SPECIAL REPORT

CLUES IN THE BRAIN

The answer to addiction may lie in the twisted corridors of the human mind

July 19 1993
SPECIAL REPORT

CLUES IN THE BRAIN

The answer to addiction may lie in the twisted corridors of the human mind

July 19 1993

CLUES IN THE BRAIN

SPECIAL REPORT

The answer to addiction may lie in the twisted corridors of the human mind

In an obscure comer of the human brain, buried inside a cluster of several thousand spidery nerve cells, bliss resides. It dwells, incongruously, within a primordial structure formed eons ago, very early in the evolution of the species. Neuroscientists call it the mesolimbic dopamine system and, while they only dimly understand how it works, they have discovered that it plays an important role in generating emotion. Eat a good meal, listen to a symphony, watch a sunset and the dopamine circuits light up, prompting feelings of well-being, pleasure—even euphoria. However, there is also a darker side: many drugs, including alcohol, will switch on the same cerebral circuits. And that is the principal reason why a growing number of researchers are becoming convinced that the brain’s primitive mesolimbic system may contain the key to a problem almost as old as humanity: drug and alcohol addiction.

plays a role, as suggested by the fact that alcoholism tends to run in families. But it is inside the twisted, tangled corridors of the brain itself that the most promising research is being carried out. And most of that exploration leads, in one way or another, to the dopamine cells in the mesolimbic system. “It certainly seems to be critical in the development of drug craving, which is one way of describing the psychological aspects of addiction,” says Jane Stewart, director of the Centre for Studies in Behavioral Neurobiology at Montreal’s Concordia University.

Neuroscientists have been drawn to that system because of its nature and function. It is, in effect, an intricate communications network, centred in the lower part of the brain at the base of the skull, with an interlocking grid of branch lines that reach all the way to the top of the brain. Several thousand nerve cells, or neurons, form the core of the dopamine system. Neurons communicate by means of electrochemical impulses: messages are received by dendrites, multi-limbed filaments radiating out from the bodies of the neurons, and transmitted by axons, long cable-like fibres.

In the addictive process, the critical events transpire

Although the phenomenon has long existed, remarkably little is known about its prime causes. Science is only now just starting to uncover clues that someday may finally unravel the mystery of the addictive process. For instance, it has been established that environmental circumstance is heavily involved, as anyone who has ever tried to break the link between a cigarette and a morning cup of coffee will testify. There is also growing suspicion that genetic inheritance often

where axon meets dendrite. Between the axon of a sending neuron and the dendrite of a receiving one, there is a minute gap, called a synapse. Messages are conveyed across this synaptic gap by chemicals known as neurotransmitters. When an electrical impulse reaches the terminal of an axon, molecules of neurotransmitter are released into the synapse. The molecules carry the impulse to receptors on the dendrite, on the other side of the gap. Once the message has been delivered, the neurotransmitter is then either destroyed or gathered up to be used again.

Psychoactive, or behavior-altering, drugs interfere with that deli-

cate process. Chronic drug use, in fact, can fundamentally alter neurotransmission, changing both the way nerve cells talk to each other as well as the messages they exchange. When that happens, addiction occurs. ‘The molecular structures inside the neural pathways are altered,” explains Dr. Eric Nestler, director of the Laboratory of Molecular Psychiatry at the Yale University School of Medicine. “It happens with many types of drugs of abuse—alcohol, opiates, cocaine, amphetamines, marijuana, nicotine. Even though these substances act in different ways on different targets, they all tend to produce a range of broadly similar effects on the brain.”

Many of those broadly similar effects occur inside the mesolimbic dopamine system. A growing body of evidence, in fact, suggests that this particular cerebral circuitry may well be implicated in all addictions. That has not been proved, but there are good reasons to suspect that it might be true. The system seems to have been crafted over the long evolutionary time for the specific purpose of producing and regulating a powerful biological force, one that is critical for the survival of any species. In scientific parlance, the force is most often referred to as positive reinforcement. A better, if less clinically accurate label, is reward.

The mesolimbic dopamine system is an integral part of the brain’s reward centre—and pleasure is the operative agent.

The system creates a sensation—such as pleasure—as reward for activity that benefits the organism, “positively reinforcing” the activity so it will be repeated. ‘The basic principle at work is pretty straightforward,” says Robert Pihl, professor of psychology and psychiatry at McGill University. “If you do something you like, the chances are good that you’ll probably want to do it all over again.”

