Discriminative stimulus effects of NMDA AMPA and mGluR5 glutamate receptor ligands in methamphetamine-trained rats

摘要

Glutamate contributes to the reinforcing and stimulant effects of methamphetamine, yet its potential role in the interoceptive stimulus properties of methamphetamine is unknown. In the current study, adult male Sprague-Dawley rats were trained to discriminate methamphetamine (1.0 mg/kg, i.p.) from saline in a standard operant discrimination task. The effects of methamphetamine (0.1-1.0 mg/kg, i.p.), the N-methyl-D-aspartate (NMDA) receptor channel blockers MK-801 (0.03-0.3 mg/kg, i.p.) and ketamine (1.0-10.0 mg/kg, i.p.), the low-affinity NMDA antagonist memantine (1.0-10 mg/kg, i.p.), the polyamine site NMDA receptor antagonist ifenprodil (1-10 mg/kg), the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1-10 mg/kg, i.p.), and the metabotropic 5 (mGluR5) receptor antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP; 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), CNQX (5.6 mg/kg) and MPEP (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; pretreatment with 3 mg/kg of ketamine, for example, decreased the ED50 value for methamphetamine by half. These results suggest that blockade of the NMDA receptor augments the interoceptive stimulus properties of methamphetamine.