Downregulation of mGluR2/3 receptors during morphine withdrawal in rats impairs mGluR2/3- and NMDA receptor-dependent long-term depression in the nucleus accumbens.

Drugs of abuse modify synaptic long-term potentiation and long-term depression (LTD) in the nucleus accumbens, and the impairment of synaptic plasticity in this brain region may be a universal feature of drug addiction. It is unknown whether metabotropic glutamate receptors (mGluRs) play a role in synaptic plasticity induced by drugs such as morphine. The neurochemical, electrophysiological, and Western blotting experiments reported here reveal a novel form of LTD in synapses of the shell region of the nucleus accumbens induced in vivo by low-frequency stimulation of the medial prefrontal cortex. This plasticity required the activation of N-methyl-d-aspartate receptors and mGluR2/3 but not mGluR5. The expression of mGluR2/3 was downregulated during withdrawal from repeated morphine exposure (10 days after the last injection), resulting in impaired low-frequency stimulation-induced LTD. These results indicate that withdrawal-induced mGluR2/3 downregulation alters neural plasticity after morphine exposure, which may be a mechanism contributing to drug addiction.