Recovery of cognitive function after traumatic brain injury (TBD is a dynamic process that likely revolves multiple neural systems. Several studies by our laboratory and others indicate that cognitive recovery can be enhanced by post injury activation of dopaminergic systems or exposure to an enriched environment. The effectors of such therapeutic activation are likely to involve simultaneous gene expression changes m numerous neural systems. The recent development of DNA microarrays has allowed scientists for the first time the ability to observe thousands of gene expression changes in parallel. While there are limitations, DNA microarrays provide a new systemic view to study brain injury and the treatments that stimulate and enhance recovery of function. Recently, we have evaluated a number of DA agonists that are clinically used off label, for their ability to enhance recovery of cognitive function in our experimental model of TBI, and found three to be beneficial: amantadine hydroehloride, bromoeriptine, and methylphenidate. While all are putative dopaminergic agonists, they have varying degrees of specificity to DA systems. We have also observed that bromoeriptine treatment, when initiated 24 hours after TBI, can attenuate hippocampal cell death. This suggests that DA agonists may have mechanisms of action beyond just being DA replacement therapies (e.g. cell survival effects). In support of this concept, we have new pilot microarray data indicating that, relative to a vehicle treatment, the DA agonist methylphenidate treatment can enhance the gene expression of DA receptors, alter injury-induced inflammatory responses, and apoptosis related gene expression. DNA microarrays are well suited to investigate the effects of DA agonists on multiple pathways. The overall goal of the project is to determine common genes that are changed by these therapies and whether these gene expression changes can be further enhanced by the addition of enriched environment therapy. Tiffs exploratory R21 application (in response to RFA#HD-02-023) will obtain the preliminary information needed for a larger-scale R01 study to increase the number of cases, refine and increase the number of genes analyzed, and to more comprehensively study those genes whose expression are related to recovery of function after TBI.