A shift in the role of glutamatergic signaling in the nucleus accumbens core with the development of an addicted phenotype

Biol Psychiatry. 2014 Nov 15;76(10):810-5. doi: 10.1016/j.biopsych.2014.02.005. Epub 2014 Feb 14.

Abstract

Background: While dopamine signaling in the nucleus accumbens (NAc) plays a well-established role in motivating cocaine use in early nonaddicted stages, recent evidence suggests that other signaling pathways may be critical once addiction has developed. Given the importance of glutamatergic signaling in the NAc for drug seeking and relapse, here we examined its role in motivating cocaine self-administration under conditions known to produce either a nonaddicted or an addicted phenotype.

Methods: Following acquisition, male and female Sprague Dawley rats were given either short access (three fixed-ratio 1 sessions, 20 infusions/day) or extended 24-hour access (10 days; 4 trials/hour; up to 96 infusions/day) to cocaine. Following a 14-day abstinence period, motivation for cocaine was assessed under a progressive-ratio schedule, and once stable, the effects of intra-NAc infusions of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate receptor antagonist CNQX (0, .01, .03, .1 μg/side) were determined. As an additional measure for the development of an addicted phenotype, separate groups of rats were screened under an extinction/cue-induced reinstatement procedure following abstinence from short-access versus extended-access self-administration.

Results: Motivation for cocaine and levels of extinction and reinstatement responding were markedly higher following extended-access versus short-access self-administration, confirming the development of an addicted phenotype in the extended-access group. CNQX dose-dependently reduced motivation for cocaine in the extended-access group but was without effect in the short-access group.

Conclusions: These results suggest that the role of glutamatergic signaling in the NAc, though not essential for motivating cocaine use in nonaddicted stages, becomes critical once addiction has developed.

Keywords: CNQX; cocaine; extended access; glutamate; motivation; nucleus accumbens.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Animals
  • Cocaine / administration & dosage*
  • Cocaine-Related Disorders / physiopathology*
  • Conditioning, Operant / drug effects
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extinction, Psychological / drug effects
  • Female
  • Glutamic Acid / physiology*
  • Male
  • Motivation / drug effects
  • Motivation / physiology*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / physiology*
  • Phenotype
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, Kainic Acid / antagonists & inhibitors
  • Reinforcement Schedule
  • Self Administration

Substances

  • Excitatory Amino Acid Antagonists
  • Receptors, AMPA
  • Receptors, Kainic Acid
  • Glutamic Acid
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • Cocaine