Cocaine withdrawal impairs metabotropic glutamate receptor-dependent long-term depression in the nucleus accumbens

Chiung Chun Huang, Che Ming Yeh, Mei Ying Wu, Alice Y.W. Chang, Julie Y.H. Chan, Samuel H.H. Chan, Kuei Sen Hsu*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

60 Scopus citations


Neuroadaptation in the nucleus accumbens (NAc), a central component of the mesolimbic dopamine (DA) system, has been implicated in the development of cocaine-induced psychomotor sensitization and relapse to cocaine seeking. However, little is known about the cellular and synaptic mechanisms underlying such adaptation. Using a mouse model of behavioral sensitization, we show that animals withdrawn from repeated cocaine exposure have a selective deficit in the ability to elicit metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) in the shell of the NAc in response to bath application of the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG). Experiments conducted in the presence of the selective mGluR1 antagonists 7-(hydroxyimino)cyclopropachromen-carboxylate ethyl esterand(S)-(+)-α- amino-4-carboxy-2-methylbenzeneacetic acid, or the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine, demonstrated that the impaired DHPG-LTD is likely attributable to a loss of mGluR5 function. Quantitative real-time reverse transcriptase-PCR and Western blot analysis revealed significant downregulation of mGluR5, but not mGluR1, mRNA and protein levels in the NAc shell. The inhibitory effect of repeated cocaine exposure on DHPG-LTD was selectively prevented when cocaine was coadministered with the selective D1-like DA receptor antagonist (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine. Furthermore, the levels of brain-derived neurotrophic factor (BDNF) protein in the NAc shell increased progressively after cocaine withdrawal, and the impairment of DHPG-LTD in the NAc shell was not found in slices from BDNF-knock-out mice after cocaine withdrawal. These results suggest that withdrawal from repeated cocaine exposure may result in increased BDNF levels in the NAc shell, which leads to a selective downregulation of mGluR5 and thereby impairs the induction of mGluR-dependent LTD.

Original languageEnglish
Pages (from-to)4194-4203
Number of pages10
JournalJournal of Neuroscience
Issue number11
StatePublished - 16 03 2011
Externally publishedYes


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