title: Oral administration of the NAALADase inhibitor GPI-5693 attenuates cocaine-induced reinstatement of drug-seeking behavior in rats.
abstract: We have recently reported that the endogenous mGlu2/3 agonist N-acetylaspartylglutamate (NAAG) and the N-acetylated-alpha-linked-acidic dipeptidase (NAALADase, a NAAG degradation enzyme) inhibitor 2-PMPA significantly inhibit cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior by attenuating cocaine-enhanced extracellular dopamine and glutamate in the nucleus accumbens. However, the poor oral bioavailability of NAAG and 2-PMPA limits their practical use in humans. In the present study, we investigated the effects of the orally active NAALADase inhibitor GPI-5693 and its enantiomers on cocaine-taking and cocaine-seeking behaviours. We found that oral administration of GPI-5693 (15, 30, 60 mg/kg, p.o.) did not significantly alter intravenous cocaine self-administration under fixed-ratio (FR2) reinforcement, but significantly inhibited cocaine-induced reinstatement of the extinguished drug-seeking behavior. This inhibition was blocked by pretreatment with LY341495, a selective mGlu2/3 receptor antagonist. Pretreatment with the same doses (15, 30, 60 mg/kg, p.o.) of GPI-16476 or GPI-16477, two enantiomers of GPI-5693, also inhibited cocaine-induced reinstatement similar to GPI-5693. In contrast, GPI-5693 altered neither oral sucrose self-administration nor sucrose-triggered reinstatement of sucrose-seeking behavior. These data suggest that orally effective NAAG peptidase inhibitors deserve further study as potential agents for the treatment of cocaine addiction.
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Peng
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Eliot L
authors.initials: EL
authors.lastname: Gardner
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: Ajit
authors.initials: A
authors.lastname: Thomas
authors.forename: Krystyna
authors.initials: K
authors.lastname: Wozniak
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: Zheng-Xiong
authors.initials: ZX
authors.lastname: Xi
mesh_terms: D000284:Administration, Oral; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D004151:Dipeptides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D005977:Glutarates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism; D012201:Reward; D012646:Self Administration; D013237:Stereoisomerism; D013395:Sucrose / Q000008:administration & dosage / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D014966:Xanthenes / Q000494:pharmacology
chemical_list: C474576:2-(3-mercaptopropyl)pentanedioic acid; D000596:Amino Acids; D004151:Dipeptides; D004791:Enzyme Inhibitors; D005977:Glutarates; C114624:LY 341495; D018094:Receptors, Metabotropic Glutamate; D013438:Sulfhydryl Compounds; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C027172:isospaglumic acid; D013395:Sucrose; D043425:Glutamate Carboxypeptidase II; D003042:Cocaine