REGULATION OF AXON GUIDANCE MOLECULE GENES: RELEVANCE TO BRAIN ADAPTATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Axon guidance molecules (AGMs) including semaphorins, ephrins, netrins and their receptors are important contributors to nervous system development and neuroadaptation. We previously demonstrated the presence of AGMs in adult primate brain. The current study investigated the hypothesis that changes in cAMP may promote changes in gene expression of AGMs, thereby linking drug-induced neuroadaptation with receptor-mediated events. Results: Using real time PCR, we detected endogenous expression of several AGMs and the D1 dopamine receptor, an indirect target of cocaine, in the SK-N-MC human neuroepithelioma cell line. Treatment of SK-N-MC cells with 10uM forskolin (N=5) to increase intracellular cAMP resulted in increased expression of EphA5, EphB2 and Neuropilin1, of 14 genes tested. The magnitude and direction of regulation for these 3 genes paralleled the findings of Bahi and Dreyer (2005) in the rat hippocampus after cocaine. In contrast, exposure of SK-N-MC cells to the dopamine receptor agonist dihydrexidine (10uM; N=5) resulted in up-regulation of EphrinA1 and down-regulation of EphrinA5, EphB1, DCC and Sema3C. Discussion: Conceivably, cocaine modifies AGM expression by blocking monoamine transporters, thereby indirectly activating monoamine receptors and altering cAMP production. AGM gene expression may be regulated, in part, by changes in cAMP and other signal transduction pathways, potentially linking receptor activation to AGM transcriptional regulation. These preliminary data offer a novel mechanism by which drugs may modify AGM expression to promote drug-induced neuroadaptation in adult brain which may be of potential relevance to addiction and the development of medications.