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

Valentina De Chiara, Francesco Angelucci, Silvia Rossi, Alessandra Musella, Francesca Cavasinni, Cristina Cantarella, Giorgia Mataluni, Lucia Sacchetti, Francesco Napolitano, Maura Castelli, Carlo Caltagirone, Giorgio Bernardi, Mauro Maccarrone, Alessandro Usiello, Diego Centonze

Research output: Contribution to journalArticle

47 Citations (Scopus)

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 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 GABAB 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.

Original languageEnglish
Pages (from-to)8127-8137
Number of pages11
JournalJournal of Neuroscience
Volume30
Issue number24
DOIs
Publication statusPublished - Jun 16 2010

Fingerprint

Cannabinoid Receptor CB1
Brain-Derived Neurotrophic Factor
gamma-Aminobutyric Acid
Corpus Striatum
Nerve Growth Factors
Haloperidol
Cocaine
Cholesterol
trkB Receptor
Endocannabinoids
Dopamine D2 Receptors
Cannabinoids
Membrane Lipids
Reward
Psychological Stress
Protein-Tyrosine Kinases
Glutamic Acid
Dopamine

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Brain-derived neurotrophic factor controls cannabinoid CB1 receptor function in the striatum. / 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; Centonze, Diego.

In: Journal of Neuroscience, Vol. 30, No. 24, 16.06.2010, p. 8127-8137.

Research output: Contribution to journalArticle

De Chiara, V, Angelucci, F, Rossi, S, Musella, A, Cavasinni, F, Cantarella, C, Mataluni, G, Sacchetti, L, Napolitano, F, Castelli, M, Caltagirone, C, Bernardi, G, Maccarrone, M, Usiello, A & Centonze, D 2010, 'Brain-derived neurotrophic factor controls cannabinoid CB1 receptor function in the striatum', Journal of Neuroscience, vol. 30, no. 24, pp. 8127-8137. https://doi.org/10.1523/JNEUROSCI.1683-10.2010
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 ; Centonze, Diego. / Brain-derived neurotrophic factor controls cannabinoid CB1 receptor function in the striatum. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 24. pp. 8127-8137.
@article{fee443d1bfa0433ca920c5b7fdc3010c,
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 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 GABAB 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.",
author = "{De Chiara}, Valentina and Francesco Angelucci and Silvia Rossi and Alessandra Musella and Francesca Cavasinni and Cristina Cantarella and Giorgia Mataluni and Lucia Sacchetti and Francesco Napolitano and Maura Castelli and Carlo Caltagirone and Giorgio Bernardi and Mauro Maccarrone and Alessandro Usiello and Diego Centonze",
year = "2010",
month = "6",
day = "16",
doi = "10.1523/JNEUROSCI.1683-10.2010",
language = "English",
volume = "30",
pages = "8127--8137",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "24",

}

TY - JOUR

T1 - Brain-derived neurotrophic factor controls cannabinoid CB1 receptor function in the striatum

AU - De Chiara, Valentina

AU - Angelucci, Francesco

AU - Rossi, Silvia

AU - Musella, Alessandra

AU - Cavasinni, Francesca

AU - Cantarella, Cristina

AU - Mataluni, Giorgia

AU - Sacchetti, Lucia

AU - Napolitano, Francesco

AU - Castelli, Maura

AU - Caltagirone, Carlo

AU - Bernardi, Giorgio

AU - Maccarrone, Mauro

AU - Usiello, Alessandro

AU - Centonze, Diego

PY - 2010/6/16

Y1 - 2010/6/16

N2 - 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 GABAB 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.

AB - 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 GABAB 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.

UR - http://www.scopus.com/inward/record.url?scp=77953775571&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953775571&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.1683-10.2010

DO - 10.1523/JNEUROSCI.1683-10.2010

M3 - Article

C2 - 20554863

AN - SCOPUS:77953775571

VL - 30

SP - 8127

EP - 8137

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 24

ER -