Brain-derived neurotrophic factor controls cannabinoid CB1 receptor function in the striatum

The role of brain-derived neurotrophic factor (BDNF) in emotional processes suggests an interaction with the endocannabinoid system. Here, we addressed the functional interplay between BDNF and cannabinoid CB₁ receptors (CB1Rs) in the striatum, a brain area in which both BDNF and CB₁s play a role in the emotional consequences of stress and of rewarding experiences. BDNF potently inhibited CB₁R function in the striatum, through a mechanism mediated by altered cholesterol metabolism and membrane lipid raft function. The effect of BDNF was restricted to CB₁Rs controlling GABA-mediated IPSCs (CB₁R_(GABA)), whereas CB₁Rs modulating glutamate transmission and GABA_B receptors were not affected. The action of BDNF on CB₁R _(GABA) function was tyrosine kinase dependent and was complete even after receptor sensitization with cocaine or environmental manipulations activating the dopamine (DA)-dependent reward system. In mice lacking one copy of the BDNF gene (BDNF^+/-), CB1R(GABA) responses were potentiated and were preserved from the action of haloperidol, a DA D₂ receptor (D₂R) antagonist able to fully abolish CB₁R _(GABA) function in rewarded animals. Haloperidol also enhanced BDNF levels in the striatum, suggesting that this neurotrophin may act as a downstream effector of D₂Rs in the modulation of cannabinoid signaling. Accordingly, 5 d cocaine exposure both reduced striatal BDNF levels and increased CB₁R_(GABA) activity, through a mechanism dependent on D₂Rs. The present study identifies a novel mechanism of CB₁R regulation mediated by BDNF and cholesterol metabolism and provides some evidence that DA D₂R-dependent modulation of striatal CB₁R activity is mediated by this neurotrophin.