Chronic administration of cocaine to rodents results in a progressive enhancement in the drug's motor-stimulating effects. The neurobiological mechanisms that underlie these observed behavioral changes are not well understood. However, the dopaminergic system plays a critical role in the long-term changes that occur after chronic exposure to cocaine. How dopamine exerts its long-term effects is unknown but the discovery that dopaminergic agonists both direct (apomorphine) and indirect (cocaine) induce the expression of a family of genes called immediate early genes (IEGs) may offer new insights. These IEGs, for example, c-fos and c-jun, are known to encode transcriptional activating (or inhibiting) factors that in turn alter the expression of other genes. It is these alterations in gene expression that likely underlie the long term behavioral changes that occur after chronic drug exposure. Pharmacogenetic techniques have proven to be valuable tools for examining the neurochemical mechanisms which underlie and contribute to drug response. However, researchers that have searched for differences in measures such as enzyme and receptor protein levels have met with limited success as far as explaining observed strain differences in more complex, multigenic phenotypes such as response to chronic drug treatment. An individual's response to chronic cocaine exposure is undoubtedly due to changes in a number of neurobiological parameters. Because the IEGs are the link between extracellular signals, such as drug exposure, and long- term adaptive changes that require alterations in gene expression in a number of systems, we have recently begun examining the effects of both acute and chronic cocaine administration on the expression of three IEGs, c-fos, c-jun and zif268, in several inbred strains of mice that have been shown to differ in their initial sensitivity to cocaine. It is possible, first, that there may be strain differences in the expression of these transcription factors that could explain observed strain differences in drug response and/or second, that examination of these transcriptional regulatory pathways may yield insights into which target proteins are being affected by chronic drug exposure.