Substance P innervation of the nucleus accumbens mediates alcohol consumption following chronic social stress.

Social defeat stress (SDS) is a rodent model used to assess the effect of chronic stress on depressive-like behavior and alcohol consumption. Our previous studies have indicated that the neurokinin-1 receptor (NK1R) mediates the behavioral responses to this stressor, especially through its actions in the nucleus accumbens (NAc). The NK1R is the high affinity, endogenous target of the neuropeptide substance P (SP). In the experiments presented here, we first infused a cre-dependent, retrogradely transported virus into the NAc of Tac1-cre mice (Tac1 is the gene for SP) to identify brain regions that send SP-expressing inputs to the NAc. We found that significant SP projections originated in the paraventricular nucleus of the thalamus (PVT). Next, we used this same tracing strategy, exposed mice to SDS or control conditions, and assessed Fos expression in the PVT. This experiment confirmed that SP projections from the PVT to the NAc are activated by SDS. To chemogenetically manipulate SP innervation of the NAc, we bilaterally infused a cre-dependent, retrogradely transported virus that expresses an inhibitory DREADD receptor into the NAc of Tac1-cre mice and delivered the DREADD actuator clozapine-n-oxide (CNO) prior to each defeat exposure. We found that this treatment had no effect on SDS-induced social avoidance, but did reduce alcohol consumption after stress. In a following experiment, CNO was administered just prior to behavioral testing, as opposed to during stress. In line with the previous experiment, chemogenetic inhibition affected post-stress drinking, but not social interaction. Conversely, chemogenetic activation of these inputs acutely increased alcohol consumption without affecting social behavior. Together, these results show that SP projections from the PVT to the NAc are activated by SDS exposure, and suggest that SP innervation of the NAc, possibly from the PVT, mediates post-stress alcohol consumption.