NR2A/B-containing NMDA receptors mediate cocaine-induced synaptic plasticity in the VTA and cocaine psychomotor sensitization

Johanna Schumann, Henry Matzner, Avner Michaeli, Rami Yaka*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Cocaine-induced modifications of glutamatergic synaptic transmission in the mesolimbic system play a key role in adaptations that promote addictive behaviors. In particular, the activation of ionotropic glutamate N-methyl-d-aspartate receptor (NMDAR) in the ventral tegmental area (VTA) is critical for both cocaine-induced synaptic plasticity induced by a single cocaine injection and for the initiation of cocaine psychomotor sensitization. In this study, we set to determine whether the NR2 subunits of the NMDAR play a specific role in triggering cocaine-induced alterations in synaptic plasticity and the development of psychomotor sensitization. We found that inhibition of NR2A-containing NMDARs by NVP-AAM077, or NR2B-containing receptors by ifenprodil, blocked cocaine-induced increase in the AMPAR/NMDAR currents ratio, a measure of long-term potentiation (LTP) in vivo, in VTA neurons 24 h following a single cocaine injection. Furthermore, inhibition of the NR2A subunit during the development of psychomotor sensitization attenuated the enhanced locomotor activity following repeated cocaine injections. Together, these results suggest that NR2-containing NMDA receptors play an important role in the machinery that triggers synaptic and behavioral adaptations to drugs of abuse such as cocaine.

Original languageAmerican English
Pages (from-to)159-162
Number of pages4
JournalNeuroscience Letters
Volume461
Issue number2
DOIs
StatePublished - 11 Sep 2009

Bibliographical note

Funding Information:
We thank Dr. Y. Auberson of the Novartis Institutes for Biomedical Research (Basel, Switzerland) for the generous gift of NVP-AAM077. This research was supported by the Israel Science Foundation (grant no. 292/05 R.Y.). R. Yaka is affiliated with the David R. Bloom Center for Pharmacy and the Brettler Center for research in molecular pharmacology and therapeutics, School of Pharmacy, The Hebrew University of Jerusalem.

Keywords

  • Cocaine
  • Ifenprodil
  • NMDA receptor
  • NVP-AAM077
  • Sensitization
  • Synaptic plasticity
  • VTA

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