Our flourishing knowledge of the brain is in large part the product of research on addiction. Identifying what happens in the brain when a drug is inhaled, injected, or eaten, why it leads to compulsive drug seeking, and learning how to disrupt that process has seemed like the last best hope for a permanent fix for addiction. Which is why, according to Alan Leshner, director of the National Institute on Drug Abuse (NIDA), researchers know more about drugs in the brain than they know about anything else in the brain.
Among the revelations: addiction is now seen to be a brain disease triggered by frequent use of drugs that change the biochemistry and anatomy of neurons and alter the way they work. Scientists have developed a basic model of addiction that presents these changes as the desperate attempt of the brain to carry on business-as-usual—to make neurons less responsive to the drugs and so restore homeostasis—while under extreme chemical siege.
But the adaptations the drugs force on the brain can be long term or even permanent. With sustained drug use, the brain adapts to this saturation bombardment, and giving up drugs leaves it bereft and demanding a return to the new homeostasis. Thus, even the brains of people who have quit using drugs and urgently wish to stay clean remain vulnerable to relapse. Deprived addicts are no longer seeking to get high, they just want to feel normal.
Genetic factors, environmental factors, and—most important—the intricate and still mysterious interaction of the two are assumed to be fundamental to the addiction process. But a great many critical details are emerging from studies of events in the brain.
The common pathway
The most compelling revelation about addiction and the brain may even deserve that tattered encomium “breakthrough.” The discovery that startled the scientists? Although each drug employs it in a somewhat different way, addictions center around alterations in a single pathway in the brain: the “reward” circuit whose chief centers of action lie in the ancient part of the brain known as the limbic system.
This pathway is involved in drug addictions of all kinds—not just addiction to illegal drugs such as heroin and cocaine, but also addiction to alcohol, tobacco, and even caffeine. Marijuana appears to employ this pathway too. And perhaps—a big perhaps because addiction experts are divided on this point—the pathway also figures in “addictions” that do not involve drugs, for example, the compulsive and destructive pursuit of eating, exercise, gambling, or sex.
The addiction pathway is the brain system that governs motivated behavior. When the pathway was first discovered, almost a half-century ago, people called it the pleasure center. Scientists now call it the brain reward region and have confirmed its role as the addiction pathway in countless animal studies (mostly with rats and mice) and many brain-imaging studies of human addicts.
The pathway is hidden deep within the brain (see illustration page 514). It begins at the ventral tegmental area in the midbrain, which sits on top of the brainstem. In evolutionary terms, this region is very old; it began with the vertebrates, which appeared 500 million years or so ago. The pathway extends to the nucleus accumbens, toward the front of the brain. This area is a traffic hub for signals to and from the addiction pathway and other parts of the brain. The nucleus accumbens is centrally located at the intersection of the stria-turn (where motion is begun and controlled) and the limbic system.
The limbic system is a collection of primeval brain structures that form a ring around the brain stem. Among those structures are the hippocampus, the brain’s center of learning and memory, and the amygdala, the postulated site of, among other things, our emotional responses to experience. These are ancient centers of cognitive processing, but they still guide our behavior, sometimes to our woe. They long antedate the neocortex, where (among other tasks) rational thought processes are believed to take place. The limbic system is also closely connected to the hypothalamus, a tiny area in the center of the brain that controls many hormones, and with them, hunger, thirst, and sexual desire.
In short, the addiction pathway has been around a lot longer than humanity and is situated within easy reach of ancient brain centers that control many basic functions, most of them unconscious, that people share with other animals.
Drugs and the dopamine path
Chemicals called neurotransmitters pass messages from one neuron to another across the gaps (synapses) that divide them. Dopamine is among the most common of the more than 100 neurotransmitters that have been identified so far, although it is made in perhaps fewer than 100,000 nerve cells out of the brain’s 100 billion. Dopamine is also the chief neuro-transmitter in the brain reward pathway. From cell bodies in the ventral tegmentum, electric commands go out, leaping along the cells’ cablelike axons to their terminals in the nucleus accumbens, where dopamine is ejaculated into the synapses.
