title: Inhibition of NAALADase by 2-PMPA attenuates cocaine-induced relapse in rats: a NAAG-mGluR2/3-mediated mechanism.
abstract: Pharmacological activation of group II metabotropic glutamate receptors (mGluR2/3) inhibits cocaine self-administration and reinstatement of drug-seeking behavior, suggesting a possible use of mGluR2/3 agonists in the treatment of cocaine dependence. In this study, we investigated whether elevation of the endogenous mGluR2/3 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 mg/kg, 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 microg/side) or NAAG (3-5 microg/side) 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 mGluR2/3 antagonist. In vivo microdialysis demonstrated that 2-PMPA (10-100 mg/kg, 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 mGluR2/3s.
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA. zxi@intra.nida.nih.gov
authors.forename: Zheng-Xiong
authors.initials: ZX
authors.lastname: Xi
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Peng
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Lauren
authors.initials: L
authors.lastname: Chun
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Gardner
authors.forename: Ajit G
authors.initials: AG
authors.lastname: Thomas
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis / Q000379:methods; D008845:Microinjections / Q000379:methods; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012055:Reinforcement Schedule; D012646:Self Administration / Q000379:methods; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage
chemical_list: C402107:2-(phosphonomethyl)pentanedioic acid; D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004151:Dipeptides; C118218:LY 379268; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D018094:Receptors, Metabotropic Glutamate; D013549:Sweetening Agents; C027172:isospaglumic acid; D018698:Glutamic Acid; D013395:Sucrose; D043425:Glutamate Carboxypeptidase II; D003042:Cocaine; D004298:Dopamine