Prenatal Δ9-tetrahydrocannabinol exposure rewires glucocorticoid-hippocampal crosstalk and impairs memory under stress in adolescent rat offspring.
Anna Brancato, Martina Cicero, Valentina Castelli, Gianluca Lavanco, Giuseppe Tringali, Maria Meli, Petr Palivec, Martin Kuchař, Carla Cannizzaro
European Journal of Pharmacology September 15, 2026 DOI: 10.1016/j.ejphar.2026.179327 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Adolescent rat offspring prenatally exposed to THC (2 mg/kg, gestational days 5-20) and control cohorts |
| Intervention | Metyrapone |
| Dose | THC 2 mg/kg, gestational days 5-20; metyrapone 50 mg/kg for 7 days |
| Duration | Prenatal exposure gestational days 5-20; metyrapone treatment 7 days during adolescence |
| Measures | Morris water maze (MWM), serum corticosterone, hippocampal mineralocorticoid/glucocorticoid receptor levels, BDNF and its receptor expression, CA1 dendritic architecture |
| Topics | Cannabis |
| Keywords | Bdnf Glucocorticoids Hippocampus Metyrapone Prenatal THC Spatial memory |
| Key findings | Prenatal THC exposure in rats produced stress-related search strategies, delayed learning, and impaired memory alongside elevated glucocorticoids, reduced hippocampal mineralocorticoid/glucocorticoid receptor ratio, decreased BDNF, and altered CA1 dendritic complexity. Metyrapone treatment reduced thigmotaxis and rescued memory performance while normalizing glucocorticoid output, receptor balance, BDNF, and dendritic morphology, suggesting glucocorticoid excess mediates the cognitive deficits. |
Abstract
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. 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. 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. 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.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cites 2
- Prenatal THC exposure and binge-like alcohol drinking in early adolescence: From sex-specific drinking vulnerability to abnormal endocannabinoid-dopamine nexus in the nucleus accumbens. Journal of Psychopharmacology February 27, 2026
- Prenatal Exposure to Δ9-Tetrahydrocannabinol Affects Hippocampus-Related Cognitive Functions in the Adolescent Rat Offspring: Focus on Specific Markers of Neuroplasticity. Pharmaceutics February 17, 2023