Drug addiction, long-term memory and other lasting behavioral changes derive from plasticity of underlying neural circuits, driven by activity-regulated gene expression. Recent behavioral analyses demonstrate critical roles for two transcription factors, CREB and AP1 (usually a dimer of Fos and Jun) in regulating cocaine addiction. Induction of ?FosB, a dominant-negative Fos isoform, in rodent nucleus accumbens causes long-term behavioral sensitization and craving for cocaine; in contrast, induction of CREB reduces drug-reward by inducing adaptation to higher levels of cocaine. Despite the obvious importance of AP1 and CREB for behavioral plasticity, little is known about the mechanism of their action. The PI's recent observations are consistent with the unexpected, important hypothesis that AP1 acts upstream of CREB.at the top of the hierarchy of known plasticity-associated transcription factors. While testing this hypotheses, this proposal aims to: a) more completely elaborate cellular functions of AP1; and b) identify molecular mechanisms that operate upstream and downstream of AP1. Exploiting the convenience of Drosophila as an experimental organism for rapid and incisive experiments on conserved biochemical pathways that underlie synapse plasticity, the proposed experiments address an area of fundamental importance in synaptic remodeling events that underlie behavioral change. The work is particularly significant because it addresses the function of Fos and Jun, two critical regulators of drug addiction. In addition, by identifying AP1 and CREB-target genes proteins in neurons the program may help identify genes that confer predisposition to drug abuse or mood disorders in humans. Early AP1- response proteins may even provde to be new molecular markers of plasticity processes that underlie addiction. Finally, results from these experiments may identify and validate new molecules to targets for pharmacological therapy. The PI is an Associate Professor in a major undergraduate university with teaching and administrative commitments that limit the amount of effort the PI can contribute to research. These commitments are is particularly onerous at a stage when the PI is not only making substantial progress on current NIDA funded research, but also has an expanding program of promising and innovative research seeded in part by an NIDA CEBRA R21 grant. The PI is a relatively recent entry to the plasticity field and desires to bridge the gap between invertebrate and vertebrate work in neural plasticity addiction research. A K02 award would provide the PI additional time to: a) successfully perform funded research; b) stabilize a currently expanding program in plasticity research; and c) by interfacing with mammalian addiction researchers, help establish himself in the broad field of neural plasticity.
