Jane behaving badly

New Scientist, 27 November 1999
ALISON MOTLUK

Dear Ms Tipple,

Your behaviour last night at the office millennium party was appalling. Within an hour of arriving, you were singing bawdy songs and shouting obscenities at your colleagues. Then, minutes later, you began to disrobe. As if that weren't bad enough, you astonished us all when you attempted to kiss the Chairmam, Mr Monk. He can be considered lucky, however, that he was out of range when, soon after, you began to vomit. Ms Stern from accounts cannot count herself so lucky. I can tell you, we were all much relieved when you passed out and were removed to the hospital for observation. Can you please explain how this happened?

POOR Jane Tipple. If it weren't for the throbbing headache keeping her tucked up in bed and the fact that many of the sorry details of the previous evening never even made it into her long-term memory, she could probably explain a good deal of what happened. The raw facts are simple. She drank too much, too quickly. And her brain became utterly intoxicated.

Getting drunk is not as straightforward as it appears. During the course of a binge, your brain becomes a veritable fairground House of Horror-with alcohol at the controls. Neurons flicker on and off, your metabolic rate rises and falls and brain signals get mixed up. As your blood alcohol levels rise, you are slowly drawn upwards along a track of excitement, with alcohol coaxing out the singing, joke-telling, gregarious you.

But as the booze levels start to peak, so do you. It's all downhill from there. Now the demon drink plays its best tricks, slurring your speech, fumbling your movements and encouraging behaviour you'd regret for the rest of your life-if only you could remember it. Out of control, you just take the ride as it comes-sniggering, stumbling, spinning and spewing on cue.

So it was for Jane. Arriving at the party straight from work, she took her first drink, a rum and Coke, just to loosen up. It worked. But although she may have felt she was relaxing, at this early stage her brain was in fact revving up.

Stimulation is the first effect of drinking, and it occurs while blood alcohol levels remain relatively low, says Boris Tabakoff, a pharmacologist at the University of Colorado Medical School in Denver. The alcohol concentration in Jane's blood was still hovering around a modest 25 milligrams per 100 millilitres (see Diagram). At that level, says Tabakoff, alcohol sensitises one of the brain's major excitatory message pathways, the N -methyl-D-aspartate (NMDA) system, making certain NMDA receptors more readily activated by the brain's main neurotransmitter glutamate. Some of the most sensitised brain regions are the thinking, remembering and pleasure-seeking parts-the cortex, hippocampus and nucleus accumbens, respectively.

Ratcheting up brain activity reduces inhibitions. And not just in humans: rats given small doses of alcohol tend to move around and explore their environments more. In fact anyone who has had a glass of Chardonnay to calm their nerves at lunch or an after-work pint with the boss knows this warm, confident feeling. At first, it helped Jane to get over the anxiety of rubbing shoulders with her more spirited colleagues. Slowly, it brought out her more vivacious side.

A snapshot of her brain at this point would probably show increased metabolism in the regions associated with movement, such as the nigrostriatal pathway. This could help explain how she became uncharacteristically animated as she started telling raucous jokes and swearing. Linda Porrino, a neuroscientist at Wake Forest University School of Medicine in Winston-Salem, North Carolina, has examined brain slices from rats given the equivalent of one drink-what she calls a "party dose". She found that motor areas and particularly the reward circuitry were all lit up. It's the effects of these low doses of alcohol that we seem to like, she says.

Jane was no exception. She reached for her second and third drinks-two shots of tequila-and quickly downed them. As she and a colleague linked arms and began belting out songs, the level of alcohol in her blood was rising, edging quickly past 50 mg per 100 ml and onwards to break the British legal driving limit of 80.

Onwards and upwards

Jane was flushed and euphoric. She thought the evening could only get better. If electrodes had been glued to her head at that moment, we'd have found an increase in alpha brain waves-the slow, rhythmic pattern seen on electroencephalographs (EEGs) which usually appears when we're relaxed. According to a study of 18 healthy men by Scott Lucas of Harvard Medical School in Boston and his colleagues, euphoria correlates well with transient boosts in alpha waves (Pharmacology Biochemistry and Behavior, vol 25, p 889).

