Increased BDNF-TrkB signaling in the nucleus accumbens plays a role in the risk for psychosis after cannabis exposure during adolescence

• Published in: Pharmacology, biochemistry and behavior Vol. 177; pp. 61 - 68
• Main Authors: Dong, Chao, Tian, Zheng, Zhang, Kai, Chang, Lijia, Qu, Youge, Pu, Yaoyu, Ren, Qian, Fujita, Yuko, Ohgi, Yuta, Futamura, Takashi, Hashimoto, Kenji
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2019
• Subjects: Animals; Azepines - pharmacology; Behavior, Animal - drug effects; Benzamides - pharmacology; Benzoxazines - administration & dosage; Benzoxazines - pharmacology; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Cannabinoid Receptor Agonists - administration & dosage; Cannabinoid Receptor Agonists - pharmacology; Cannabinoids - pharmacology; Cannabis; Cannabis - chemistry; Central Nervous System Stimulants - pharmacology; Dentate Gyrus - metabolism; Locomotion - drug effects; Male; Marijuana Abuse - metabolism; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - metabolism; Methamphetamine - pharmacology; Mice; Mice, Inbred C57BL; Morpholines - administration & dosage; Morpholines - pharmacology; Naphthalenes - administration & dosage; Naphthalenes - pharmacology; Nucleus accumbens; Nucleus Accumbens - metabolism; Prefrontal Cortex - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Psychoses, Substance-Induced - pathology; Psychosis; Risk; TrkB antagonist; Nucleus accumbens; Psychosis; Cannabis; Brain-derived neurotrophic factor; TrkB antagonist
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2019.01.002

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. •Exposure of cannabinoid agonist during adolescence increased methamphetamine-induced hyperlocomotion in adulthood.•Increased BDNF-TrkB signaling in the nucleus accumbens play a role.•TrkB antagonists would be therapeutic drugs for psychosis in adult with cannabis use during adolescence.