Neuroimmune signaling: a key component of alcohol abuse

Abstract

Molecular and behavioral studies corroborate a pivotal role for the innate immune system in mediating the acute and chronic effects of alcohol and support a neuroimmune hypothesis of alcohol addiction. Changes in expression of neuroimmune genes and microglial transcripts occur in post-mortem brain from alcoholics and animals exposed to alcohol, and null mutant animals lacking certain innate immune genes show decreased alcohol-mediated responses. Many of the differentially expressed genes are part of the toll like receptor signaling pathway and culminate in increased expression of pro-inflammatory immune genes. Compounds known to inhibit inflammation, microglial activation, and neuroimmune gene expression have shown promising results in reducing alcohol-mediated behaviors in animal models, indicating that neuroimmune signaling pathways offer unexplored targets in the treatment of alcohol abuse.

Opportunities for the Development of Neuroimmune Therapies in Addiction

“…Interestingly, despite its inability to antagonize opioid receptors, (+) naloxone was found to reduce stimulant-induced locomotor activity (Chatterjie, Alexander, Sechzer, & Lieberman, 1996;Chatterjie, Sechzer, Lieberman, & Alexander, 1998), which is congruent with findings suggesting that TLR4 contributes to the acute effects of drugs of abuse (Hutchinson et al, 2012) and the ability of opioid receptor antagonists to affect such responses (Wu et al, 2012). The activation of TLR4 predominantly contributes to glial activation and the subsequent release of numerous proinflammatory cytokines (Mayfield et al, 2013). Importantly, these TLR4-related processes are involved in the behavioral and neuroinflammatory effects of drugs of abuse (Mayfield et al, 2013), as TLR4 activation has been shown to be integral to alcohol-induced glial activation and proinflammatory signaling (Alfonso-Loeches, Pascual-Lucas, Blanco, Sanchez-Vera, & Guerri, 2010;Blanco, Pascual, Valles, & Guerri, 2004;Blanco, Valles, Pascual, & Guerri, 2005;Fernandez-Lizarbe, Pascual, & Guerri, 2009), as well as alcohol's behavioral effects in rodents (Wu et al, 2012).…”

“…Several studies have demonstrated that neuroinflammation plays a role in alcohol use and abuse, with chronic alcohol use being associated with microglia activation and increased innate immune cell signaling (Mayfield, Ferguson, & Harris, 2013). Glial cell line-derived neurotrophic factor (GDNF) is a protein that is essential for the maintenance and survival of dopamine (DA) neurons (Boger et al, 2006) and can inhibit microglial activation (Rocha, Cristovão, Campos, Fonseca, & Baltazar, 2012).…”

“…The activation of TLR4 predominantly contributes to glial activation and the subsequent release of numerous proinflammatory cytokines (Mayfield et al, 2013). Importantly, these TLR4-related processes are involved in the behavioral and neuroinflammatory effects of drugs of abuse (Mayfield et al, 2013), as TLR4 activation has been shown to be integral to alcohol-induced glial activation and proinflammatory signaling (Alfonso-Loeches, Pascual-Lucas, Blanco, Sanchez-Vera, & Guerri, 2010;Blanco, Pascual, Valles, & Guerri, 2004;Blanco, Valles, Pascual, & Guerri, 2005;Fernandez-Lizarbe, Pascual, & Guerri, 2009), as well as alcohol's behavioral effects in rodents (Wu et al, 2012). Furthermore, in rodents, naltrexone attenuates proinflammatory TLR4-related signaling (Hutchinson et al, 2011) and blocks ethanolinduced glial activation and neuronal death (Qin & Crews, 2012), while (+) naloxone reduces acute alcohol-induced sedation and motor impairment (Wu et al, 2012).…”

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

“…Similarly, acute EtOH exposure–induced endotoxin responses are reduced by antibiotic treatment reducing gut bacteria (Rivera et al., 1998). Increased systemic endotoxin and blood cytokines impact brain cytokines and microglia (Mayfield et al., 2013). It is possible our CORT response to stress is maximal, preventing further increases by endotoxin or other mechanisms.…”

“…Innate immune signaling cytokines alter EtOH consumption (Marshall et al., 2017, 2017), and cytokine receptors contribute to stress‐induced EtOH consumption (Karlsson et al., 2017). Further, immune signaling molecules are increased in postmortem human alcoholic brain (Crews et al., 2017) and regulate preference for alcohol drinking in animal studies (Mayfield et al., 2013). Cytokines also enhance stressful emotional states following alcohol withdrawal (Breese et al., 2008).…”