Alcohol, Glutamate, and the NMDA Receptor

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Image retrieved from on October 2nd, 2014.

One of the major neurotransmitters used to send “fire” messages from one neuron to another is a molecule called glutamate. When glutamate is released into a synapse, it docks at a receptor that lets positive ions rush in. Since this makes it more likely that the receiving cell will fire, glutamate is called an excitatory neurotransmitter.
When you take a drink, alcohol molecules that escape destruction in the liver are quickly pumped up to the brain, where they infiltrate synapses every where. There they can bind to glutamate receptors. Nobody knows precisely where on the receptor alcohol binds, but it somehow warps the structure of the receptor just enough to interfere with its ability to open normally, thus muting glutamate's normal “fire” message. Alcohol's inhibition of glutamate receptors can be profound. After consumption of the equivalent of about two drinks in the space of an hour, glutamate receptor function can be reduced by more that 80 percent (Weight et al. 1993).
By inhibiting the brain's most common excitatory neurotransmitter, alcohol effectively slows down activity in many parts of the brain. If the neurons in those areas control muscles, the inhibition can lead to relaxation and discoordination. If the neurons control speech, words slur and become increasingly imprecise. If the neurons control automatic bodily functions, heart rate and breathing are impaired. From a public health point of view, these are among alcohol's most dire effects. The inhibition of glutamate receptors is the molecular foundation of such grim statistics as the annual death of more than 20,000 people in alcohol-related traffic accidents.
The inhibition of glutamate receptors may also disable one of our most coveted intellectual capacities: the ability to learn.
Although it's often compared to a computer, the brain more closely resembles a tablet of wet clay into which impressions can be made, erased, and made again over time. This flexibility enables us to learn and remember. The current theory of memory suggests that you remember something when a specific constellation of neurons is stimulated vigorously. Whether it's a whiff of cinnamon or a catchy song, an incoming stimulus instantly lights up a particular constellation of neurons in the constellation are automatically strengthened in the process. If this pattern of neurons is stimulated in exactly the same way again, the network “lights up” more easily than it did previously. The original sensation is thus “stored” in these discrete patterns of tuned connections. The more often a particular pattern is stimulated, the more sensitive and permanent the connections between the neurons in the pattern become.
The technical term for such long-lasting changes in the strength of synaptic connections is long-term potentiation, or LTP. (A mirror phenomenon—long-term inhibition—is also likely to be involved in memory formation). The discovery of LTP in 1973 provided the first plausible mechanism to support the theory outlined earlier. When this phenomenon was investigated closely, it was discovered that LTP is blocked when a specific kind of glutamate receptor is disabled—the NMDA receptor.
Disruption NMDA receptors has serious consequences. Rats, rabbits, and other animals injected with chemicals that block NMDA-receptor channels can't learn new tasks, such as negotiating their way through a maze, and they are incapable of forming new memories. Their abilities return when the effects of the chemicals wear off.
The salient point here is that, of all the glutamate-receptor channels (there are three basic types) the NMDA receptor is the most sensitive to alcohol (Weight et al. 1993). Experiments show a 30 percent reduction in LTP at alcohol concentrations reached after only a single drink (Blitzer et al. 1990). The impairment worsens with higher alcohol concentrations, stabilizing at roughly 80 percent with a concentration roughly equivalent to serious inebriation: a blood alcohol level of .2 percent-about twice the legal limit for intoxication in most states
This research shows that alcohol--even at very low doses—disrupts the cellular machinery most widely believed to underlie our ability to form new memories. Since the disruption can occur at levels below those causing more obvious impairments of motor function and speech, people may not appreciate the degree to which their memories are being impaired.
Interestingly, the impairment is of the ability to form new memories, not the ability to recall stored memories. Intoxicated people who were asked to recall a list of words learned prior to intoxication showed no impairment of their recall ability already intoxicated, their ability to recall the words later dropped significantly (Jones 1973). Results such as these suggest that the operations of memory acquisition and memory retrieval are separated in the brain and rely on different kinds of molecular machinery.
The memory impairment resulting from alcohol ranges from a barely detectable “cocktail-party amnesia” to the full-blown memory blackouts experienced by alcoholics. Inhibition of NMDA channels is the most likely cause of the moderate impairments, but the molecular basis for alcoholic black outs has not been determined. It may be due to the combined effects of the inhibition of NMDA channels and the alteration of other types of ion channels that produce a massive inhibition of nerve-cell firing in the hippocampus, a portion of the brain critical to memory formation.
If alcohol affected only neurons and neural networks that rely on the neurotransmitter glutamate, it would still be a powerful substance. But such effects alone would not make for a very popular drug. Indeed, people drink alcohol despite the fact that it depresses overall brain function and can radically interfere with the ability to learn. Accounting for alcohol's enormous popularity and explaining its myriad other effects requires that we look beyond glutamate to some of the brain's other important neurotransmitters.

pp. 49-52 of Buzz The Science and Lore of Alchohol and Caffeine by Stephen Braun (1996)

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