Another glimpse into her brain might have shown extra blood flowing to the front, to the prefrontal cortex, and to the right side, the right temporal cortex. This is what Nora Volkow of the Brookhaven National Laboratory in New York found when she used positron emission tomography (PET) to peek into the brains of drunks. Increased blood flow to these areas might account for Jane's heightened mood. But no PET scan can explain Jane's ill-fated attempt to seduce a balding bachelor.

The brain has a complex "biphasic" relationship with alcohol, and if Jane's first hour was a titillating ride onwards and upwards, she was now poised to plummet. Now, with her blood awash with alcohol, the very NMDA receptors that helped to perk her up earlier in the evening when she'd drunk only a little were refusing to respond. For most people, the turning point seems to be three or four drinks, says Tabakoff, who has looked at the effect of alcohol on NMDA receptors in humans, rodents and cell cultures (Neuron, vol 16, p 909).

Not only was Jane's NMDA excitement waning, but another set of pathways in her brain, known as the gamma-aminobutyric acid system, or GABA, was coming online. Unfortunately for Jane, who wanted to keep on rocking, GABA is one of the major inhibitory systems in the brain. It stops neurons from firing and dulls activity. Indeed, this is the very system activated by benzodiazepines such as Valium. From here on, rather than winding a person up, alcohol begins to act more as a sedative. "Now they're feeling more relaxed not simply because they've become less inhibited in behaviour," says Tabakoff. "They really are more relaxed." Jane was feeling very relaxed indeed and, while licking her fourth drink, a beer, off a plate, she began to take her clothes off.

By this time, Jane had consumed what Porrino calls the "spending too much time at the bar" dose and new areas of her brain were being affected. Porrino has compared the effects of the equivalent of one drink and four drinks on rats' brains-and the two are completely different. While low doses increase neural activity, particularly in motor and reward areas, high doses slow the hippocampus, which processes memory, and the thalamus, which helps to deal with sensory and motor information. "Different alcohol doses distinctly affected different brain regions rather than acted on a single system in a dose-dependent way," she says in the journal Alcohol Health & Research World (vol 19, p 300).

Once she'd finished her fifth drink, whatever it was, Jane's mouth had forgotten how to speak, let alone sing, and standing seemed like too much effort, so she slumped into a corner. Volkow's work, another PET study, suggests this could be because alcohol reduces blood flow to the cerebellum, a structure at the back of the brain that is involved in motor coordination and posture. Volkow asked volunteers to drink the equivalent of three shots of vodka, then scanned their brains once the alcohol had been absorbed. "The cerebellum may be one of the brain areas most sensitive to alcohol," she says (Alcohol Health & Research World, vol 19, p 296).

Volkow also looked at glucose metabolism, asking 10 healthy people to drink the equivalent of three small drinks to boost their blood alcohol levels to about 80 mg per 100 ml. To her surprise, she found that the drunken brain consumed 25 per cent less glucose than the sober one. "I am very intrigued by this," she says. "If neurons are not consuming glucose, they won't be working properly. That could account for many of the impairments."

And when she looked at the brain region by region, it became clear what was behind some of the specific symptoms of intoxication. She found that the greatest decrease in metabolism occurred at the back of the brain, in the occipital lobe, where glucose consumption was down by 29 per cent. This is where the visual cortex is and may help explain the blurry vision that accompanies late-stage drunkenness. The second biggest decrease in glucose uptake, down 27 per cent, was in the cerebellum. When the volunteers were rated on how they moved and spoke and recalled, it was found that fine motor skills, speech and memory were all affected.

Sitting there quietly in the corner, Jane was overwhelmed with a groggy feeling. She has no recollection of sipping her sixth drink-a fancy green concoction specially prepared and delivered to her by a bartender who found her amusing.

As a person continues to drink to excess, a series of other brain receptors comes into play, says Tabakoff. "Depending on the dose consumed and the blood alcohol levels, different receptors are differentially affected," he says. These include certain acetylcholine receptors-the same ones that respond to nicotine-and some receptors for serotonin, a wide-ranging neurotransmitter that can affect anything from mood and aggression to sexual motivation and attention.

According to Tabakoff, there's a great deal of genetic variation in how particular receptors respond to these higher levels of alcohol. Some individuals are genetically inclined to pick a fight. Others doze off. This dichotomy is as true in monkeys and mice as in people, he says. "There are very different reactions." Jane was the sleepy kind.

