DEVELOPMENTAL CONSEQUENCES OF GESTATIONAL CANNABIS EXPOSURE IN RAT ACROSS THE LIFESPAN

Cannabis use has become more widely accepted over the last decade, with increasing reports of use during pregnancy. Despite the growing diversity of product availability, smoking remains the primary route of Cannabis consumption in Canada. However, preclinical research on gestational Cannabis exposure (GCE) primarily focuses on the effects of Δ9-Tetrahydrocannabinol (THC) through injection models, which fail to accurately reflect human usage patterns. This dissertation aimed to develop a more representative model to study the pharmacokinetics, neurobehavioural, and biochemical effects of GCE via smoke exposure. Chapter 2 performs a pharmacokinetic validation of GCE via passive smoke exposure and compares it to injection-based methods for THC and Cannabidiol (CBD). Maternal plasma levels of cannabinoids and metabolites were measured at gestational days (GD) 6 and 20 following exposure to High-THC or High-CBD smoke, or injected THC or CBD. The results showed that THC and CBD levels in maternal plasma were 20x and 100x higher in injection models than in the smoke-exposed groups. Injections of THC and CBD also resulted in smaller litter sizes, increased uterine reabsorptions, and heightened inflammatory cytokine expression in placental and fetal brains, whereas smoke exposure had fewer effects on litter, pup health and cytokine and chemokine profiles. These findings demonstrate that injection models produce different pharmacokinetic and health effects than those observed with GCE to smoke. Chapter 3 examines the behavioural effects of GCE on adolescent and adult offspring. The results showed that i.p. THC and CBD produced more severe effects on maternal health and offspring behaviour compared to smoke exposure in adulthood. Female adolescent offspring exposed to High-THC smoke exhibited normalized behaviour in adulthood, while injected THC effects persisted. Both GCE and injected treatments impacted offspring performance in various tests of sensorimotor gating, MK-801 induced locomotor activity, social interaction, incidental memory, and exploratory behaviour, highlighting differences between smoke and injection exposure routes. Chapter 4 utilized X-ray Fluorescence (XFI) and Fourier Transform Mid-Infrared spectroscopy to investigate biochemical changes in offspring brains. THC exposure led to decreased Cu in the corpus callosum, and altered lipid and protein content in the hippocampus, and lateral ventricle, pointing to neurochemical dysregulation linked to GCE. This research emphasizes the importance of using translational models to assess GCE's effects, considering route, dose, and cannabinoid type for accurate risk assessment.

Name thesis:degree_name

Doctor of Philosophy (Ph.D.)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Pharmacy

Grantor

University of Saskatchewan

Year dc:date.issued

2025

Author dc:creator

• Black, Tallan Aran Kerry

Advisors dc:contributor.advisor

• Howland, John G
• Laprairie, Robert B

Committee members dc:contributor.committeemember

• Paterson, Phyllis G
• Evans, Charity C
• Borowsky, Ron
• Laviolette, Steven R
• Machtaler, Steven
• Taylor, Jeff

• cannabis
• endocannabinoid system
• development
• neurodevelopment
• rodent
• in-utero
• gestational
• prenatal
• behaviour
• behavior
• X-ray fluorescence
• Fourier Transformed Mid-Infrared spectroscopy
• pharmacokinetics

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10388/17337

OAI identifier oai:identifier

oai:harvest.usask.ca:10388/17337