Endocannabinoid LTD in Accumbal D1 Neurons Mediates Reward-Seeking Behavior
Ainhoa Bilbao,
Daniela Neuhofer,
Marja Sepers,
Shou-peng Wei,
Manuela Eisenhardt,
Sarah Hertle,
Olivier Lassalle,
Almudena Ramos-Uriarte,
Nagore Puente,
Raissa Lerner,
Aurore Thomazeau,
Pedro Grandes,
Beat Lutz,
Olivier J. Manzoni,
Rainer Spanagel
Affiliations
Ainhoa Bilbao
Behavioral Genetics Research Group, Heidelberg University, Medical Faculty Mannheim, 68159 Mannheim, Germany; Institute of Psychopharmacology, Central Institute of Mental Health, Heidelberg University, Medical Faculty Mannheim, 68159 Mannheim, Germany; Corresponding author
Daniela Neuhofer
INSERM U1249, Parc Scientifique de Luminy - BP 13 - 13273, Marseille Cedex 09, France; Aix-Marseille University, Jardindu Pharo, 58 Boulevard Charles Livon, Marseille, 13007, France
Marja Sepers
INSERM U1249, Parc Scientifique de Luminy - BP 13 - 13273, Marseille Cedex 09, France; Aix-Marseille University, Jardindu Pharo, 58 Boulevard Charles Livon, Marseille, 13007, France
Shou-peng Wei
Behavioral Genetics Research Group, Heidelberg University, Medical Faculty Mannheim, 68159 Mannheim, Germany; Institute of Psychopharmacology, Central Institute of Mental Health, Heidelberg University, Medical Faculty Mannheim, 68159 Mannheim, Germany
Manuela Eisenhardt
Behavioral Genetics Research Group, Heidelberg University, Medical Faculty Mannheim, 68159 Mannheim, Germany; Institute of Psychopharmacology, Central Institute of Mental Health, Heidelberg University, Medical Faculty Mannheim, 68159 Mannheim, Germany
Sarah Hertle
Behavioral Genetics Research Group, Heidelberg University, Medical Faculty Mannheim, 68159 Mannheim, Germany; Institute of Psychopharmacology, Central Institute of Mental Health, Heidelberg University, Medical Faculty Mannheim, 68159 Mannheim, Germany
Olivier Lassalle
INSERM U1249, Parc Scientifique de Luminy - BP 13 - 13273, Marseille Cedex 09, France; Aix-Marseille University, Jardindu Pharo, 58 Boulevard Charles Livon, Marseille, 13007, France; Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, INSERM-Indiana University, 107 S Indiana Avenue, Bloomington, IN 47405, USA
Almudena Ramos-Uriarte
Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain; Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain
Nagore Puente
Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain; Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain
Raissa Lerner
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg, University Mainz, Duesbergweg 6, 55099 Mainz, Germany
Aurore Thomazeau
INSERM U1249, Parc Scientifique de Luminy - BP 13 - 13273, Marseille Cedex 09, France; Aix-Marseille University, Jardindu Pharo, 58 Boulevard Charles Livon, Marseille, 13007, France
Pedro Grandes
Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain; Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain
Beat Lutz
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg, University Mainz, Duesbergweg 6, 55099 Mainz, Germany
Olivier J. Manzoni
INSERM U1249, Parc Scientifique de Luminy - BP 13 - 13273, Marseille Cedex 09, France; Aix-Marseille University, Jardindu Pharo, 58 Boulevard Charles Livon, Marseille, 13007, France; Cannalab, Cannabinoids Neuroscience Research International Associated Laboratory, INSERM-Indiana University, 107 S Indiana Avenue, Bloomington, IN 47405, USA; Corresponding author
Rainer Spanagel
Institute of Psychopharmacology, Central Institute of Mental Health, Heidelberg University, Medical Faculty Mannheim, 68159 Mannheim, Germany; Corresponding author
Summary: The nucleus accumbens (NAc) plays a key role in drug-related behavior and natural reward learning. Synaptic plasticity in dopamine D1 and D2 receptor medium spiny neurons (MSNs) of the NAc and the endogenous cannabinoid (eCB) system have been implicated in reward seeking. However, the precise molecular and physiological basis of reward-seeking behavior remains unknown. We found that the specific deletion of metabotropic glutamate receptor 5 (mGluR5) in D1-expressing MSNs (D1miRmGluR5 mice) abolishes eCB-mediated long-term depression (LTD) and prevents the expression of drug (cocaine and ethanol), natural reward (saccharin), and brain-stimulation-seeking behavior. In vivo enhancement of 2-arachidonoylglycerol (2-AG) eCB signaling within the NAc core restores both eCB-LTD and reward-seeking behavior in D1miRmGluR5 mice. The data suggest a model where the eCB and glutamatergic systems of the NAc act in concert to mediate reward-seeking responses. : Neuroscience; Behavioral Neuroscience; Molecular Neuroscience Subject Areas: Neuroscience, Behavioral Neuroscience, Molecular Neuroscience
