Abstract
SummaryThe 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.
Highlights
The brain reward system mediates motivational responses to natural rewards such as drinking, eating, and reproduction
RESULTS metabotropic glutamate receptor 5 (mGluR5) in D1-Containing Neurons Mediate Drug- and Natural Reward-Seeking Behavior Using a conditional mouse model with a knockdown of mGluR5 in dopamine D1-receptor-containing neurons (D1miRmGluR5 mice), we recently demonstrated that mGluR5 in this specific neuronal population mediates cue-induced reinstatement of cocaine-seeking behavior (Novak et al, 2010)
We further asked if reward-seeking responses toward other drugs of abuse and natural rewards are affected by this selective deletion of mGluR5 in D1-containing neurons
Summary
The brain reward system mediates motivational responses to natural rewards such as drinking, eating, and reproduction. Stimulation of prelimbic cortex afferents at naturally occurring frequencies can cause long-term depression (LTD) of NAc glutamatergic synapses—an effect mediated by eCB release and presynaptic cannabinoid type 1receptor (CB1R) (Robbe et al, 2002; Zlebnik and Cheer, 2016; Araque et al, 2017). This form of eCB-mediated synaptic plasticity in the NAc depends on postsynaptic metabotropic glutamate receptor 5 (mGluR5) and is eliminated following exposure to drugs of abuse (Mato et al, 2004; Fourgeaud et al, 2004; Zlebnik and Cheer, 2016)
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