Opposite regulation of cannabinoid CB1 and CB2 receptors in the prefrontal cortex of rats treated with cocaine during adolescence

The endocannabinoid system is implicated in the neurobiology of cocaine addiction, although it is not clear how cocaine regulates brain CB1 and CB2 receptors, especially during adolescence, a critical moment for shaping adult response to drug use. This study evaluated CB1 and CB2 protein levels in prefrontal cortex (PFC) and hippocampus (HC) by western blot analysis with specific and validated antibodies: (1) basally during adolescence (post-natal day PND 40, PND 47, PND 54), (2) by a sensitizing regimen of cocaine (15 mg/kg, 7 days, i.p.) during different windows of adolescence vulnerability (PND 33-39, PND 40-46, PND 47-53), and (3) following repeated cocaine administration during adolescence (PND 33-39) in adulthood (PND 64). The results demonstrated a dynamic and opposite basal modulation of CB1 and CB2 receptors in PFC and HC during adolescence. CB1 receptor levels were increased while CB2 receptors were decreased as compared to adulthood with asymptotes values around mid adolescence (PND 47) both in PFC (CB1: +45 ± 22, p < 0.05; CB2: −24 ± 6%, p < 0.05) and HC (CB1: +53 ± 23, p < 0.05; CB2: −20 ± 8%, p < 0.05). Interestingly, cocaine only altered CB1 (+55 ± 10%, p < 0.05) and CB2 (−25 ± 10%, p < 0.05) receptors when administered during early adolescence and only in PFC. However, the changes observed in PFC by repeated cocaine administration in adolescence were transient and did not endure into adulthood. These results identified a period of vulnerability during adolescence at which cocaine dysregulated the content of CB receptors in PFC, suggesting an opposite role for these receptors in the effects mediated by cocaine.