Alcohol Addiction and Tlr4 Receptors

Topics: Immune system, Alcoholism, Nervous system Pages: 5 (1692 words) Published: April 21, 2013
GABA receptor and TLR4 are linked to the cause alcohol addiction
Alcohol has long been known to increase the activity of the γ-aminobutyric acid (GABA) receptor but recent studies have shown that the Toll-like receptors (TLR) also play a significant role in the long term effects of alcohol on the brain (Szabo et al., 2007). Excessive drinking is a big killer in the United States today, taking an average of nearly 75,000 lives a year (Liu et al., 2011). Binge drinking, defined as having a blood-alcohol level ≥ 0.08 g% in a 2-hr period, is an extremely problematic form of alcohol intake and can often lead to addiction (Liu et al., 2011). The GABA receptor and TLR4 are linked to the cause of the addiction to alcohol.

The GABA receptor is a transmembrane receptor, and is one of the major inhibitory receptors in the central nervous system (CNS) (Sundstorm et al., 2002). As an inhibitory receptor, GABA receptors create a passive transport pore for a chloride ion when activated (Sundstorm et al., 2002). This is inhibitory because of the negative charge of the chloride ions as they flow across the gradient into the cell. The GABA receptor is a ligand gated ion channel that is usually activated by 4-aminobutanoic acid (GABA) (Szabo et al., 2007). The GABA receptor can also be allosterically activated by many depressant drugs of abuse including alcohol (Sundstorm et al., 2002).

A TLR is a transmembrane dimer that can be classified as a pattern recognition receptor (PRR), which will send signals as a response to pathogen-associated molecular patterns (PAMPs) (Okun et al., 2009). This means that a TLR is a membrane spanning protein that signals the cell to act once it has been activated by a PAMP. When a TLR comes into contact with its specific PAMP the cell will secrete a cytokine, or a molecule that acts as a signal somewhere else in the body (Szabo et al., 2007).

TLRs are located throughout the body and play a role in bone metabolism, neurogenesis, and brain development (Okun et al., 2009). Their main influence though is over the inate, or nonspecific, immune system. In the CNS TLRs will likely send signals to microglia or other immune system cells also located in the CNS such as astrocytes or oligodendrocytes (Okun et al., 2009).

TLR4 is a specific TLR that usually recognizes lipopolysaccharides (LPS), a common feature on the outer cell membrane of gram-negative bacteria (Okun et al., 2009). TLR4 can also be stimulated by many depressant drugs, such as ethanol (Pascual et al., 2011). When TLR4 is stimulated on a human microglia, the cell will secrete a proinflammatory cytokine (Bhatty et al., 2001). This will cause inflammation nearby and can lead to apoptosis, programmed cell death, in some cells (Okun et al., 2009). Apoptosis can be especially dangerous in the CNS because neurons are not able to replicate like other bodily cells do.

Because TLR4 can lead to microglia releasing proinflammation cytokine, when TLR4 is active many nearby cells are going to become inflamed (Bhatty et al., 2001). This can be detrimental in the nervous system, because it is likely that the inflammation will cause many neurons will be harmed and die (Okun et al., 2009). Many CNS diseases are caused by inflammation, including chronic neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease (Pascual et al., 2011). It is known that alcohol can cause brain damage, and occasionally lead to neurodegeneration (Pascual et al., 2011). It has also been shown that alcohol activates the TLR4 receptor, and that chronic ethanol consumption increases neuroinflammation and increases cell damage in rat brains (Pascual et al., 2011).

An experiment was designed to figure out TLR4’s role in ethanol-induced microglial activation and the affect on brain damage (Alfonso-Loeches et al., 2010). Two separate groups of mice were used in the experiment. The first group was a control and contained mice with regularly...
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