Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the nucleus accumbens core in cue-induced reinstatement of cocaine seeking in rats

Psychopharmacology (Berl). 2007 Jul;192(4):571-80. doi: 10.1007/s00213-007-0753-8. Epub 2007 Mar 9.


Rationale: Nucleus accumbens glutamate transmission has been implicated in drug-seeking behavior, but the involvement of glutamate receptor subtypes in drug seeking maintained by drug-associated cues has not been fully investigated.

Objective: This study examined the effects of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate, N-methyl-D-aspartate (NMDA) and mGlu5 receptor blockade in the nucleus accumbens core on cue-induced reinstatement of cocaine seeking.

Method: Wistar rats were trained to self-administer cocaine and associate a compound stimulus (light and tone) with the drug under an FR4(FR5:S) second-order schedule of reinforcement. After extinction, during which neither cocaine nor the compound stimulus was available, responding was reinstated by contingent presentations of the compound stimulus. The effects of the intra-accumbal AMPA/kainate receptor antagonist 6-cyano-7-nitro-quinoxaline-2, 3-dione (CNQX; 0, 0.01, and 0.03 microg/side), the NMDA antagonist D-2-amino-5-phosphonopentanoate (D-AP5; 0, 1, and 2 microg/side), and the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP; 0, 0.5, and 1 microg/side) on reinstatement were examined in a within-subjects design.

Results: CNQX and D-AP5 attenuated cue-induced reinstatement of cocaine seeking dose-dependently. MPEP, however, decreased cocaine seeking only relative to baseline because also the saline vehicle included in the within-subjects series of injections decreased responding, possibly reflecting conditioned anhedonic effects of MPEP. In additional experiments, none of the antagonists attenuated locomotor activity or responding for sucrose pellets.

Conclusions: The results suggest that cue-induced reinstatement of cocaine seeking after a period of withdrawal from cocaine is sensitive to AMPA/kainate and NMDA receptor antagonism in the nucleus accumbens core and give further evidence for the role of the accumbal glutamate transmission in modulation of drug-seeking behavior.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Animals
  • Cocaine / administration & dosage*
  • Cocaine-Related Disorders / physiopathology*
  • Cocaine-Related Disorders / psychology
  • Conditioning, Psychological / drug effects
  • Cues
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extinction, Psychological / drug effects
  • Male
  • Motor Activity / drug effects
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / physiopathology
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Kainic Acid / antagonists & inhibitors
  • Receptors, Kainic Acid / physiology*
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / physiology*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Self Administration


  • Dopamine Uptake Inhibitors
  • Excitatory Amino Acid Antagonists
  • Grm5 protein, rat
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Kainic Acid
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • 2-Amino-5-phosphonovalerate
  • 6-methyl-2-(phenylethynyl)pyridine
  • Cocaine