Alcohol use disorder (AUD) negatively impacts the lives of millions of people in the United States each year. Major depressive disorder commonly co-occurs with AUD. Factors such as stress and inflammation may contribute to symptoms or development of these disorders. Substance P and its preferred receptor, the neurokinin-1 receptor (NK1R), are involved in both stress and inflammatory signaling. The following dissertation further characterizes the Substance P and the NK1R as a potential target for AUD. In an inflammatory model, lipopolysaccharide (LPS) administration induced significantly increased proinflammatory cytokine gene expression in both male and female mice, but only LPS-treated female mice had decreased social interaction measures, reflective of increased depressive-like behavior. LPS administration escalated alcohol consumption in both male and female mice. Systemic NK1R antagonism reduced alcohol consumption in the LPS-treated female mice but not the LPS-treated male mice. A model of vicarious defeat stress (VDS) in female mice induced increased depressive-like behaviors as measured by social interaction, expression of proinflammatory cytokine genes, and alcohol consumption. The alcohol consumption was significantly reduced with NK1R antagonist administration. To better understand the role of Substance P within the nucleus accumbens (NAC), a region important for reward and motivated behaviors, tract tracing, neuronal activation analysis, and chemogenetic modulation of the SP inputs to the NAC were performed. Of the regions which project SP to the NAC, the paraventricular nucleus of the thalamus projections were significantly activated by social defeat stress. Inhibition either chronically during social defeat stress or acutely prior to the behavior reduced alcohol consumption. Activation of SP inputs to the NAC increased alcohol consumption. Neither activation nor inhibition impacted social interaction behavior. Overall, this dissertation further validated a LPS and VDS model to study inflammation or stress in alcohol consumption and depressive-like phenotypes in female mice. Furthermore, the characterization of the SP and NK1R involvement in these behaviors in the NAC will improve general understanding of mechanisms which drive AUD. These findings support NK1R as a promising therapeutic target for AUD.
