Alcoholism is a serious condition that affects the lives of millions of Americans, but successful treatment has been elusive. Some medications are currently approved for treatment, but they lack widespread efficacy, which in some cases is due to pharmacogenetic interactions. Future research must continue to identify potential targets for medications development, and address factors that influence response to pharmacotherapy. Brain stress systems can influence alcohol consumption and alcohol seeking in both humans and animal models. In rodents, exposure to stress results in the release of substance P (SP) and activation of its neurokinin 1 receptor {NK1R), and NK1R blockade suppresses alcohol seeking and consumption. The efficacy of NK1R antagonists is enhanced in alcohol preferring rats, which we have shown to have an upregulated NK1R system. One outstanding question is whether this NK1R system hypersensitivity is a predisposing factor for alcoholism, results from chronic alcohol exposure, or both. This proposal will directly address this question by determining if NK1R expression is increased following chronic alcohol exposure, and rf this associates with increased alcohol seeking behavior that is sensitive to NK1R antagonism. The findings of these experiments will have a significant impact on clinical treatment, as they will identify if NK1R antagonism would be beneficial for most alcoholics with long term history of abuse, or if the efficacy of this drug would be confined to a portion of the population that exhibits NK1R hypersensitivity. While the role of NK1R in alcohol seeking and consumption is well documented, less is known about underlying intracellular signaling mechanisms. The NK1R induces the activity of the transcription factor Nuclear Factor kappa B (NFkB), which serves as a transcriptional modulator for a wide range of genes. This transcription factor is activated in rodents both by stressors and alcohol, and therefore is an intriguing target for influencing NK1 R-mediated stress-alcohol interactions. In the studies outlined here, I will first describe the relationship between NK1R and NFkB activation following alcohol exposure, and determine the downstream behavioral effects that result from this interaction, such as withdrawal anxiety and alcohol reward. NK1R and NFkB also regulate morphine-induced behaviors, suggesting that agents targeting these systems could be useful treatments for alcohol, opiate, and polysubstance abuse. This has important therapeutic implications, since polysubstance abuse is very common in drug dependent individuals. As a transition grant, training was a major component of the K99 phase. In addition to the research aims described above, this proposal was designed to facilitate my transition from mentored post-doctoral research fellow to independent, tenure track research faculty at an academic institution. During the mentored phase, 1 learned new techniques in molecular biology including electromobility shift assays, which will enhance my ability to answer scientific questions on multiple levels. Outside of this important scientific training, I gained experience in project management, student mentorship, grant writing, and scientific communication. The mentored phase of this grant was highly successful, resulting in the publication of several peer-reviewed manuscripts, providing beneficial training, and helping to set me up -for future success. A primary goal of the mentored year was to obtain a tenure track assistant professor position, and this was accomplished. In January 2014,1 will begin a position as an Assistant Professor in the Department of Physiology and Pharmacology at the University of Georgia.