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Abstract
Alcoholism is one of the most prevalent psychiatric disorders not only in the United States, but worldwide. Despite its prevalence, less than 10% of those diagnosed with alcohol use disorder (AUD) receive treatment each year. Alcoholism is a chronic, relapsing disorder that is vastly heterogenous in nature, with a combination of biological, environmental, and genetic factors all contributing to its development. As such, identifying treatments that are successful in subgroups of alcoholics, perhaps determined by their psychiatric comorbidities, may be an effective approach. In this report, we explore the transcription factor nuclear factor kappa light chain enhancer of activated B cells (NFkB) and the neurokinin-1 receptor (NK1R) in the processes underlying alcoholism and its comorbidity with depression. Using conditioned place preference and Daun02 selective inactivation, we report that NFkB is activated in the nucleus accumbens (NAC) shell during alcohol place conditioning, and that inactivation of NFkB-expressing cells in this region during conditioning attenuates alcohol CPP. This data indicates that NFkB has a functional role in the rewarding effects of alcohol. We then shifted our focus to processes underlying alcoholism and depression comorbidity. Our group has previously found that forced chronic alcohol exposure via intragastric gavage increases sensitivity to social defeat stress (SDS). However, it is unknown if voluntary intermittent ethanol access (IEA) has the same effect. We found that, like alcohol gavage, voluntary consumption on an IEA schedule increases sensitivity to SDS. We also assessed effects of IEA and chronic alcohol gavage on components of the NFkB pathway and found that both of these alcohol exposures increase NFkB in the central nucleus of the amygdala (CEA). Lastly, we explored the role of the NK1R in the behavioral phenotypes induced by SDS, including decreased social interaction and increased alcohol consumption. We found that NK1R antagonism prior to defeat sessions protected against the decrease in social interaction, but not increased alcohol consumption, following chronic SDS. In addition, overexpression of NK1R in the NAC shell increased sensitivity to SDS. Together, these data support the further investigation of NFkB and NK1R as potential pharmacotherapeutic targets for alcoholism and its comorbidity with depression.