title: Discriminative stimulus effects of NMDA, AMPA, and mGluR5 glutamate receptor ligands in methamphetamine-trained rats.
abstract: Glutamate contributes to the reinforcing and stimulant effects of methamphetamine, yet its potential role in the interoceptive stimulus properties of methamphetamine is unknown. In this study, adult male Sprague-Dawley rats were trained to discriminate methamphetamine [1.0 mg/kg, intraperitoneally] from saline in a standard operant discrimination task. The effects of methamphetamine (0.1-1.0 mg/kg, intraperitoneally); N-methyl-D-aspartate (NMDA) receptor channel blockers, MK-801 (0.03-0.3 mg/kg, intraperitoneally) and ketamine (1.0-10.0 mg/kg, intraperitoneally); polyamine site NMDA receptor antagonist, ifenprodil (1-10 mg/kg); α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (1-10 mg/kg, intraperitoneally); and metabotropic 5 glutamate receptor antagonist, 6-methyl-2-(phenylethynyl)pyridine (1-10 mg/kg), given alone were determined in substitution tests. The effects of MK-801 (0.03 and 0.1 mg/kg), ketamine (1.0 and 3.0 mg/kg), ifenprodil (5.6 mg/kg), 6-cyano-7-nitroquinoxaline-2,3-dione (5.6 mg/kg), and 6-methyl-2-(phenylethynyl)pyridine (5.6 mg/kg) were also tested in combination with methamphetamine to assess for alterations in the methamphetamine cue. In substitution tests, none of the test drugs generalized to the methamphetamine cue. However, ketamine and ifenprodil produced significant leftward shifts in the methamphetamine dose-response curve. In addition, the potention by MK-801 nearly attained significance. These results suggest that blockade of the NMDA receptor augments the interoceptive stimulus properties of methamphetamine.
authors.affiliation: Department of Psychology, College of Arts and Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wooters
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bardo
mesh_terms: D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects*; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D008024:Ligands; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D008694:Methamphetamine