Effects of N-methyl-D-aspartate receptor antagonists on reinstatement of cocaine-seeking behavior by priming injections of cocaine or exposures to cocaine-associated cues in rats

Behav Pharmacol. 2000 Feb;11(1):37-44. doi: 10.1097/00008877-200002000-00004.


The reinstatement of extinguished cocaine self-administration behavior was studied in rats pretreated with N-methyl-D-aspartate receptor antagonists. Rats were trained to self-administer intravenous cocaine (0.32 mg/kg/infusion) during five consecutive daily sessions that were followed by five consecutive daily extinction sessions, during which cocaine was unavailable and cocaine-associated cues (sound and light) were absent. Neither the competitive N-methyl-D-aspartate receptor antagonist D-CPPene (0.3-3 mg/kg) nor the low-affinity N-methyl-D-aspartate receptor channel blocker memantine (1-10 mg/kg) reinstated extinguished responding. Priming injections of intravenous cocaine (Experiment 1), and exposures to cocaine-associated stimuli (buzzer and light; Experiment 2) engendered responding on the reinforced lever in excess of that on the non-reinforced lever. In Experiment 1, administration of D-CPPene or memantine prior to the priming injection of cocaine eliminated the difference between reinforced-lever and non-reinforced-lever response rates. For both D-CPPene and memantine, however, this effect was largely due to increased responding upon the non-reinforced lever rather than to decreased reinforced-lever responding. In Experiment 2, D-CPPene, but not memantine, abolished in a dose-dependent manner the selective increase in reinforced-lever over non-reinforced-lever responding that was induced by exposures to cocaine-related stimuli. This effect of D-CPPene was not due to increased non-reinforced-lever responding. These data help define the boundaries within which N-methyl-D-aspartate receptor antagonists can prevent reinstatement of cocaine-seeking behavior (e.g. type of antagonist used and reinstatement procedure).

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cocaine / administration & dosage
  • Cocaine / pharmacology*
  • Cocaine-Related Disorders / psychology*
  • Conditioning, Operant / drug effects
  • Cues
  • Dopamine Uptake Inhibitors / administration & dosage
  • Dopamine Uptake Inhibitors / pharmacology*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extinction, Psychological / drug effects
  • Injections, Intravenous
  • Male
  • Memantine / pharmacology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Piperazines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Self Administration


  • Dopamine Uptake Inhibitors
  • Excitatory Amino Acid Antagonists
  • Piperazines
  • Receptors, N-Methyl-D-Aspartate
  • SDZ EAA 494
  • Cocaine
  • Memantine