Variations in the stimulus salience of cocaine reward influences drug-associated contextual memory

Shervin Liddie, Yossef Itzhak

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Drugs of abuse act as reinforcers because they influence learning and memory processes resulting in long-term memory of drug reward. We have previously shown that mice conditioned by fixed daily dose of cocaine (Fix-C) or daily escalating doses of cocaine (Esc-C) resulted in short- and long-term persistence of drug memory, respectively, suggesting different mechanisms in acquisition of cocaine memory. The present study was undertaken to investigate the differential contribution of N-methyl-D-aspartate receptor (NMDAR) subunits in the formation of Fix-C and Esc-C memory in C57BL/6J mice. Training by Esc-C resulted in marked elevation in hippocampal expression of Grin2b mRNA and NR2B protein levels compared with training by Fix-C. The NR2B-containing NMDAR antagonist ifenprodil had similar attenuating effects on acquisition and reconsolidation of Fix-C and Esc-C memory. However, the NMDAR antagonist MK-801 had differential effects: (1) higher doses of MK-801 were required for post-retrieval disruption of reconsolidation of Esc-C memory than Fix-C memory; and (2) pre-retrieval MK-801 inhibited extinction of Fix-C memory but it had no effect on Esc-C memory. In addition, blockade of NMDAR downstream signaling pathways also showed differential regulation of Fix-C and Esc-C memory. Inhibition of neuronal nitric oxide synthase attenuated acquisition and disrupted reconsolidation of Fix-C but not Esc-C memory. In contrast, the mitogen-activating extracellular kinase inhibitor SL327 attenuated reconsolidation of Esc-C but not Fix-C memory. These results suggest that NMDAR downstream signaling molecules associated with consolidation and reconsolidation of cocaine-associated memory may vary upon changes in the salience of cocaine reward during conditioning. We hypothesized that conditioning by different schedules of cocaine result in variations in formation of drug memory. Memory encoded by escalating doses of cocaine (Esc-C) was associated with a marked elevation in hippocampal Grin2b mRNA and NR2B protein levels and was disrupted by blockade of mitogen-activating extracellular kinase (MEK) and not nitric oxide (NO) pathway. Memory encoded by fixed daily dose of cocaine (Fix-C) was associated with a minor elevation in hippocampal NR2B subunit and was disrupted by inhibition NO but not MEK pathway. Results suggest different mechanism in formation of Esc-C and Fix-C memory.

Original languageEnglish (US)
Pages (from-to)242-254
Number of pages13
JournalAddiction Biology
Issue number2
StatePublished - Mar 1 2016


  • Addiction
  • NR2B
  • cocaine
  • place preference
  • reconsolidation

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology
  • Psychiatry and Mental health


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