Bilbao Ainhoa, Neuhofer Daniela, Sepers Marja, Wei Shou-Peng, Eisenhardt Manuela, Hertle Sarah, Lassalle Olivier, Ramos-Uriarte Almudena, Puente Nagore, Lerner Raissa, Thomazeau Aurore, Grandes Pedro, Lutz Beat, Manzoni Olivier J, Spanagel Rainer
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.
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.
iScience. 2020 Mar 27;23(3):100951. doi: 10.1016/j.isci.2020.100951. Epub 2020 Feb 28.
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 (D1mGluR5 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 D1mGluR5 mice. The data suggest a model where the eCB and glutamatergic systems of the NAc act in concert to mediate reward-seeking responses.
伏隔核（NAc）在与药物相关的行为和自然奖赏学习中起关键作用。NAc中多巴胺D1和D2受体中型多棘神经元（MSNs）的突触可塑性以及内源性大麻素（eCB）系统与奖赏寻求有关。然而，奖赏寻求行为的确切分子和生理基础仍然未知。我们发现，在表达D1的MSNs中特异性缺失代谢型谷氨酸受体5（mGluR5）（D1mGluR5小鼠）可消除eCB介导的长时程抑制（LTD），并阻止药物（可卡因和乙醇）、自然奖赏（糖精）和脑刺激寻求行为的表达。在体内增强NAc核心内的2-花生四烯酸甘油（2-AG）eCB信号传导可恢复D1mGluR5小鼠的eCB-LTD和奖赏寻求行为。数据表明了一种模型，其中NAc的eCB和谷氨酸能系统协同作用以介导奖赏寻求反应。
