Behavioral sensitization can be initiated by repetitive stress or stimulant drug administration. Our laboratory has recently cloned and sequenced a glucocorticoid-induced receptor (GIR) cDNA from rat prefrontal cortex in a stress model of learned helplessness. The full-length GIR cDNA encodes a protein belonging to the G protein-coupled receptor superfamily, whose ligand is unknown. This protein shares 31 percent-34 percent amino acid identity to the tackykinin receptors NK-1, NK-2, NK-3. As regulation of neuronal gene expression is hypothesized to be one mechanism by which amphetamine leads to long-term behavioral sensitization, we propose to explore the relationship of GIR to the initiation or maintenance of sensitization. Our preliminary studies demonstrate that chronic amphetamine administration results in elevated expression of GIR in rat prefrontal cortex, which persists long-term (7 days) following drug discontinuing. These findings lead us to hypothesize that modulation of GIR expression may be involved in the physiological regulation and neuroadaptation in the addictive process. This proposal will determine the time-dependent and region-specific expression of GIR in rats sensitized to amphetamine, explore the cellular localization of GIR through in situ hybridization and immunocytochemistry, and generate a transgenic mouse model overexpressing rat GIR.
