1. Brain-Derived Neurotrophic Factor Controls Cannabinoid CB1 Receptor Function in the Striatum.
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De Chiara, Valentina, Angelucci, Francesco, Rossi, Silvia, Musella, Alessandra, Cavasinni, Francesca, Cantarella, Cristina, Mataluni, Giorgia, Sacchetti, Lucia, Napolitano, Francesco, Castelli, Maura, Caltagirone, Carlo, Bernardi, Giorgio, Maccarrone, Mauro, Usiello, Alessandro, and Centonze, Diego
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BRAIN ,NEUROTROPHINS ,EMOTIONS ,GABA ,CHOLESTEROL metabolism ,DOPAMINE ,LABORATORY mice - Abstract
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 CB
1 receptors (CB1 Rs) in the striatum, a brain area in which both BDNF and CB1 s play a role in the emotional consequences of stress and of rewarding experiences. BDNF potently inhibited CB1 R function in the striatum, through a mechanism mediated by altered cholesterol metabolism and membrane lipid raft function. The effect of BDNF was restricted to CB1 Rs controlling GABA-mediated IPSCs (CB1 R(GABA) ), whereas CB1 Rs modulating glutamate transmission and GABAB receptors were not affected. The action of BDNF on CB1 R(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+/- ), CB1 R(GABA) responses were potentiated and were preserved from the action of haloperidol, a DA D2 receptor (D2 R) antagonist able to fully abolish CB1 R(GABA) function in rewarded animals. Haloperidol also enhanced BDNF levels in the striatum, suggesting that this neurotrophin may act as a downstream effector of D2 Rs in the modulation of cannabinoid signaling. Accordingly, 5 d cocaine exposure both reduced striatal BDNF levels and increased CB1 R(GABA) activity, through a mechanism dependent on D2 Rs. The present study identifies a novel mechanism of CB1 R regulation mediated by BDNF and cholesterol metabolism and provides some evidence that DA D2 R-dependent modulation of striatal CB1 R activity is mediated by this neurotrophin. [ABSTRACT FROM AUTHOR]- Published
- 2010
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