TRANSCRIPTION FACTORS MEDIATING OPIOID PLASTICITY

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The long range goals of this proposal are to better understand how neural activity regulates opioid gene expression, and to understand how these processes contribute to environmental and drug induced stable/adaptive changes in the nervous system. A better understanding of these processes will help to define the adaptive biochemical changes underlying addiction, withdrawal, and drugseeking behaviors. The primary objectives of this research proposal have not changed. The major focus is still to identify and characterize transcription factors which mediate activity-dependent regulation of proenkephalin gene expression via their interaction with a well characterized second messenger inducible DNA enhancer. Studies will focus on defining components the AP-l/ AP-4, and NF-l/ ZFX nucleoprotein complexes which mediate regulation of proenkephalin transcription. Functional and biochemical interactions with the proenkephalin inducible DNA enhancer and signals transmitted through intracellular signaling pathways will be investigated. Recent findings indicate that JunD activates proenkephalin transcription in a fashion which is completely dependent upon the cyclic-AMP dependent protein kinase (PKA), an effect which can be effectively blocked by JunB. We have increased our emphasis on understanding regulation by JunD/JunB in light of the above findings, and the recent discovery that drugs of abuse such as cocaine, amphetamine, and morphine regulate AP-1 (fos/jun complexes) expression in brain. Together, this analysis will define at the molecular level interactions between intracellular signaling pathways, transcription factors, and the DNA elements which regulate endogenous opioid signaling in response to neurotransmitters, drugs, and synaptic inputs.