You, Illuminated

Commonsense explanations of neuroscience

Your Brain on Alcohol

Is the conventional wisdom wrong about booze?

Alcohol is the most widely consumed drug worldwide. For many, drinking is as much a part of daily life as having dinner. Although we consume it regularly, we don't really know what it does to us, or why it causes (some of) us to suddenly find streaking naked through a college campus a brilliant idea. Alcohol, according to conventional wisdom, is a depressant. Yet, that doesn't fully explain alcohol's effects. People often drink to liven up a party, not mellow it out. A few drinks can spark energy, elation and excitement; it gives you a buzz. Alcohol may be more than simply a depressant.

Classification of drugs can be explained by their chemical targets within the brain. Stimulants may influence dopamine or norepinephrine. Depressants target a chemical called GABA, the primary inhibitory neurotransmitter within the brain.

As early research failed to show that alcohol targeted a specific receptor, scientists speculated that alcohol non-specifically altered cell membranes. A gatekeeper, the cell membrane's job is to regulate what goes in and out of a cell. Alcohol might disrupt cell membranes throughout our body, making them leaky.

At this point, our understanding of alcohol's effects was a bit cloudy, as if rather than looking through a microscope, we were wearing beer goggles. More things could get into our cells, but we didn't know what those things were or why it was happening. Our scientific explanation was as precise as our lay explanation. When we drink, our cells get messed up. Is this the best we could do?

At the same time, behavioral researchers sought to understand the physiological and psychological effects of drinking. Drinking profoundly alters mood, arousal, behavior, and neuropsychological functioning. However, studies have found that the specific effects depend not just on how much someone drinks, but also on whether blood alcohol content (BAC) is rising or falling; while in the process of drinking, alcohol acts as a stimulant, but as drinking tapers off it begins to act more as a sedative.

As BAC ascends, drinkers report increases in elation, excitement and extroversion, with simultaneous decreases in fatigue, restlessness, depression and tension. Conversely, a descending BAC corresponds to a decrease in vigor and an increase in fatigue, relaxation, confusion, and depression.

A subsequent group of researchers found that drinking increases levels of norepinephrine, the neurotransmitter responsible for arousal, which would account for heightened excitement when someone begins drinking. Norepinephrine is the chemical target of many stimulants, suggesting that alcohol is more than merely a depressant. Elevated levels of norepinephrine increase impulsivity, which helps explain why we lose our inhibitions drinking. Drunken brains are primed to seek pleasure without considering the consequences; no wonder so many hook-ups happen after happy hour.

Although increased norepinephrine offers some explanation of alcohol's effects, it doesn't tell us where in the brain changes are occurring. To see which regions of the brain were more or less active while drinking, researchers gave a group of subjects a PET scan after injecting them with harmless radioactive glucose, the brain's preferred source of energy. Highly active regions consume more glucose, and those regions are brightly lit during the PET scan, whereas less active regions are dimmer.

The regions of the brain with the greatest decrease in activity were the prefrontal cortex and the temporal cortex. Decreased activity in the prefrontal cortex, the region responsible for decision making and rational thought, further explains why alcohol causes us to act without thinking. The prefrontal cortex also plays a role in preventing aggressive behavior, so this might help explain the relationship between alcohol and violence (see my last post). The temporal cortex houses the hippocampus, the brain region responsible for forming new memories. Reduced activity in the hippocampus might account for why people black out when drinking.

Alcohol also decreases energy consumption in the cerebellum, a brain structure that coordinates motor activity. With a cerebellum running at half-speed, it would be hard to walk a straight line or operate heavy machinery.

Despite gaining insight into which brain regions were less active, we still had no mechanism that could explain why alcohol was reducing these brain functions.
Alcohol has been found to affect over 100 unique receptors in the brain. However, many systems in the brain are interrelated. It's not clear if alcohol directly acts on all those receptors or if they're a downstream result of its action elsewhere. The smoking gun would be to isolate a receptor and show that alcohol affects it. If alcohol is a depressant, it should facilitate GABA receptors.

When GABA receptors were first isolated, they did respond to alcohol, but not until alcohol concentrations reached .33 mL/L. The legal limit for driving is .08 mL/L. For the normal human, concentrations over .3 ml/L are enough to cause someone to pass out and vomit. How would that account for the buzz we feel after a few glasses of wine?

Nonetheless, alcohol shared properties with classical depressants, like valium. Experiments in mice showed that when given valium regularly, not only did they develop a tolerance to it, but they also developed increased tolerance to alcohol. Called cross-tolerance, it indicates that both drugs act at the same receptor, the GABA receptor. Mounting evidence suggested that alcohol acted at GABA receptors, but research had still been unable to pin down a specific mechanism.

Part of the problem stemmed from the fact that GABA receptors are as varied as the beer menu at Oktoberfest. Each receptor is composed of five subunits, and there are multiple subunits to choose from. Is it possible that we just hadn't tested the right one?
Yes, it turned out. One of the less common types of GABA contains a delta subunit (they are all labeled with Greek letters). In the past ten years, researchers began suspecting that the delta receptor might differ from other GABA receptors. When isolated, they found that it responded to low levels of alcohol, like the amount in a glass of wine. Cheers, we found the smoking gun.

The delta receptor is concentrated in the prefrontal cortex, the hippocampus and the cerebellum, the same regions which had lowered activity in the PET scanner. Like in The Hangover, where a wild night of partying clouded the memory of the previous evening's events, it took some time, but the pieces of this story were slowly coming together.
Although GABA activity doesn't entirely explain alcohol's effects and we don't know exactly what the delta receptor does, a big part of the mystery seems to have come unraveled. Because GABA is the primary inhibitory neuron in the brain, it can affect virtually every system. Alcohol is more than simply a depressant.

The physical structure of the brain remains constant, but the addition of a tiny chemical drastically alters brain function and ultimately behavior. Understanding how alcohol affects our brain also offers insight into how our brains work in general. So the next time you drink, even though you may be killing some valuable brain cells, you can toast to the fact that you're contributing to neuroscience.

 

Notes:

Giancola PR, Zeichner A. The biphasic effects of alcohol on human physical aggression. J Abnorm Psychol. 1997 Nov;106(4):598-607. 

McDougle CJ, Krystal JH, Price LH, Heninger GR, Charney DS. Noradrenergic response to acute ethanol administration in healthy subjects: comparison with intravenous yohimbine. Psychopharmacology (Berl). 1995 Mar;118(2):127-35.

Volkow ND, Hitzemann R, Wolf AP, Logan J, Fowler JS, Christman D, Dewey SL, Schlyer D, Burr G, Vitkun S, et al. Acute effects of ethanol on regional brain glucose metabolism and transport. Psychiatry Res. 1990 Apr;35(1):39-48.

Olsen RW, Hanchar HJ, Meera P, Wallner M. GABAA receptor subtypes: the "one glass of wine" receptors. Alcohol. 2007 May;41(3):201-9.

Joshua Gowin, Ph.D., earned his doctorate in behavioral neuroscience at the University of Texas Health Science Center in Houston.

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