title: Brain-derived neurotrophic factor controls cannabinoid CB1 receptor function in the striatum.
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 (CB(1)Rs) in the striatum, a brain area in which both BDNF and CB(1)s play a role in the emotional consequences of stress and of rewarding experiences. BDNF potently inhibited CB(1)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 CB(1)Rs controlling GABA-mediated IPSCs (CB(1)R(GABA)), whereas CB(1)Rs modulating glutamate transmission and GABA(B) receptors were not affected. The action of BDNF on CB(1)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(+/-)), CB(1)R(GABA) responses were potentiated and were preserved from the action of haloperidol, a DA D(2) receptor (D(2)R) antagonist able to fully abolish CB(1)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 D(2)Rs in the modulation of cannabinoid signaling. Accordingly, 5 d cocaine exposure both reduced striatal BDNF levels and increased CB(1)R(GABA) activity, through a mechanism dependent on D(2)Rs. The present study identifies a novel mechanism of CB(1)R regulation mediated by BDNF and cholesterol metabolism and provides some evidence that DA D(2)R-dependent modulation of striatal CB(1)R activity is mediated by this neurotrophin.
authors.affiliation: Clinica Neurologica and Clinica Psichiatrica, Dipartimento di Neuroscienze, Università Tor Vergata, 00133 Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: De Chiara
authors.forename: Francesco
authors.initials: F
authors.lastname: Angelucci
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musella
authors.forename: Francesca
authors.initials: F
authors.lastname: Cavasinni
authors.forename: Cristina
authors.initials: C
authors.lastname: Cantarella
authors.forename: Giorgia
authors.initials: G
authors.lastname: Mataluni
authors.forename: Lucia
authors.initials: L
authors.lastname: Sacchetti
authors.forename: Francesco
authors.initials: F
authors.lastname: Napolitano
authors.forename: Maura
authors.initials: M
authors.lastname: Castelli
authors.forename: Carlo
authors.initials: C
authors.lastname: Caltagirone
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D012201:Reward; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018682:GABA Agents; D010636:Phenols; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; C103505:AM 251; C062898:lavendustin A; D013759:Dronabinol; D002784:Cholesterol; D003042:Cocaine; D006220:Haloperidol; C062018:HU 211