Given the system’s function, it will come as no surprise to learn that the dopamine network plays a crucial role in processes involving learning, memory and motivation. Any activities that satisfy biological needs or offer survival value or reproductive advantage will switch on the circuits, inducing feelings that, according to Pihl, “include satisfaction, expansiveness, a sense of increased power and energy.” Naturally occurring stimuli abound, covering the range of human sensations. Food, water and sex will turn on the system, but so will the quiet contemplation of nature, art and music.

Drugs activate it, too, but drugs cheat. They hijack the brain’s reward circuits by activating the system at the point of neurotransmission, bypassing the sensory equipment and communications gear that the natural stimuli use. They manage to accomplish this task in various ingenious ways.

Heroin mimics the effects of a series of natural neurotransmitters known as endorphins, which are morphine-like and produce a sense of well-being. Marijuana, nicotine, caffeine and Valium do the same with other types of neurotransmitters. Cocaine does not mimic a neurotransmitter but it affects the nervous system by preventing dopamine, itself a neurotransmitter, from being regathered after messages have been transported across the synapse. Amphetamines also flood synapses with dopamine. LSD blocks the receptors for a neurotransmitter, serotonin. Ethanol, the active ingredient in alcohol, also interferes with a neurotransmitter.

Most of these drug-induced neural events are, in a clinical sense, positively reinforcing, or rewarding. In short, they evoke emotions such as pleasure. They switch on the brain’s reward circuits and make people feel good, thereby encouraging a repeat of the same activity. What is more, the reward offered by drugs may well be even more intense than that evoked by natural stimuli for the simple reason that those substances are not filtered through any of the body’s normal receiving channels but, rather, act directly on the circuits inside the brain. Drug “highs,” in other words, may be more powerful than any of those available naturally.

That is one explanation for the difficulty in breaking an addiction.

There is another, with more ominous implications. While the evidence is still inconclusive, the chronic use of some drugs seems to lead to more or less permanent brain damage that encourages more drug use. “We’re pretty certain that lasting neural injury takes place,” says Yale University’s Nestler. The end result, broadly, is a brain that learns to depend on drugs for reward, even to the point where drugs appear to be as important for survival as food and water.

Anecdotal evidence collected from human addicts certainly suggests that this is the case. And laboratory experiments with animals support it. Both rats and monkeys, with similar primitive brain structures as humans, will happily abuse most of the same drugs as those used by humans. Rats hooked up to a drug pump will blithely ignore food, water and willing sexual partners in order to self-administer cocaine, morphine, heroin, amphetamines and ethanol—sometimes to the point of death.

But not all rats react to drugs in the same way. There is, in fact, an inbred strain of laboratory animal known as the Lewis rat, that seems to be predisposed to substance abuse. Lewis rats are addiction-prone. They will self-administer opiates, cocaine and alcohol at much higher rates than other rat strains, all of which suggests that inheritance may be at play.

The same situation may apply to humans. Neuroscientists have long suspected that genetic factors may make some individuals prone to drug and alcohol addiction. But there has been no conclusive proof, particularly in the case of psychoactive drugs. In the last three years, however, researchers have started to move slowly towards the identification of genes that may be involved. The evidence so far is preliminary, even controversial. But the genetic markers that have been singled out as possible candidates are all closely associated with dopamine, the system’s prime chemical neurotransmitter.

So far, the research has revealed just a hint of the mechanisms underlying addiction. “We are really only at the very beginning of our search,” notes Concordia’s Stewart. Despite all the interest of neuroscientists and the steadily mounting body of evidence, the mesolimbic dopamine system still hides many of its secrets. But for addiction researchers, those nerve cells contain clues to the cause, and possibly the cure, of an affliction borne by humanity for countless centuries.

BARRY CAME in Montreal

THE RAVAGES OF ALCOHOL

Alcohol is absorbed into the blood from the stomach, small intestine and colon. Its effects on the drinker are measured according to the number of milligrams found in each decilitre (10th of a litre) of blood. Two drinks consumed quickly may create a blood alcohol concentration of 50 mg/dL in an average person. In most jurisdictions, 80 mg/dL constitutes impairment in a driver. This table shows what an average drinker experiences as the blood alcohol concentration increases (in mg/dL):

50

100

150

250

350

500

Mild intoxication. Feeling of warmth, skin flushed, judgment impaired, fewer inhibitions.

Obvious intoxication. Judgment, inhibition, ability to pay attention and self-control further impaired, muscles not working as they should, reflexes slowed.

Staggering gait, slurred speech, double vision, comprehension and memory loss.

Extreme intoxication. Inability to stand, vomiting, incontinence, sleepiness.

Coma. Unconsciousness, incontinence, body temperature and blood pressure fall, skin clammy.

Death likely.