title: Cocaine Withdrawal Impairs mGluR5-Dependent Long-Term Depression in Nucleus Accumbens Shell Neurons of Both Direct and Indirect Pathways.
abstract: We previously reported that animals withdrawn from repeated cocaine exposure exhibited a selective deficit in the ability to elicit metabotropic glutamate receptor 5 (mGluR5)-dependent long-term depression (LTD) in the nucleus accumbens (NAc) shell. To determine whether such impairment occurs in the NAc in a cell-type-specific manner, we used bacterial artificial chromosome (BAC) transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of gene regulatory elements for the dopamine D1 receptor (Drd1) or dopamine D2 receptor (Drd2) to identify distinct subpopulations of medium spiny neurons (MSNs). We found that bath application of group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) reliably induced LTD in both NAc shell and core MSNs of wild-type, hemizygous Drd1-eGFP, and Drd2-eGFP mice. Confirming our previous results, cocaine withdrawal selectively impaired DHPG-LTD in NAc shell Drd1-expressing direct and Drd2-expressing indirect pathway MSNs. We also found that the expression of DHPG-LTD in NAc MSNs was not affected by the Ca(2+)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist 1-naphthyl acetyl spermine. Furthermore, systemic administration of mGluR5-negative allosteric modulator fenobam before the daily injection of cocaine preserved mGluR5 function and significantly reduced the expression of cocaine-induced behavioral sensitization. These results reveal that withdrawal from repeated cocaine exposure may result in the impairment of NAc mGluR5-LTD in a subregion- but not cell-type-specific manner and suggests that pharmacological antagonism of mGluR5 may represent a potential strategy for reducing cocaine-induced addictive behaviors.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan, 701, Taiwan.
authors.forename: Chiung-Chun
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan, 701, Taiwan.
authors.forename: Ying-Ching
authors.initials: YC
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan, 701, Taiwan.
authors.forename: Cheng-Che
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan, 701, Taiwan. richard@mail.ncku.edu.tw.
authors.forename: Kuei-Sen
authors.initials: KS
authors.lastname: Hsu
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D003042:Cocaine / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D059290:Dopaminergic Neurons / Q000145:classification / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D017930:Genes, Reporter; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D009714:Nucleus Accumbens / Q000378:metabolism / Q000503:physiopathology*; D011720:Pyrazoles / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000502:physiology; D012118:Resorcinols / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome
chemical_list: C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D001549:Benzamides; D002867:Chromones; C000600618:DRD2 protein, mouse; C583261:Drd1 protein, mouse; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D011720:Pyrazoles; D011724:Pyridazines; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012118:Resorcinols; C032794:fenobam; C079215:3,5-dihydroxyphenylglycine; C121465:6-methyl-2-(phenylethynyl)pyridine; C049853:gabazine; D003042:Cocaine; D005998:Glycine
keywords: Behavioral sensitization; Cocaine; Long-term depression; Metabotropic glutamate receptor 5; Nucleus accumbens