title: Glutamate carboxypeptidase II (GCPII) inhibitor 2-PMPA reduces rewarding effects of the synthetic cathinone MDPV in rats: a role for N-acetylaspartylglutamate (NAAG).
abstract: BACKGROUND
  Metabotropic glutamate 2 and 3 (mGluR2/3) receptors are implicated in drug addiction as they limit excessive glutamate release during relapse. N-acetylaspartylglutamate (NAAG) is an endogenous mGluR2/3 agonist that is inactivated by the glutamate carboxypeptidase II (GCPII) enzyme. GCPII inhibitors, and NAAG itself, attenuate cocaine-seeking behaviors. However, their effects on the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) have not been examined.
  
  
  OBJECTIVE
  We determined whether withdrawal following repeated MDPV administration alters GCPII expression in corticolimbic regions. We also examined whether a GCPII inhibitor (2-(phosphonomethyl)-pentanedioic acid (2-PMPA)), and NAAG, reduce the rewarding and locomotor-stimulant effects of MDPV in rats.
  
  
  METHODS
  GCPII was assessed following repeated MDPV exposure (7 days). The effects of 2-PMPA and NAAG on acute MDPV-induced hyperactivity were determined using a locomotor test. We also examined the inhibitory effects of 2-PMPA and NAAG on MDPV-induced place preference, and whether the mGluR2/3 antagonist LY341495 could prevent these effects.
  
  
  RESULTS
  MDPV withdrawal reduced GCPII expression in the prefrontal cortex. Systemic injection of 2-PMPA (100 mg/kg) did not affect the hyperactivity produced by MDPV (0.5-3 mg/kg). However, nasal administration of NAAG did reduce MDPV-induced ambulation, but only at the highest dose (500 μg/10 μl). We also showed that 2-PMPA (10-30 mg/kg) and NAAG (10-500 μg/10 μl) dose-dependently attenuated MDPV place preference, and that the effect of NAAG was blocked by LY341495 (3 mg/kg).
  
  
  CONCLUSIONS
  These findings demonstrate that MDPV withdrawal produces dysregulation in the endogenous NAAG-GCPII signaling pathway in corticolimbic circuitry. Systemic administration of the GCPII inhibitor 2-PMPA, or NAAG, attenuates MDPV reward.
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA, 19140, USA.|Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Callum
authors.initials: C
authors.lastname: Hicks
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA, 19140, USA.|Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Gregg
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA, 19140, USA.|Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Sunil U
authors.initials: SU
authors.lastname: Nayak
authors.affiliation: Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Lee Anne
authors.initials: LA
authors.lastname: Cannella
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA, 19140, USA.|Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Giana J
authors.initials: GJ
authors.lastname: Schena
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA, 19140, USA.|Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Tallarida
authors.affiliation: Fox Chase Chemical Diversity Center, Doylestown, PA, USA.
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
authors.affiliation: Fox Chase Chemical Diversity Center, Doylestown, PA, USA.
authors.forename: Garry R
authors.initials: GR
authors.lastname: Smith
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA, 19140, USA. scott.rawls@temple.edu.|Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA. scott.rawls@temple.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Rawls
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D052117:Benzodioxoles / Q000008:administration & dosage*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology; D012201:Reward; D014966:Xanthenes / Q000494:pharmacology; D000094982:Synthetic Cathinone
chemical_list: C402107:2-(phosphonomethyl)pentanedioic acid; D000470:Alkaloids; D000596:Amino Acids; D052117:Benzodioxoles; D004151:Dipeptides; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D009943:Organophosphorus Compounds; D011759:Pyrrolidines; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C027172:isospaglumic acid; C023665:cathinone; D043425:Glutamate Carboxypeptidase II; D000094982:Synthetic Cathinone
keywords: 2-PMPA; Glutamate; MDPV; NAAG; Reward; Synthetic cathinone