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

doi:10.1016/j.isci.2020.100951

Endocannabinoid LTD in Accumbal D1 Neurons Mediates Reward-Seeking Behavior

iScience. 2020 Mar 27;23(3):100951. doi: 10.1016/j.isci.2020.100951. Epub 2020 Feb 28.

Authors

Affiliations

¹ 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. Electronic address: ainhoa.bilbao@zi-mannheim.de.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg, University Mainz, Duesbergweg 6, 55099 Mainz, Germany.
⁷ 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. Electronic address: olivier.manzoni@inserm.fr.
⁸ Institute of Psychopharmacology, Central Institute of Mental Health, Heidelberg University, Medical Faculty Mannheim, 68159 Mannheim, Germany. Electronic address: rainer.spanagel@zi-mannheim.de.

Abstract

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 (D1^miRmGluR5 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 D1^miRmGluR5 mice. The data suggest a model where the eCB and glutamatergic systems of the NAc act in concert to mediate reward-seeking responses.

Keywords: Behavioral Neuroscience; Molecular Neuroscience; Neuroscience.