The Neurokinin-1 Receptor as a Mediator of Alcoholism and Depression Comorbidity

Summary The extended amygdala is an interconnected network of mostly limbic system structures that regulates complex behaviors including stress responses, anxiety, social behavior, depression, and drug/alcohol seeking. The nucleus acccumbens (NAC) and amygdala are key hubs in this network, and these regions play an important role in integrating the effects of stress on motivated behavior. The neurokinin-1 receptor (NK1R) is the high affinity endogenous target of the neuropeptide substance P, and the NK1R is expressed throughout the extended amygdala, especially in the NAC and amygdala. The SP/NK1R system has been shown to influence neurophysiological and behavioral responses to stress and drugs of abuse. During the current funding period, we have identified a role of the NK1R in the NAC shell in the behavioral phenotypes and escalated alcohol consumption that are induced by the major stressor of social defeat stress (SDS). We have found that SP expressing projections to the NAC shell from the paraventricular thalamus (PVT) are activated during SDS exposure. Interestingly, we have also observed significant SP-expressing projections from the PVT to the central nucleus of the amygdala (CeA). Much of our prior work has focused on these two regions, the NAC shell and the CeA, in NK1R effects on escalated alcohol consumption and stress-induced alcohol seeking. In this renewal application, we will examine the characteristics of the PVT SP+ projections to the CeA and NAC shell, determining how these neurons are organized anatomically and the behavioral roles played by these discrete circuits. Additionally, we will use in vivo fiber photometry to examine the patterns of activation in these specific circuits during alcohol consumption. Finally, since chronic alcohol exposure induces neuroadaptations in stress-sensitive neurons, we will use translating ribosome affinity purification to isolate mRNA transcripts that are actively translating in SP cells and will assess cell type specific alterations in PVT gene expression following chronic alcohol exposure, determining in which SP-expressing pathways the identified genes of interest are expressed. This will also allow for a detailed assessment of transcriptional changes in these cells following chronic alcohol exposure, and will enable the detection of potential sex differences. Overall, these experiments will provide valuable information on the circuit and gene expression changes that mediate the response to alcohol, and will identify targets for the development of novel treatment strategies.