ABSTRACT
Effects of cannabis reported by users range from experiences of euphoria and anxiolytic effects to paranoia, anxiety, and increased risk of depression. Previous studies attempting to reconcile the apparent contradictions in user response have not been conclusive. Here, we utilized selectively-bred mice with dominant (Dom) and submissive (Sub) behavioral patterns exhibiting resilience and sensitivity to stress, respectively to elucidate this contradiction. Following short-term, repeated treatment with cannabis oil containing the plant’s main psychoactive component delta-9-tetrahydrocannabinol (THC) at two different doses (1.5 mg/kg and 15 mg/kg), Sub mice presented significant place aversion in a conditioned place preference paradigm at a higher dose, whereas Dom mice displayed no place preference or aversion. After 6-week washout period, mice were subjected to several stressor tests. In forced swim test Sub mice displayed a reduction of depressive-like behavior after administration of the lower dose whereas those that got higher dose showed similar levels of depressive-like behavior to the naïve animals. Despite the lack of place preference/aversion, Dom animals receiving 15 mg/kg THC displayed depressive-like behavior similar to the socially-submissive, stress-prone mice. Interestingly, serum corticosterone levels were elevated at the 15 mg/kg dose regardless of the population tested. We conclude here that differences in dominance behavior and stress vulnerability are involved in regulation of cannabis response among users and should be considered when prescribing THC-containing medications to patients.