IL-1β, indicating it can function in a non-inflammatory neuromodulatory role (Schneider et al., 1998). The cytokine IL-6 has crucial roles in neurogenesis and overall brain function (Erta et al., 2012). TNF-α regulates activity-dependent synaptic scaling (Stellwagen and Malenka, 2006) and synaptic strength through reorganization of corticostriatal circuits (Lewitus et al., 2014). Pro-inflammatory immune signaling also has neuroexcitatory effects; for example, TNF-α modulates expression of AMPA and NMDA receptors, decreases neuronal GABAA receptor expression (Olmos and Lladó, 2014), inhibits astrocytic glutamate uptake (Tilleux and Hermans, 2007), and increases astrocytic glutamate re-lease (Habbas et al., 2015). IL-6 suppresses inhibitory transmission by reducing GABA-A and glycine receptor function (Kawasaki et al., 2008). Intranigral injection of the pro-inflammatory cytokine C-C motif chemokine ligand 2 (CCL2) increases striatal dopamine release, and prolonged exposure to CCL2 increases excitability of dopaminergic neurons (Guyon et al., 2009). Thus, different immune molecules in the brain regulate neuronal excitability and plasticity, processes also critical in AUD. A chronic imbalance of neuroimmune signaling may contribute to the development of maladaptive addictive behaviors.
