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Author Notes:

Address correspondence and reprint requests to Dr Scott E. Hemby, Medical Center Boulevard, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. shemby@wfubmc.edu.

We appreciate the technical support of Margaret Basile (University of Miami) for assisting with brain tissue harvesting and regional dissections and editorial suggestions from Dr Jim Smith.

A portion of this research was conducted at the Yerkes National Primate Research Center.

Subjects:

Research Funding:

This work was supported by National Institutes of Health grants DA013772 (SEH), MH01194 (ECM), K02DA00517 (LLH), RR00165 (Yerkes Base Grant).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Neurosciences
  • Neurosciences & Neurology
  • cocaine
  • glutamate
  • nucleus accumbens
  • protein expression
  • putamen
  • VENTRAL TEGMENTAL AREA
  • CYCLIC-AMP SYSTEM
  • SEEKING BEHAVIOR
  • INDUCED REINSTATEMENT
  • PREFRONTAL CORTEX
  • DOPAMINE NEURONS
  • GENE-EXPRESSION
  • PROTEIN-KINASE
  • ION CHANNELS
  • RAT-BRAIN

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

Tools:

Journal Title:

Journal of Neurochemistry

Volume:

Volume 95, Number 6

Publisher:

, Pages 1785-1793

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2005 The Authors

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