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 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.
De Chiara
Valentina
V
Clinica Neurologica and Clinica Psichiatrica, Dipartimento di Neuroscienze, Università Tor Vergata, 00133 Rome, Italy.
Angelucci
Francesco
F
Rossi
Silvia
S
Musella
Alessandra
A
Cavasinni
Francesca
F
Cantarella
Cristina
C
Mataluni
Giorgia
G
Sacchetti
Lucia
L
Napolitano
Francesco
F
Castelli
Maura
M
Caltagirone
Carlo
C
Bernardi
Giorgio
G
Maccarrone
Mauro
M
Usiello
Alessandro
A
Centonze
Diego
D
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
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