Distinguished Professor at University of North Carolina School of Medicine, Chapel Hill

Neuroimmune Signaling creates the Neurobiology of Alcohol Dependence

Fulton T. Crews

Our experiments modeling alcoholic binge drinking have led to thae hypothesis that neuroimmune gene induction contributes to addiction neurobiology and neurodegeneration.  Neuroimmune genes are generally associated with monocyte innate immune responses, but are expressed in brain.  These genes include cytokines-chemokines, toll-like receptors (TLR), oxidases such as COX, NOX and iNOS, proteases and high mobility group box 1(HMGB1-amphoterin), an endogenous TLR4 agonist cytokine.  Neuroimmune genes share signaling mechanisms that activate NFkappaB, a transcription factor that increases expression of most neuroimmune genes and their receptors which further activate NFkappaB creating amplifying loops.  Multiple mechanisms can contribute to neuroimmune activation.  One mechanism involves acute high dose ethanol, stress or other factors that increase gut permeability leaking bacterial factors that activate liver innate immune genes that contribute to activation of brain responses.  Another mechanism involves neuronal excitation releasing HMGB1 from neurons that activate TLR4 and other receptors.  Genetic studies find NFkB as a central gene related to alcohol drinking and stimulant preferring transcriptomes in rodents.  Opiates also interact with TLR4 receptors and naltrexone, a pharmacotherapy for alcoholism, blocks HMGB1-TLR4 signaling. Transgenic mice lacking neuroimmune genes drink less alcohol and induction of neuroimmune genes with endotoxin in normal mice increases alcohol preference and drinking for months. Neuroimmune genes are hypothesized to disrupt frontal cortical circuits due to hyperexcitability, reducing behavioral flexibility and increasing negative affect increasing risks of abuse in heavy drinkers. 

An early age of drinking onset is associated with increased risk of alcohol dependence during the lifetime.  Adolescent binge drinking models find persistent and progressive increases in neuroimmune gene expression that last long into adulthood and are associated with alterations in choline acetyltransferase and tyrosine hydroxylase expression as well as a persistent loss of hippocampal neurogenesis.   Adolescent binge drinking exposure also leads to adult delayed discounting dysfunction, sleep disturbances, perseveration and a persistence of adolescent phenotype, perhaps defining an Adolescent Binge Alcohol Syndrome.  Studies of post-mortem human brain find alcoholics have increased neuroimmune gene expression in orbital frontal cortex.  HMGB1 and TLR expression in OFC correlates across all human subjects with age of drinking onset and lifetime alcohol consumption consistent with the progressive and persistent induction of neuroimmune signaling contributing to the chronic relapsing nature of dependence.  Neuroimmune signaling may be an important target for pharmacotherapies for dependence.