Inhibition of NAALADase by 2-PMPA attenuates cocaine-induced relapse in rats: A NAAG-mGluR23-mediated mechanism

Zheng Xiong Xi, Xia Li, Xiao Qing Peng, Jie Li, Lauren Chun, Eliot L. Gardner, Ajit G. Thomas, Barbara S. Slusher, Charles R. Ashby

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Pharmacological activation of group II metabotropic glutamate receptors (mGluR23) inhibits cocaine self-administration and reinstatement of drug-seeking behavior, suggesting a possible use of mGluR23 agonists in the treatment of cocaine dependence. In this study, we investigated whether elevation of the endogenous mGluR23 ligand N-acetyl-aspartatylglutamate (NAAG) levels by the N-acetylated-alpha-linked-acidic dipeptidase inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA) attenuates cocaine self-administration and cocaine-induced reinstatement of drug seeking. N-acetylated-alpha-linked-acidic dipeptidase is a NAAG degradation enzyme that hydrolyzes NAAG to N-acetylaspartate and glutamate. Systemic administration of 2-PMPA (10-100 mgkg, i.p.) inhibited intravenous self-administration maintained by low unit doses of cocaine and cocaine (but not sucrose)-induced reinstatement of drug-seeking behavior. Microinjections of 2-PMPA (3-5 μgside) or NAAG (3-5 μgside) into the nucleus accumbens (NAc), but not into the dorsal striatum, also inhibited cocaine-induced reinstatement, an effect that was blocked by intra-NAc injection of LY341495, a selective mGluR23 antagonist. In vivo microdialysis demonstrated that 2-PMPA (10-100 mgkg, i.p.) produced a dose-dependent reduction in both extracellular dopamine (DA) and glutamate, an effect that was also blocked by LY341495. Finally, pre-treatment with 2-PMPA partially attenuated cocaine-enhanced extracellular NAc DA, while completely blocking cocaine-enhanced extracellular NAc glutamate in rats during reinstatement testing. Intra-NAc perfusion of LY341495 blocked 2-PMPA-induced reductions in cocaine-enhanced extracellular NAc glutamate, but not DA. These findings suggest that 2-PMPA is effective in attenuating cocaine-induced reinstatement of drug-seeking behavior, likely by attenuating cocaine-induced increases in NAc DA and glutamate via pre-synaptic mGluR23s.

Original languageEnglish (US)
Pages (from-to)564-576
Number of pages13
JournalJournal of Neurochemistry
Issue number2
StatePublished - Jan 2010
Externally publishedYes


  • 2-(phosphonomethyl)pentanedioic acid
  • Cocaine
  • Dopamine
  • Glutamate
  • N-acetyl-aspartatylglutamate
  • Relapse

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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