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.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1. Neuroanatomical components of the neurobiology of addiction

A simplified schematic diagram of the human brain frontal-cortical and limbic circuitry that contribute to addiction. Shown are internal structures highlighted with projections indicated by arrows with the structure color. Frontal cortical brain regions select attention, monitor the environment and planning by assessing information and predicting outcomes (Schoenbaum et al. 2006; Schoenbaum and Shaham 2008). Limbic regions including the amygdala (AMG) and entorhinal cortex (ENT) also project to VS, from the temporal lobe. The harmful behaviors of severe alcohol, opiate and stimulant drug dependence involve changes in frontal lobes leading to loss of attention, poor decision making, and decreased cognitive flexibility as well as increased temporal lobe anxiety-negative affect urgency that promote the progressive loss of behavioral control over drug use. Frontal cortex regulation of limbic structures and communication with sensory thalamic input is glutamatergic. Glutamatergic hyperexcitability, due to disrupted innate immune gene induction (Zou and Crews 2005; Crews et al. 2006), inactivates frontal cortical responses (Gruber 2010). Temporal lobe limbic signaling involves GABAergic and peptidergic projection neurons that show increased bad feelings due to activation of innate immune genes in hippocampus and amygdale and loss of frontal cortical control increasing urgency-negative affect. Thus, innate immune gene induction in frontal and temporal lobes of brain disrupt neurocircuitry and signaling consistent with addiction.

Figure 2. Loops of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation of transcription increases chemokines-cytokines, oxidases and proteases

NF-κB is a key transcription factor involved in induction of innate immune genes (Ghosh and Hayden 2008). Stimuli such as stress, drugs, peptides chemokines, cytokines, reactive oxygen species, ultraviolet irradiation, bacteria, viruses, trauma and other factors increase NF-κB-DNA binding and transcription (Fig. 2). Reactive oxygen species (ROS) from oxidases such as NADPH-oxidase (NOX) or ethanol metabolism by Cyp2E1 increase NF-κB transcription of NOX2phox (gp91) a key NOX catalytic subunit (Cao et al. 2005) that produces ROS (Qin et al. 2008). Cytokines and chemokines, such as TNFα, IL1β, IL6 and MCP-1, as well as their receptors (TNFR in figure) are induced creating another amplification loop. Toll Like-Receptors (TLR) are increased by ethanol (Alfonso-Loeches et al. 2010) as are other damage-associated molecular pattern (DAMP) receptors and there agonists creating positive activation loops (Garg et al. 2010). TLR and HMGB1 create another activation-amplification loop. Persistent and repeated activation occurs through positive cycles of activation (+ loops). These loops spread innate immune signaling through paracrine and autocrine mechanisms across brain altering neurocircuitry and neurobiology.

Figure 3. Increased CCL2 in post-mortem human alcoholic brain, chronic alcohol treated mouse brain and ethanol treatment of rat hippocampal-entorhinal cortex (HEC) brain slices cultures

Left-MCP-1 protein levels from human brain homogenate contain increased MCP-1 in ventral tegmental area, substantia nigra, hippocampus and amygdala. (He and Crews 2008). Middle: Mouse Brain MCP-1 is increased by chronic ethanol treatment. Mice (C57Bl/6) were treated with10 daily doses of ethanol (5 gm/kg. i.g., (Qin et al. 2008). Shown are brain levels of MCP-1 in mice 8 days after chronic ethanol treatment Right: Rat Hippocampal HEC brain-slice cultures treated with ethanol for 4 days. Shown are MCP-1 and tPA. (Zou and Crews 2010). These studies indicate ethanol induces the innate immune chemokine MCP-1 in mouse and rat brain and suggest alcoholics induce MCP-1 through alcohol drinking. Elevated MCP-1 in post-mortem human alcoholic brain is consistent with ethanol activation of innate immune genes contributing to alcoholism.

Figure 4. Chronic alcohol self-administration induces depression-like behavior and inhibits hippocampal neurogenesis: reversal by the antidepressant Desipramine

C57BL/6J mice self-administered ethanol (10% v/v) or water for 28 days. Forced Swim Test (FST) immobility is an index of depression-like behavior. The increase in FST immobility reflects chronic alcohol induced depression-negative affect. Treatment with the antidepressant, Desipramine, reverses depression-like behavior, e.g. decreases immobility. (Middle) Ethanol decreases doublecortin (DCX+IR), a marker of neurogenesis. Desipramine treatment reverses ethanol DCX-neurogenesis. (Right) Pictures of DCX stain in water-control animals and alcohol animals. These findings are consistent with drug induced negative affect reflected in loss of neurogenesis and depression-like behavior. This figure is adapted from Stevenson (Stevenson et al. 2009).