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Health and Behavioral Consequences of Perinatal Cannabidiol Exposure in Mice Raised to Adult

Martina Compagno

Florida State University

Co-authors: Claudia Silver1, Kari Basso2, Amber Berstein, Caroline Bishop1, Aidan Carley1, Joshua Cazorla1, Jenna Claydon1, Alexis Cox1, Ashleigh Crane1, Chloe Crispy1, Emma Curley1, Tyla Dolezel1, Ezabelle Franck1, Camilla May1, Alejandro Navarez1, Frank Pacheco1, Olivia Turner1, and Debra Ann Fadool1
1Florida State University, 2University of Florida

Objective: Anxiety-like and memory behaviors were examined in adult mice following gestational exposure to cannabidiol (CBD), the non-psychoactive ingredient of cannabis.

Methods: Primiparous dams were orally administered 100 mg/kg CBD or ethanol vehicle mixed in strawberry jam. Dams and pups were assessed for health outcomes. At 3 months of age, offspring were metabolically profiled using a comprehensive laboratory animal monitoring system (CLAMS) and challenged via glucose tolerance testing. Adult offspring were behaviorally phenotyped using the buried marble, light-dark box (LDB), elevated-plus maze (EPM), and object memory recognition.

Results: CBD was detected in maternal plasma using GC-MS 10-min post consumption (34.2 + 1.7 ng/ul), peaked within 30 min (371.0 + 34.0 ng/ul), and below our detection limit by 4 hours (< 10 ng/ul). Fetal exposure to CBD significantly decreased survival of the pups; 38% of CBD-treated pups died before weaning age (23 days) whereas only 8% of jam-treated pups died prior to weaning. Cross-fostering a CBD-treated pup to a drug-free dam allowed survival rates similar to that of jam-treated pups. We did not observe changes in litter size, maternal body weight or pup birth weight (postnatal day 0, P0) between CBD- vs. jam-treated animals, however, by postnatal day 10 and 21, CBD-exposed male mice weighed significantly less, which could be rescued by cross-fostering to a drug-free dam. Perinatal exposure to CBD increased meal size and caloric intake for adult male offspring in the dark cycle (1w ANOVA, p<0.05), while early postnatal CBD exposure decreased fasting glucose, but had no effect on glucose clearance. Adult female offspring showed increased drink size if exposed to CBD during early postnatal development, independent of light cycle.  In utero exposure caused mice of both sexes to bury more marbles (1w ANOVA, p≤0.05), and females, not males, lost this behavior if they were cross-fostered to control dams.  In utero exposure decreased time spent in the light compartment of an LDB apparatus when females were raised to adults. In utero exposure decreased performance of male mice in the 24-hour object recognition test (p=0.0123). Adult female mice spent less time in the closed arms of the EPM if exposed to CBD in utero and this was unchanged with cross-fostering to a drug-free dam.

Conclusion: The use of CBD during pregnancy in mice affects pup survival, and later, OCD-like, anxiety-like, and long-term memory as an adult. Perinatal CBD exposure affects adult meal size, caloric intake, drink size, and fasting glucose.