427 - Developing a Preclinical Model of Prenatal Delta-9-Tetrahydrocannabinol Exposure to Further Characterize Impact on Neurodevelopmental Outcomes

Publication Number: 427.4417

Zarena M. Dominguez, University of New Mexico School of Medicine, Albuquerque, NM, United States; Suzy Davies, University of New Mexico School of Medicine, Albuquerque, NM, United States; Tyler Hipple, University of New Mexico, Albuquerque, NM, United States; Curtis D. Mowry, University of New Mexico, Albuquerque, NM, United States; Daniel D. Savage, UNM HSC Department of Neurosciences, Albuquerque, NM, United States; Jessie Maxwell, University of New Mexico School of Medicine, Albuquerque, NM, United States

Background: Delta-9-Tetrahydrocannabinol (THC), the psychoactive component of cannabis, is historically illegal in the United States, although many states are now legalizing recreational use. This results in many individuals consuming THC during pregnancy for various reasons, not being aware of the potential impact on fetal development. Historical studies have revealed that prenatal cannabis exposure (PCE) affects critical social and behavioral skills, sleep, and attention in offspring. Unfortunately, with the changing potency and use by the general population, studies are lacking to describe in detail the potential effects on specific brain regions, such as the medial prefrontal cortex (mPFC).

Objective: We aim to develop a preclinical model of voluntary THC ingestion during pregnancy more aligned with the reported typical use (oral consumption to alleviate nausea) to further describe the impact on neurodevelopmental outcomes.

Design/Methods: Adult female Long Evans rats voluntarily consumed 3 mg/kg/day of THC-infused treats (Oreo® mini cookies with peanut butter) for 2 weeks. Those with consistent ingestion continued in the experimental design. Following a break with no treats, the rats were bred. Upon confirmation of a vaginal plug, the rats were randomized to receive either a plain or THC-infused treat daily until embryonic day 22 (E22) to mimic moderate PCE. Throughout pregnancy, tail vein serum samples were collected to measure THC levels via mass spectrometry. Following birth of offspring, each litter was weighed daily from postnatal day 1 (P1) through P21 and again on P28. Non-invasive neurodevelopmental testing began on P2 and continued daily until P18 on offspring.

Results: THC serum concentrations were collected 1.5 hours after voluntary consumption of 3 mg/kg/day of THC yielding an average measurement of 14.8 ± 1.35 ng/mL which is slightly above target levels of 8.6 – 12.4 ng/mL and indicate that voluntary consumption is feasible. Litter size and maternal weight gain were similar between groups. The mortality rate (percent death from birth to P2) and birth weight were nearing significance between controls and PCE (0% vs 0.04%, p=0.06 and 6.25 vs 5.96 grams, p=0.07, respectively). Offspring in the control group developed bilateral forelimb grasp slightly earlier than the PCE group (P2.67 vs P4.0, p=0.06).

Conclusion(s): A preclinical model of moderate PCE via voluntary ingestion is feasible and will allow for additional in-depth investigations of neurodevelopmental outcomes. Future studies will add to the growing literature warning of the impact of PCE on fetal development.