Detrimental effects of adolescent escalating low‐dose Δ 9 ‐tetrahydrocannabinol lead to a specific bio‐behavioural profile in adult male rats

Background and purpose Clinical research shows that adolescent cannabis use associates with adult psychopathology. Experimental studies demonstrate the long-lasting effects of adolescent THC on adult rats, mostly using higher THC doses. The present study aims to determine the specific adult bio-behavioural profile after adolescent low-dose THC, which better mirrors adolescent recreational cannabis use. Experimental approach Adolescent male Sprague-Dawley rats were treated with escalating low-dose THC. In adulthood they were evaluated for their spontaneous locomotion, sensorimotor gating, higher-order and spatial cognitive functions. Dopaminergic activity and cannabinoid receptor expression were measured in distinct brain regions. Hippocampal neurogenic activity of neural stem cells was determined, and protein levels of neuroplasticity-related biomarkers were quantified. Adolescent low-dose THC exposure increased spontaneous open-field activity, without affecting pre-pulse inhibition and attentional set-shifting performance. Region-specific dopaminergic alterations and CB1 receptor upregulation in the prefrontal cortex were observed. Impaired spatial memory, as assessed with the Object Location Task and Morris Water Maze Test, was associated with significantly decreased proliferative activity (SOX2-positive cells), neurogenic potential (decreased DCX-positive cells) in the adult hippocampus, and defective neuroplasticity, including reduced BDNF expression in the hippocampus and prefrontal cortex. Key results Our findings reveal the adverse impact of adolescent low-dose THC on the psychomotor profile, dopaminergic neurotransmission, compensatory cannabinoid receptor response and cognition-related neurobiological and behavioural functions. Conclusion and implications Our adolescent low-dose THC animal model does not induce tangible psychotic-like effects, such as those reported in high-dose THC studies, but it impairs cognitive functions and points to hippocampal vulnerability and disrupted neurogenesis.