels gradually rose across days in both groups. *Nicotine + THC < Nicotine, p < 0.05.

FIGURE 8

Pregnant dams exposed to the combination of Nicotine + THC had lower THC-OH metabolite levels than those exposed to THC alone on gestational days 5 (A), 10 (B), and 15 (C). However, this effect was not seen by the last day of vapor inhalation (D), as metabolite levels gradually rose in the combination group. *Nicotine + THC < Nicotine, p < 0.05.

FIGURE 9

Pregnant dams exposed to the combination of Nicotine + THC had lower THC-COOH metabolite levels than those exposed to THC alone on gestational days 5 (A), 10 (B), and 15 (C). However, this effect was not seen by the last day of vapor inhalation (D), as metabolite levels gradually rose in both exposure groups. *Nicotine + THC < Nicotine, p < 0.05.