The immune system, in turn, can modulate the activity of the HPA axis. For instance, IL-1 induces HPA axis activation and glucocorticoid release that suppresses the immune system (Sapolsky, Rivier et al. 1987). Cultures of neonatal rat PVN show norepinephrine-induced CRH release is regulated by IL-1 signaling (Hsieh, Li et al. 2010) and in male rat PVN slices, IL-1β depolarized magnocellular and parvocellular neurons (Ferri and Ferguson 2003, Ferri, Yuill et al. 2005), suggesting that cytokines could impact the stress response at the level of CRH neurons in the hypothalamus. Cytokines are also proposed to cross the blood-brain barrier and produce sickness behavior (Watkins, Maier et al. 1995), which is comorbid with AUD (Dantzer, Bluthe et al. 1998). Ethanol administration (4g/kg) in male rats increased IL-6 but decreased TNF-α expression in PVN, an effect that was blunted or reversed after long-term ethanol self-administration (Doremus-Fitzwater, Buck et al. 2014). Cytokines can also modulate important behavioral functions including learning and memory (Hao, Jing et al. 2014) possibly due to their role in neuroplasticity (Sheridan, Wdowicz et al. 2014). Many gaps remain in
