LONG-TERM CONSEQUENCES OF ADOLESCENT EXPOSURE TO JWH-018 IN MALE AND FEMALE WILD-TYPE AND BDNF VAL66MET MICE

The use of synthetic cannabinoids during adolescence has been proposed as a potential risk factor for developing psychiatric disorders later in life. The BDNF Val66Met polymorphism, which affects intracellular trafficking and activity-dependent release of BDNF, has been associated with altered vulnerability to psychiatric conditions, although existing evidence remains inconsistent.
Here, we investigated whether exposure to the synthetic cannabinoid JWH-018 during adolescence is associated with long-lasting behavioral and molecular alterations in mice, and whether these effects are influenced by sex and the BDNF Val66Met polymorphism.
Male and female BDNF Val66Met knock-in and wild-type (Val/Val) mice were exposed to escalating doses of JWH-018 (0.05, 0.1, 0.2 mg/kg) from post-natal day 35 to 55. Behavioral assessments were conducted in adulthood. In parallel, gene expression analyses were performed in the prefrontal cortex to explore potential molecular correlates of behavioral outcomes.
Adolescent exposure to JWH-018 was associated with reduced anxiety-like behavior in adulthood, with more pronounced effects in female mice. Additionally, male BDNF Val66Met mice exposed to JWH-018 showed improved performance in memory-related tasks. In contrast, amphetamine-induced hyperactivity was increased in BDNF Val66Met mice regardless of JWH-018 treatment. Molecular analyses revealed sex- and genotype-dependent differences in gene expression profiles.
Overall, these findings suggest that adolescent cannabinoid exposure can result in long-lasting behavioral and molecular changes that depend on both sex and genetic background. In particular, the BDNF Val66Met variant appears to shape behavioral responses to environmental challenges in a context- and phenotype-specific manner, highlighting the complexity of gene–environment interactions relevant to psychiatric vulnerability.