Endocannabinoid LTD in Accumbal D1 Neurons Mediates Reward-Seeking Behavior

Ainhoa Bilbao (1) , Daniela Neuhofer (2) , Marja Sepers (2) , Shou-Peng Wei (1) , Manuela Eisenhardt (1) , Sarah Hertle (1) , Olivier Lassalle (2) , Almudena Ramos-Uriarte (3) , Nagore Puente (3) , Raissa Lerner (4) , Aurore Thomazeau (2) , Pedro Grandes (3) , Beat Lutz (4) , Olivier Manzoni (2) , Rainer Spanagel (5)

1 University of Heidelberg, Medical Faculty
2 INMED - INSERM U1249 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
3 UPV/EHU - University of the Basque Country/Euskal Herriko Unibertsitatea
4 JGU - Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University
5 Heidelberg University Hospital [Heidelberg]

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.

Keywords: Neuroscience; Behavioral Neuroscience; Molecular Neuroscience

Domains: Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]

Ainhoa Bilbao, Daniela Neuhofer, Marja Sepers, Shou-Peng Wei, Manuela Eisenhardt, et al.. Endocannabinoid LTD in Accumbal D1 Neurons Mediates Reward-Seeking Behavior. iScience, 2020, 23 (3), pp.100951. ⟨10.1016/j.isci.2020.100951⟩. ⟨hal-03007155⟩