Differential effects of gestational Cannabis smoke and phytocannabinoid injections on male and female rat offspring behavior

Our understanding of the implications of gestational Cannabis exposure (GCE) remains unclear as Cannabis use increases worldwide. Much of the existing knowledge of the effects of GCE has been gained from preclinical experiments using injections of isolated Δ⁹-tetrahydrocannabinol (THC) at relatively high doses. Few investigations of the effects of GCE to smoke from the whole Cannabis flower have been conducted, despite this being the most common mode of human consumption. Here, we compared the effects of repeated gestational exposure to high-THC or high-cannabidiol (CBD) Cannabis smoke to i.p. THC or i.p. CBD to those of GCE to high-THC or high-CBD Cannabis smoke on litter health and the offspring. We found that injecting phytocannabinoids generally had a more severe impact on measures of maternal and litter health and produced distinct behavioral phenotypes when compared to offspring from dams treated with high-THC and high-CBD smoke during gestation. GCE to high-THC smoke decreased prepulse inhibition (PPI) and MK-801-induced locomotor activity in female adolescent offspring, which normalized in adulthood. GCE to i.p. THC increased exploratory behavior in the open field test in adolescent offspring of both sexes. GCE had a negative impact on offspring performance in the Identical Stimuli Test and Different Stimuli Test with odors regardless of gestational treatment, sex, or age. CBD (i.p) impaired PPI in both male and female offspring in adulthood and increased time spent in proximity during social interaction for male offspring. There were no effects of GCE in the 5 Choice Serial Reaction Time Task. These data establish distinct behavioral phenotypes in the offspring between smoked and injected GCE, further demonstrating that route and specific phytocannabinoid dose produce differential outcomes across offspring lifespan. Smoked Cannabis is still the most common means of consumption, and more preclinical investigation is needed to determine the effects of smoked Cannabis on developmental trajectories.