Characterization of cannabinoid plasma concentration, maternal health, and cytokine levels in a rat model of prenatal Cannabis smoke exposure

Abstract

Cannabis sativa has gained popularity as a “natural substance”, leading many to falsely assume that it is not harmful. This assumption has been documented amongst pregnant mothers, many of whom consider Cannabis use during pregnancy as benign. The purpose of this study was to validate a Cannabis smoke exposure model in pregnant rats by determining the plasma levels of cannabinoids and associated metabolites in the dams after exposure to either Cannabis smoke or injected cannabinoids. Maternal and fetal cytokine and chemokine profiles were also assessed after exposure. Pregnant Sprague–Dawley rats were treated daily from gestational day 6–20 with either room air, i.p. vehicle, inhaled high-Δ9-tetrahydrocannabinol (THC) (18% THC, 0.1% cannabidiol [CBD]) smoke, inhaled high-CBD (0.7% THC, 13% CBD) smoke, 3 mg/kg i.p. THC, or 10 mg/kg i.p. CBD. Our data reveal that THC and CBD, but not their metabolites, accumulate in maternal plasma after repeated exposures. Injection of THC or CBD was associated with fewer offspring and increased uterine reabsorption events. For cytokines and chemokines, injection of THC or CBD up-regulated several pro-inflammatory cytokines compared to control or high-THC smoke or high-CBD smoke in placental and fetal brain tissue, whereas smoke exposure was generally associated with reduced cytokine and chemokine concentrations in placental and fetal brain tissue compared to controls. These results support existing, but limited, knowledge on how different routes of administration contribute to inconsistent manifestations of cannabinoid-mediated effects on pregnancy. Smoked Cannabis is still the most common means of human consumption, and more preclinical investigation is needed to determine the effects of smoke inhalation on developmental and behavioural trajectories.

Oral pre‐ and early postnatal cannabis exposure disinhibits ventral tegmental area dopamine neuron activity but does not influence cocaine preference in offspring in mice

“…Although the cannabis oil used was low in cannabidiol (CBD) (<1 mg/mL), we were interested in CBD levels in the dams and pups, as it acts as negative allosteric modulator of CB1R (Laprairie et al., 2015), and has its own effects of neurodevelopment (Black et al., 2023; Iezzi et al., 2022; Swenson et al., 2023). CBD plasma concentrations showed a similar pattern (Figure 1c), with no significant effect of time (one‐way ANOVA, F (4,20) = 1.72, p = .19).…”

“…Passive vapor exposure has gained popularity recently (Black et al, 2023;Manwell et al, 2014;Moore et al, 2021) and has been used in prenatal models (Baglot et al, 2022;Black et al, 2023;Weimar et al, 2020Weimar et al, , 2023, though the dose each animal receives is not as easily controlled as with injections or oral gavage, as how much animals inhale cannot be regulated. Furthermore, each of these modes of cannabis or THC exposure induce stress (Baglot et al, 2021;Brown et al, 2000;Du Preez et al, 2020), which has its own implications for neurodevelopment and behavior in overlapping domains with prenatal cannabis exposure (Estanislau & Morato, 2005;Michelsen et al, 2007;Takahashi et al, 1992;Yang et al, 2006).…”

“…Animal models have provided important evidence on the impacts of mechanisms of prenatal cannabis exposure while controlling for dose, timing, and environmental factors. Preclinical studies have variably shown that prenatal cannabis (or THC or cannabinoid receptor type 1 [CB1R] agonist) exposure is associated with decreased birth weight (Benevenuto et al., 2017; Roeder et al., 2024; but not Black et al., 2023), social behavior deficits (Bara et al., 2018; but not Sandini et al., 2023), increased anxiety‐like behavior (Sandini et al., 2023; but not Bara et al., 2018), and increased opioid seeking (Solinas et al., 2004; Spano et al., 2007). This research has further uncovered sex‐specific disruptions to mesocorticolimbic function, including hyperexcitable ventral tegmental area (VTA) dopamine neurons with increased dopamine release in the nucleus accumbens (Frau et al., 2019; Traccis et al., 2021), increased excitability of medial prefrontal cortex pyramidal neurons (Bara et al., 2018), and altered expression of D2‐like dopamine receptors and endogenous opioids (DiNieri et al., 2011; Spano et al., 2007).…”

“…Traditionally, animal models have used injection of THC or CB1R agonists, which allows easy control of dose, but does not match human consumption patterns and has a different pharmacokinetic and behavioral profile than vapor (Baglot et al., 2021; Manwell et al., 2014; Moore et al., 2021) or oral administration (English et al., 2024; Sallam et al., 2023). Passive vapor exposure has gained popularity recently (Black et al., 2023; Manwell et al., 2014; Moore et al., 2021) and has been used in prenatal models (Baglot et al., 2022; Black et al., 2023; Weimar et al., 2020, 2023), though the dose each animal receives is not as easily controlled as with injections or oral gavage, as how much animals inhale cannot be regulated. Furthermore, each of these modes of cannabis or THC exposure induce stress (Baglot et al., 2021; Brown et al., 2000; Du Preez et al., 2020), which has its own implications for neurodevelopment and behavior in overlapping domains with prenatal cannabis exposure (Estanislau & Morato, 2005; Michelsen et al., 2007; Takahashi et al., 1992; Yang et al., 2006).…”

Reduced fetal cerebral blood flow predicts perinatal mortality in a mouse model of prenatal alcohol and cannabinoid exposure

“…However, this controlled administration may interact with cannabinoid-associated outcomes, particularly regarding pregnancy. In a recent study, pregnant rats receiving either CBD or Δ9-THC via intraperitoneal injection experienced more fetal resorptions than rats administered the same substances through inhalation [ 65 ]. Route of administration may not always alter fetal measurements, however, as a previous study determined that ethanol exposure via either intragastric gavage or intraperitoneal injection produced similar reductions in fetal arterial blood flow [ 39 ].…”