Cocaine-induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non-human primates

Scott E. Hemby, Wenxue Tang, Emil C. Muly, Michael J. Kuhar, Leonard Howell, Deborah C Mash

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Chronic cocaine and withdrawal induce significant alterations in nucleus accumbens (NAc) glutamatergic function in humans and rodent models of cocaine addiction. Dysregulation of glutamatergic function of the prefrontal cortical-NAc pathway has been proposed as a critical substrate for unmanageable drug seeking. Previously, we demonstrated significant up-regulation of NMDA, (±)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptor subunit mRNAs and protein levels in the ventral tegmental area (VTA), but not the substantia nigra, of cocaine overdose victims (COD). The present study was undertaken to examine the extent of altered ionotropic glutamate receptor (iGluR) subunit expression in the NAc and the putamen in cocaine overdose victims. Results revealed statistically significant increases in the NAc, but not in the putamen, of NMDA receptor subunit (NR)1 and glutamate receptor subunit (GluR)2/3 wit trends in GluR1 and GluR5 in COD. These results extend our previous finding and indicate pathway-specific alterations in iGluRs in COD. In order to determine that changes were related to cocaine intake and not to other factors in the COD victims, we examined the effects of cocaine intravenous self-administration in rhesus monkeys for 18 months (unit dose of 0.1 mg/kg/injection and daily drug intake of 0.5 mg/kg/session). Total drug intake for the group of four monkeys was 37.9 ± 4.6 mg/kg. Statistically significant elevations were observed for NR1, GluR1, GluR2/3 and GluR5 (p < 0.05) and a trend towards increased NR1 phosphorylated at serine 896 (p = 0.07) in the NAc but not putamen of monkeys self-administering cocaine compared with controls. These results extend previous results by demonstrating an up-regulation of NR1, GluR2/3 and GluR5 in the NAc and suggest these alterations are pathway specific. Furthermore, these changes may mediate persistent drug intake and craving in the human cocaine abuser.

Original languageEnglish
Pages (from-to)1785-1793
Number of pages9
JournalJournal of Neurochemistry
Volume95
Issue number6
DOIs
StatePublished - Dec 1 2005

Fingerprint

Ionotropic Glutamate Receptors
Nucleus Accumbens
Cocaine
Primates
Putamen
Pharmaceutical Preparations
Haplorhini
Up-Regulation
Kainic Acid Receptors
Cocaine-Related Disorders
Ventral Tegmental Area
Wit and Humor
Self Administration
AMPA Receptors
Protein Subunits
Substantia Nigra
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Macaca mulatta
Glutamate Receptors

Keywords

  • Cocaine
  • Glutamate
  • Nucleus accumbens
  • Protein expression
  • Putamen

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Cocaine-induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non-human primates. / Hemby, Scott E.; Tang, Wenxue; Muly, Emil C.; Kuhar, Michael J.; Howell, Leonard; Mash, Deborah C.

In: Journal of Neurochemistry, Vol. 95, No. 6, 01.12.2005, p. 1785-1793.

Research output: Contribution to journalArticle

Hemby, Scott E. ; Tang, Wenxue ; Muly, Emil C. ; Kuhar, Michael J. ; Howell, Leonard ; Mash, Deborah C. / Cocaine-induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non-human primates. In: Journal of Neurochemistry. 2005 ; Vol. 95, No. 6. pp. 1785-1793.
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