Prenatal Δ9-tetrahydrocannabinol exposure rewires glucocorticoid–hippocampal crosstalk and impairs memory under stress in adolescent rat offspring

Background: Stress is a major determinant of psychopathology, with coping and cognitive impairment arising from abnormal glucocorticoid activity and brain-derived neurotrophic factor (BDNF)-dependent neuroplasticity in the hippocampus. The endocannabinoid system modulates stress and hippocampal functioning since early development, thus its early-life disruption may program vulnerability to stress-related cognitive deficits. Methods: We investigated whether prenatal exposure to tetrahydrocannabinol (pTHC; 2 mg/kg, gestational days 5-20) alters spatial learning and memory in adolescent offspring using the Morris water maze (MWM). Serum corticosterone and hippocampal mineralocorticoid/glucocorticoid receptor levels were measured at baseline and after MWM. We assessed hippocampal plasticity by measuring BDNF- and its receptor expression, as well as CA1 dendritic architecture. To probe the contribution of glucocorticoid signaling, corticosterone synthesis was inhibited with metyrapone (50 mg/kg, 7 days)in another cohort of animals at the same time points. Results: pTHC offspring showed stress-related search strategy, i.e. thigmotaxis, delayed learning, and impaired memory, accompanied by elevated glucocorticoid output and responsivity. In the hippocampus, they showed reduced mineralocorticoid/glucocorticoid receptor ratio, decreased BDNF, and altered CA1 dendritic complexity. Metyrapone reduced thigmotaxis and rescued memory performance, normalized glucocorticoid output, as well as hippocampal mineralocorticoid/glucocorticoid receptor balance, BDNF levels, and dendritic morphology. Conclusion: These findings demonstrate that prenatal THC exposure programs a stress-related vulnerability in hippocampal memory processing, which can be mitigated by reducing excessive glucocorticoid availability during adolescence.