SCHEDULE-CONTROLLED BEHAVIORAL-EFFECTS OF THE SELECTIVE AMINO-3-(5-METHYL-3-HYDROXYISOXAZOL-4-YL)PROPANOIC ACID ANTAGONIST LY293558 IN PIGEONS

Behavioral effects of the selective 2-amino-3-(5-methyl-3-hyd roxyisox azol-4-yl)propane acid (AMPA) antagonist LY293558, along with its race mate (LY215490) and opposing enantiomer (LY293559) were evaluated in p igeons. When responding was maintained under a multiple fixed ratio 50 responses, fixed interval 5 minute (FRFI) schedule of food presentati on, LY215490 completely antagonized the rate suppression induced by AM PA (10 mg/kg) and by the AMPA analog, -amino-3-hydroxy-5-tert-butyl-4- isoxazolepropionic acid (ATPA; 40 mg/kg) at 1.25 and 2.5 mg/kg, respec tively. in contrast, LY215490, up to 10 mg/kg, was unable to antagoniz e the rate suppression induced by N-methyl-D-aspartic acid. LY293558, at 0.32 mg/kg, completely blocked the rate suppression produced by AMP A in both components of the multiple schedule. Similarly, LY293558, at 0.64 mg/kg, blocked the rate suppression induced by ATPA in both comp onents. In contrast, the opposing enantiomer, LY293559, up to 10 mg/kg , was without effect on rate suppression produced by AMPA in this mode l. In additional studies, behavior was maintained under a schedule in which responding was maintained by food presentation in the presence o f one key color and in the presence of a second key color, responding was maintained by food and simultaneously suppressed by electric shock (''punished responding''). LY215490 significantly increased punished responding at In and 30 mg/kg, whereas unpunished responding was unaff ected until 56 mg/kg depressed it. LY293558 significantly increased pu nished responding at 3 mg/kg without having an effect on unpunished re sponding. LY293559, oh the other hand, was unable to significantly inc rease punished responding at doses up to 175 mg/kg. This 175 mg/kg dos e also had very little effect on unpunished responding. The results of these experiments suggest that LY293558 is an antagonist at those glu tamate receptors activated by AMPA. Additionally, those compounds that act as antagonists at the AMPA subtype of glutamate receptor produce increases in punished responding in pigeons.