Immune function genes, genetics, and the neurobiology of addiction.

Activation of microglia and astrocytes by alcohol in the brain. Microglia and astrocytes undergo multiple stages of activation that include characteristic changes in morphology. Resting microglia become ramified microglia with that express molecules called major histocompatibility complex (MHC) on their surface. Similarly, astrocytes begin to show markers of reactive astrocytes. Alcohol-induced glial activation is associated with increased expression of innate immune genes, including increased expression of the chemokine monocyte chemoattractant protein-1 (MCP1); the cytokines tumor necrosis factor-α (TNFα), interleukin-1 β (IL-1β), and interleukin-6 (IL-6); the proteases matrix metalloproteinase (MMP) and tissue plasminogen activator (TPA); and the oxidases nicotinamide adenine dinucleotide phosphate oxidase (NOX), cyclooxygenase (COX), and nitric oxide synthetase (NOS). The alcohol-induced activation of glial innate immune genes increases neuronal hyperexcitability (Crews et al. 2011).

Mechanisms of alcohol-induced excessive glutamate activity in the cortex and loss of cortical focus. Ethanol-induced activation of microglia and astrocytes increases the levels of proinflammatory cytokines, including tumor necrosis factor-alpha (TNFα). (Left panel) TNFα creates a state characterized by excess activity of the neurotransmitter glutamate (i.e., a hyperglutamate state). Thus, TNFα reduces the levels of the primary glutamate transporters, GLT-1, in the astrocytes, in the cerebral cortex, and inhibits glutamate transport, possibly through induction of TNFα and other proinflammatory genes. As a result, glutamate levels outside the neurons, and particularly at the synapse, increase, resulting in a hyperglutamate state. In addition, TNFα increases the levels of certain molecules that interact with glutamate (i.e., AMPA receptors). All these processes causes excessive neuronal excitability. (Right panel) Hyperexcitability disrupts cortical focus. The left image shows the response of a normal adult auditory cortex to a series of tones with a frequence of 2–32 kHz colorized as blue to red. The response to a specific tone involves activation of a specific focal cortical region, which likely relates to the ability to distinguish specific tones of sounds. The right image shows the disrupted hyperglutamate-state–like response to sound that involves the entire auditory cortex without specific tonal areas of focus. The hyperglutatamate state increases cortical excitability, which in turn decreases function because it results in loss of focal activation and likely loss of tonal discrimination. In alcoholism, the hyperglutamate state most strongly affects the frontal cortex, which may disrupt decision making as well as attention and behavioral control mechanisms.SOURCE: Image in right panel adapted from Chang and Merzenich (2003).

Innate immune gene polymorphisms associated with risk for alcoholism. The schematic shows a representative astrocyte or microglial cell. Genes associated with genetic risk for alcoholism are in light blue. Nuclear factor κ-lightchain–enhancer of activated B cells (NF-κB) is a key transcription factor involved in induction of innate immune genes that is sensitive to reactive oxygen species (ROS). These ROS are generated by the enzyme CYP2E1 during alcohol metabolism, and certain DNA sequences (i.e., polymorphisms) in the CYP2E1 gene are associated with alcoholism. CYP2E1 is highly expressed in monocyte-like cells, which are activated when CYP2E1 metabolizes alcohol. The ROS formed during this process activate proinflammatory NF-κB responses. Chronic ethanol treatment increases CYP2E1 expression in the brain, particularly in astrocytes.The resulting elevated ROS levels activate NF-κB–mediated transcription of innate immune genes, and this response may be amplified in the presence of certain NF-κB polymorphisms (i.e., NF-κB1). Certain variants of other genes also are associated with alcoholism, including polymorphisms of T NFα, interleukin-10 (IL-10), interleukin-1 receptor antagonist (IL-1RA), and other components of the IL-1 gene complex, as well as of certain proteins in the space surrounding the cells (i.e., extracellular matrix proteins [ECM]).