Brain-derived neurotrophic factor downregulates immunoglobulin heavy chain binding protein expression after repeated...

Brain-derived neurotrophic factor (BDNF) is a key molecule involved in the regulation of glutamatergic neurotransmission in response to chronic stimulation of psychostimulants. This study demonstrated that BDNF in the dorsal striatum regulates the endoplasmic reticulum (ER) stress response after repeated exposure to cocaine. The results showed that unilateral intracaudate infusion of BDNF (0.40, 0.75, or 1.50μg/μL) decreased the repeated cocaine-induced increase in the expression of immunoglobulin heavy chain binding protein (BiP) sensing unfolded or misfolded proteins in a dose-dependent manner. Unilateral intracaudate infusion of BDNF (0.75μg/μL) also decreased the phosphorylation of c-Jun N-terminal kinase (JNK), which had been initially elevated by seven consecutive daily intraperitoneal injections of cocaine (20mg/kg/day). These decreases were reversed by unilateral intracaudate infusion of the specific tropomyosin receptor kinase B (TrkB) antagonist, cyclotraxin B (1ng/μL). These findings suggest that BDNF regulates the unfolded protein response via TrkB-linked JNK inactivation in the dorsal striatum after repeated cocaine administration, thus contributing to the restoration of the ER functions.