Drunks seldom get a good night's sleep, however, as alcohol interferes with normal sleep patterns. Though it causes sedation, alcohol also suppresses rapid eye movement (REM) sleep-the dream phase-by as much as 20 per cent, says Timothy Roehrs, a sleep researcher at the Henry Ford Hospital in Detroit, Michigan.

Worse, after you have fallen asleep, and alcohol has gradually been eliminated from your body, you can become aroused again and wake up. Roehrs has studied how long it takes people to fall asleep. He found that drinkers whose blood alcohol level is rising take longer than controls to drop off, while those whose blood alcohol is falling take less time. But he also thinks that alcohol-induced sleepiness and memory loss may be linked.

No recollection

He noticed that people who get drunk and then forget what happened have memory impairments similar to those suffered by people with sleep disorders. "What's really interesting is that this is an important phenomenon in patients who have daytime sleepiness," he says. They can get to work but can't remember having driven there. Similarly, drunks can get home from the pub without the faintest recollection of who they insulted while they were there, how they travelled back-or even who they brought with them. For her part, Jane doesn't recall vomiting on Ms Stern.

Roehrs wanted to examine further the relationship between sleepiness and memory loss, so he gave volunteers-some under the influence, some not-16 word pairs to remember. The more they drank, the fewer word pairs they recalled 30 minutes later. In fact, the dose-related memory effect was very similar to the dose-related sedative effect. "More than likely, what has been disturbed was the transfer of memory to the long term store," he says.

Everyone agrees that memory is impaired when a person drinks too much, but, says Roehrs, there is little consensus on why. His hunch is that the GABA signals that bring on the sleepiness can interfere with both the early and late stages of memory formation, known as stimulus registration and consolidation. He knows that chemicals that mimic GABA can do this (Alcohol Health & Research World, vol 19, p 130). And he points out that there are many GABA receptors in the hippocampus, the brain's memory centre. "This is probably the mechanism by which alcohol has affected memory loss," he says.

Jane does vaguely remember one thing towards the end of her evening: as she tried to snooze in the corner, she had the strong sensation that the room was spinning. This effect is called "positional alcohol nystagmus"-basically a booze-induced version of an eye reflex that is normally triggered by the inner ear's balance organs when they detect head rotation. Ironically, nystagmus is one way of maintaining clear vision while you turn your head.

Ken Money, former astronaut, and senior scientist at the Defence and Civil Institute of Environmental Medicine in Toronto, looked into the phenomenon while working on space sickness and the effect of weightlessness on balance. He points out that when you're drunk and your head is tilted, the nystagmus reflex is induced by the ear's fluid-filled semicircular canals picking up the effect of gravity-something they don't normally do as they monitor the head turning. And it was not at all clear why. "Gravity is not supposed to act in the semicircular canals," says Money. He found that in some circumstances, however, the canals do respond to gravity-such as after a double on an empty stomach.

Alcohol has a lower density than water, and when you get drunk, that lower density creates a "light spot" in the inner ear fluid. When you lie down, that light spot allows a sensor called the cupula to sink, sending a faulty report to the brain that your head is rotating and that your eyes need to rotate too. So when you're lying with your right cheek on the dance floor, your eyeballs are turning slowly to the left, then flicking quickly back to the right-and therein lies the wooziness. Lie with the other cheek down, and the world spins the other way. The effect, says Money, peaks at around an hour and a half after a heavy drinking bout begins-and revisits you in reverse about 10 hours later.

To prove this, Money got 10 volunteers to drink deuterium oxide, or heavy water. This created a "heavy" spot, so the spinning was in the opposite direction to that induced by alcohol. In cats, he showed that the effects of the alcohol and the heavy water cancelled each other out (Nature, vol 247, p 404). Fred Miles of the National Eye Institute in Bethesda, Maryland, suggests mixing all drinks with heavy water to keep the specific gravity at one, the same as body fluids, to avoid the post-indulgence spins. "The problem is," he says, "this makes the cocktails very expensive!"

Jane spun and edged her way up to the anaesthetic dose, but was still safely short of the blood alcohol concentration of 500 mg per 100 ml that is considered lethal. At that concentration, the brain centres that keep you breathing shut down. But Jane was definitely breathing; her loud snores were reverberating around the hospital ward.

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