Neurons also express inflammatory mediators and receptors that regulate immune and neuronal function (Oetjen et al., 2017; Veiga-Fernandes and Artis, 2018). For example, TLRs expressed on neuronal precursor cells mediate hippocampal neurogenesis (Rolls et al., 2007), and TLR4 activation in neuronal cultures initiates inflammatory responses in endothelial cells (Leow-Dyke et al., 2012). Inflammatory molecules and receptors localized in neurons also regulate ethanol drinking. For example, ethanol treatment induces neuronal expression of HMGB1, which can then activate glial and neuronal TLRs to stimulate pro-inflammatory cytokine production (Crews et al., 2013). As previously mentioned, conditional deletion of IKKβ in a primarily neuronal population in the NAc or CeA reduces voluntary ethanol intake and preference in mice and corroborates findings using a pharmacological inhibitor of IKKβ (Truitt et al., 2016). Furthermore, silencing neuronal Tlr4 or Ccl2 in the CeA and VTA regulates binge drinking in P rats (June et al., 2015). PPAR isotypes are also strongly expressed in neurons of several brain regions relevant to addiction (Warden et al., 2016), providing further evidence that the effects of PPAR agonists on ethanol consumption (Blednov et al., 2014a; Ferguson et al., 2014) may be mediated through neuronal PPARs.