Addictions center around alterations in the brain’s mesolimbic dopamine pathway, also known as the reward circuit, which begins in the ventral tegmental area (VTA) above the brain stem. Cell bodies of dopamine neurons arise in the VTA, and their axons extend to the nucleus accumbens. This centrally located hub connects with many other brain structures, such as the limbic system (the so-called emotional brain, in evolutionary terms very old). Some dopamine fibers also project to a much newer structure, the prefontal cortex, which is involved in cognitive tasks such as memory, planning, attention, and social behavior.
Addictions center around alterations in the brain’s mesolimbic dopamine pathway, also known as the reward circuit, which begins in the ventral tegmental area (VTA) above the brain stem. Cell bodies of dopamine neurons arise in the VTA, and their axons extend to the nucleus accumbens. This centrally located hub connects with many other brain structures, such as the limbic system (the so-called emotional brain, in evolutionary terms very old). Some dopamine fibers also project to a much newer structure, the prefontal cortex, which is involved in cognitive tasks such as memory, planning, attention, and social behavior. Illustration courtesy of the National Institute on Drug Abuse, National Institutes of Health.
Once in the synapse, neurotransmitters swim across it and attach themselves to receptors on the surface of the receiving (postsynaptic) cell. Depending on the neurotrans-mitter, the attachment commands the postsynaptic cell to either do something or not do something. (The nature of the “something” also depends on the neurotransmitter.) Once it has carried out its task, the neurotransmitter is broken up by enzymes or vacuumed up by a transporter molecule and stored for reuse by the presynaptic cell that released it.
After dopamine has been ejected into a synapse, it normally doesn’t remain there long; the presynaptic neuron’s transporter sucks it right back up. But addictive drugs interfere with normal dopamine handling, prolonging its sojourn in the synapses and so its agreeable sensations. Some drugs do this by forcing the presynaptic cell to release more than the usual amounts of dopamine, others by preventing re-uptake by the transporter; some may even do a little of both. Cocaine, for example, imitates dopamine so well that it can bind to the transporter and block dopamine re-uptake. Amphetamines reverse the transporter’s normal function, preventing re-uptake while also using the transporter to pump additional dopamine into the synapse from the presynaptic cell.
As with the other substances in its chemistry set, the brain usually keeps strict control over supplies of dopamine. Too little, and people will develop the tremors and characteristic stoop of Parkinson’s disease. Too much may be responsible for the visions and delusions of schizophrenia. But the right amount of dopamine, scientists think, creates our subjective feelings of enjoyment, delight, even rapture—not just from drugs, but when we are eating ice cream, or making love, or getting a compliment. Defined biochemically, bliss is what we experience when that bolt of dopamine lightning strikes in the nucleus accumbens.
Addictive drugs share one pivotal characteristic: they all increase brain levels of dopamine. Many of the effects of the stimulants amphetamine and cocaine can be explained by their ability to elevate synaptic levels of dopamine and block the dopamine transporter, observes Marina Wolf, who studies addiction in rats at the Chicago Medical School in North Chicago. “So it was logical to go from the importance of dopamine systems in the acute actions of these drugs to proposing that the adaptations that occur when the drugs are given chronically—from the cellular level all the way up to a behavioral level—might be attributable to changes within the dopamine system,” she says.
Opioids also stimulate release of abnormally large amounts of dopamine, employing one of nature’s intricate juryrigged contraptions. Dopaminergic neurons in the ventral tegmentum are regulated by other neurons that keep them from releasing too much dopamine. Those regulatory neurons are studded with opioid receptors; when drugs such as morphine lock on to those receptors, they inhibit the inhibitory neurons. That is, they prevent the neurons from doing their normal job of holding down dopamine production, resulting in the release of large amounts of dopamine.
Nicotine probably activates both the dopamine and opioid overproduction systems, but the details are not yet clear. Ethanol, too, appears to employ the opioid method of disinhibiting dopamine neurons (in addition to its many other activities), but also increases their firing rate in the ventral tegmentum.
In short, each drug makes use of the dopamine pathway in a different way and recruits other brain chemicals (including other neurotransmitters) to help. What follows is a selective and much-simplified account of some consequences of the dizzyingly complicated process of addiction