This study examines how stress-coping phenotypes influence the effect of prenatal \(\:\varDelta\:\) 9-tetrahydrocannabinol (THC) exposure (PTE) on selectively bred Dominant (Dom) and Submissive (Sub) mice offspring exhibiting stress resilience and vulnerability, respectively. Pregnant Dom and Sub dams of generation 54 received THC (20 mg/kg, intraperitoneally) on gestation days 13, 15, and 17. Our findings indicate that PTE significantly reduced body weight (measured at postnatal day (PND) 7 and 30), increased anxiety-like behaviors in two-month-old Dom offspring, and enhanced sociability and reduced anxiety-like behaviors in Sub offspring. Brain mRNA expression analysis revealed phenotype-specific alterations in endocannabinoid (ECS) and dopaminergic (DAs) system genes. Remarkably, fatty acid amide hydrolase (FAAH) expression, responsible for anandamide degradation, was downregulated in the prefrontal cortex and hippocampus of Sub PTE offspring on PND 7 and 30, alongside changes in CB1, CB2, D1, D2, and D5 receptors expression. Our findings suggest that the intergenerational effect of PTE depends on individual temperament, with ECS modulation during prenatal development offering a potential intervention for stress vulnerability. However, we state that stress resilience does not necessarily confer protection against PTE’s adverse effects, emphasizing the complexity of cannabis exposure during pregnancy.
