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

Brancato A.; Cicero M.; Castelli V.; Lavanco G.; Tringali G.; Meli M.; Palivec P.; Kuchar M.; Cannizzaro C. · European journal of pharmacology · 2026

**Background & Methods** This experimental study investigated whether prenatal tetrahydrocannabinol (THC) exposure affects spatial learning, memory, and stress responses in adolescent rat offspring. Pregnant dams received THC (2 mg/kg) during gestational days 5-20, and offspring were evaluated using the Morris water maze task combined with measurements of serum corticosterone, hippocampal receptor expression, brain-derived neurotrophic factor (BDNF) levels, and dendritic architecture. A subset of animals received metyrapone to inhibit corticosterone synthesis, allowing investigation of glucocorticoid signaling's causal role in observed deficits. **Key Findings** • Prenatal THC-exposed offspring displayed stress-related memory impairment characterized by thigmotaxis (wall-hugging behavior), delayed spatial learning, and poor memory retention compared to controls, alongside elevated baseline and stress-induced corticosterone levels and reduced mineralocorticoid/glucocorticoid receptor ratios in the hippocampus. • Hippocampal neuroplasticity was significantly compromised in prenatally exposed animals, including decreased BDNF expression and altered CA1 dendritic complexity, suggesting structural and molecular bases for cognitive dysfunction. • Metyrapone administration reversed the cognitive and behavioral deficits by normalizing glucocorticoid output, restoring mineralocorticoid/glucocorticoid receptor balance, and recovering BDNF expression and dendritic morphology, establishing excessive glucocorticoid signaling as a critical mechanistic driver of THC-induced memory impairment. **Dosage & Administration** Prenatal THC: 2 mg/kg administered during gestational days 5-20 (route not specified). Metyrapone: 50 mg/kg administered daily for 7 days. **Safety & Adverse Effects** Not reported. The study focused on functional and molecular outcomes rather than documenting adverse effects. **Evidence Quality** This is an experimental animal study with moderate internal validity. Strengths include mechanistic exploration through multiple outcome measures (behavioral, endocrine, molecular, and morphological) and pharmacological validation using metyrapone. Limitations include reliance on rodent models with uncertain human translatability, lack of dose-response analysis, and absence of long-term follow-up beyond adolescence. The 2026 publication date and review classification suggest this may be a narrative or systematic review rather than original research, potentially affecting direct evidence assessment. Findings provide preclinical evidence for glucocorticoid-mediated mechanisms but require clinical validation.

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