Although epidemiological data suggest that repeated use of cannabis during adolescence may increase the risk for psychosis, its precise molecular mechanisms remain undetermined. In this study, we examined whether brain-derived neurotrophic factor (BDNF) and its receptor TrkB signaling plays a role in the risk for psychosis after exposure of cannabinoid (CB) receptor agonist during adolescence. Repeated administration of the CB receptor agonist WIN55,212-2 (2 mg/kg/day) during adolescence (P35 - P45) significantly increased methamphetamine (METH: 1 mg/kg)-induced hyperlocomotion in adulthood (P70 - P74) compared with vehicle-treated mice. Western blot analysis showed that BDNF-TrkB signaling in the nucleus accumbens (NAc) of WIN55,212-2-treated mice were significantly higher than that of vehicle-treated mice. Interestingly, an increase in the METH-induced locomotion in WIN55,212-2-treated mice was significantly attenuated by subsequent repeated administration of the TrkB antagonist ANA-12 (0.5 mg/kg/day from P70 to P83). Furthermore, increased BDNF-TrkB signaling in the NAc from WIN55,212-2-treated mice was also significantly attenuated after subsequent repeated administration of ANA-12. These findings suggest that increased BDNF-TrkB signaling in the NAc plays an important role in the increase in METH-induced locomotion in adulthood after repeated WIN55,212-2 administration during adolescence. Therefore, TrkB antagonists would be potential prophylactic and therapeutic drugs for psychosis in adult with cannabis use during adolescence.
Keywords: Brain-derived neurotrophic factor; Cannabis; Nucleus accumbens; Psychosis; TrkB antagonist.
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