title: Cocaine withdrawal impairs metabotropic glutamate receptor-dependent long-term depression in the nucleus accumbens.
abstract: 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 Using a mouse model of behavioral sensitization, we show that animals withdrawn from repeated cocaine exposure have a selective deficit in the ability to elicit metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD)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 ester and (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 D(1)-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.
authors.affiliation: Department of Pharmacology, and Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City 701, Republic of China.
authors.forename: Chiung-Chun
authors.initials: CC
authors.lastname: Huang
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Yeh
authors.forename: Mei-Ying
authors.initials: MY
authors.lastname: Wu
authors.forename: Alice Y W
authors.initials: AY
authors.lastname: Chang
authors.forename: Julie Y H
authors.initials: JY
authors.lastname: Chan
authors.forename: Samuel H H
authors.initials: SH
authors.lastname: Chan
authors.forename: Kuei-Sen
authors.initials: KS
authors.lastname: Hsu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003042:Cocaine / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D004594:Electrophysiology; D004797:Enzyme-Linked Immunosorbent Assay; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000503:physiopathology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018094:Receptors, Metabotropic Glutamate; D003042:Cocaine