Adolescent Δ⁹-THC Exposure Differentially Affects Mice Depending on Their Personality

Background: Adolescence is a sensitive period for brain maturation during which exposure to Δ⁹-tetrahydrocannabinol (THC) can induce long-lasting neurobehavioral alterations. Yet, preclinical and clinical studies report inconsistent long-term outcomes of adolescent THC exposure, ranging from clear impairments to apparently normalizing effects. We hypothesize that these discrepancies reflect stable individual differences in stress-coping abilities. Methods: To test this, selectively bred Dominant (Dom; stress-resilient, risk-prone) and Submissive (Sub; stress-vulnerable, depressive-like) Sabra mice received THC or vehicle during adolescence and were assessed in adulthood. Results: Anxiety-like and exploratory behavior, measured in the hole-board test, were differentially affected by THC as a function of stress vulnerability: in Sub mice, THC increased exploration and reduced anxiety-like behavior, whereas in Dom mice THC produced the opposite pattern. Recognition memory, evaluated by the novel object recognition test, showed modest, line-dependent alterations. Sensitivity to N-methyl-D-aspartate (NMDA) receptor hypofunction, a widely used index of vulnerability to schizophrenia-like symptoms, was examined using MK-801-induced locomotion. Adolescent THC potentiated MK-801-evoked hyperlocomotion in Dom mice but attenuated it in Sub mice. Conclusions: In the context of increasing medical and recreational cannabis exposure, these in vivo findings suggest that stress-vulnerability-related traits may be an important variable to consider in future preclinical and translational studies of adolescent THC exposure.