Transduction of a discriminative stimulus through a diazepam-insensitive gamma-aminobutyric acidA receptor

Although there appear to be a large number of possible isoforms of the gamma-aminobutyric acid (GABA)A receptor, the relationship of a particular isoform to a specific behavior or behavioral process has not been identified. In the present study we describe a functional role for a diazepam-insensitive (DI) isoform of the GABAA receptor in the control of a complex discrimination. Pigeons were trained to discriminate the benzodiazepine antagonist flumazenil (100 micrograms/kg) from vehicle by requiring 30 keypeck responses on one key when flumazenil was given and on a different key when vehicle was given. Only ligands with high affinities for DI sites fully substituted for the discriminative stimulus effects of flumazenil. A significant positive correlation was observed between ligand affinities for DI sites and ED50 values for discriminative stimulus effects. These compounds mimicked the discriminative stimulus effects of flumazenil despite partial agonist, inverse agonist or antagonist actions at other diazepam-sensitive GABAA receptors. A specific role of DI GABAA receptors in the control of this behavior was confirmed further by the inability of either a high-affinity agonist (midazolam) or antagonist (ZK 93,426) at diazepam-sensitive receptors (that possess low affinities for DI sites) to block the discriminative stimulus effects of flumazenil. These findings establish a link between a GABAA receptor isoform and a specific behavior.