title: Induction of innate immune genes in brain create the neurobiology of addiction.
abstract: Addiction occurs through repeated abuse of drugs that progressively reduce behavioral control and cognitive flexibility while increasing limbic negative emotion. Recent discoveries indicate neuroimmune signaling underlies addiction and co-morbid depression. Low threshold microglia undergo progressive stages of innate immune activation involving astrocytes and neurons with repeated drug abuse, stress, and/or cell damage signals. Increased brain NF-κB transcription of proinflammatory chemokines, cytokines, oxidases, proteases, TLR and other genes create loops amplifying NF-κB transcription and innate immune target gene expression. Human post-mortem alcoholic brain has increased NF-κB and NF-κB target gene message, increased microglial markers and chemokine-MCP1. Polymorphisms of human NF-κB1 and other innate immune genes contribute to genetic risk for alcoholism. Animal transgenic and genetic studies link NF-κB innate immune gene expression to alcohol drinking. Human drug addicts show deficits in behavioral flexibility modeled pre-clinically using reversal learning. Binge alcohol, chronic cocaine, and lesions link addiction neurobiology to frontal cortex, neuroimmune signaling and loss of behavioral flexibility. Addiction also involves increasing limbic negative emotion and depression-like behavior that is reflected in hippocampal neurogenesis. Innate immune activation parallels loss of neurogenesis and increased depression-like behavior. Protection against loss of neurogenesis and negative affect by anti-oxidant, anti-inflammatory, anti-depressant, opiate antagonist and abstinence from ethanol dependence link limbic affect to changes in innate immune signaling. The hypothesis that innate immune gene induction underlies addiction and affective disorders creates new targets for therapy.
authors.affiliation: Bowles Center for Alcohol Studies, Department of Pharmacology and Psychiatry, The School of Medicine, The University of North Carolina at Chapel Hill, 1021 Thurston-Bowles Building, CB #7178, Chapel Hill, NC 27599-7178, USA. fulton_crews@med.unc.edu
authors.forename: F T
authors.initials: FT
authors.lastname: Crews
authors.forename: Jian
authors.initials: J
authors.lastname: Zou
authors.forename: Liya
authors.initials: L
authors.lastname: Qin
mesh_terms: D016739:Behavior, Addictive / Q000276:immunology* / Q000378:metabolism; D001921:Brain / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015213:Neuroimmunomodulation; D019966:Substance-Related Disorders / Q000235:genetics / Q000276:immunology* / Q000378:metabolism