Research

Drugs affect the functioning of the brain's chemistry. As a result of these effects, a person who uses drugs can become a slave to them. But the brain has its own processes that set the stage for addiction. Research attempts to identify what those processes are and how they work. Addiction is a uniquely human problem, yet the qualities of addiction can be modeled in animals. Research shows that even rats can be turned into drug addicts.

When it comes to choosing an addicting drug, rats are not all that different from people. Scientists can set up experiments in which rats will give themselves repeated doses of drugs that humans find appealing and addicting. Research into human drug addiction that relies on animals may reveal new ways to treat, and even prevent, human problems with addictive drugs.

Reward Center

Experiments have shown that rats with a tiny wire placed in the pleasure-sensing region of the brain will repeatedly press a bar that sends a slight current out of this probe's microscopic tip. Called an electrode, the wire is designed to deliver the small amount of electricity to a brain region that the researcher selects, based on available maps of the brain.

Self-stimulation experiments in rats have repeatedly demonstrated the presence of a reward center in the brain. Scientists observe the behavior of the rats fitted with electrodes. They count the number of times the rats press the bar, and compare the number of bar presses that results when the electrode is in the reward area, compared to the number that results when the electrode is just outside that area.

To train a rat to press a bar, scientists use food as the reward. Before the experiment begins, electrodes are placed in the rat's brain under surgical anesthesia. Then, for a few days, the rats are given less food than they usually would eat. Next, they are put into a box (called a Skinner box after the behavioral scientist B. F. Skinner, who invented it in the 1930s). The box has a bar that, when pressed, delivers food. The rat does what rats naturally do in a new place—it explores the box by sniffing around and rearing up on its hind legs. The rat can smell that there is food somewhere near, and the rat is hungry. By chance, when coming down from a rearing position, the rat's paw will hit the bar. Suddenly, food appears. The rat learns fairly quickly to repeat this behavior to get more food. It becomes very efficient at pressing that bar to get food, an action called self- administering.

Now, the mechanism that gives food when the rat presses the bar is changed so that no food is delivered, and the electrode is activated. The question is, will the rat continue to press the bar? In other words, will the feeling created by the current inside the brain be rewarding in and of itself, and substitute for food? If the electrode stimulates the reward circuitry inside the brain, the answer is yes. However, if the electrode missed its mark, the rat will soon stop pressing the bar. The bar presses no longer deliver anything of interest to the rat.

How Research Proceeds

Based on this rat model of reward, scientists concluded that the brain has a specific place where rewarding feelings are generated. Researchers were able to determine that any area stimulated by an electrode and giving a sustained rate of bar pressing was in fact a reward area. They could count the number of times that a rat pressed the bar, comparing a weakly rewarding area to a strongly rewarding area. By interpreting the data—the rates of bar pressing—region by region, the researchers were able to map a set of places in the brain that consistently generate reward.

Researchers collected these measurements of reward regions from their rat experiments, and compared the active reward areas to the existing maps of brain functions, including areas where they know which neurotransmitters are present. The researchers predicted that the electrode had to be in regions that are rich in the neurotransmitter dopamine for the rats to press the bar repeatedly.

In another method of experimenting, scientists used a tiny, hollow tube to deliver minute amounts of drugs directly into the reward areas of the brain. The animals pressed a bar until they were exhausted in order to deliver such substances as heroin, cocaine, and other drugs into the specific brain structures making up the reward system. Rats self-administer the most popular drugs of abuse to the point of ignoring food and even sex in some instances—just as people do.

There are several variables in these experiments that must be considered before interpreting the results, or data. These variables include: the location of the electrode inside the brain; the amount of current used; and, in the case of drug delivery directly into the brain, the amount, or dose, of drug given. Checking to see that the electrode is working properly is essential to conducting a good experiment. If it is not, this variable can make it impossible to interpret data correctly. The electrodes are intended to deliver the current only at their tips. The researchers locate just where the tips are placed in the brain in order to make their maps of the reward circuit. They make sure that the insulation placed around the wire up to the tip is not leaky so that current will not leak out along the shaft of the electrode. If it does leak, some other brain area that the electrode passes through will be stimulated.

Even the sex of the tested animal is important to take into consideration when interpreting results. For some drugs, certain experiments reveal differences between males and females. For instance, female rats appear more sensitive to morphine-like drugs, and continue to self-administer these types of drugs long after male rats stop.

Rat Research and Brain Opiates

Opiates, such as morphine, are drugs made from the opium poppy that have powerful effects on the brain. One of these effects is to stop pain. Opiates are used as analgesia to make a patient more able to tolerate pain after surgery, or for conditions where pain itself is the problem, such as cancer. In the 1970s, the results of a set of experiments showed that the brain is somehow able to control pain on its own. The brain can regulate how it perceives pain by releasing its own painkiller molecules. These simple protein-like materials, produced within an animal's nerve cells, work in much the same way as the molecules of the opium poppy plant. Scientists had discovered the brain's own opiates.

An experiment with rats that had electrodes placed in a core region of the brain showed that they could undergo surgery without any anesthesia if these electrodes were activated. Other scientists then analyzed the region, called the central grey region, using opiate drugs as tracers. These opiate drugs were tagged with a chemical or radioactive label that would show up under the microscope. The opiate drugs stuck to the central grey region in large amounts—in other words, this region was rich in opiate receptors, specific binding sites that take up the drugs. Teams of scientists at Johns Hopkins University in Baltimore, Stanford University in Stanford, California, New York University in New York City, and at a research center in Sweden all helped demonstrate that certain receptors specifically accept morphine and related drugs. The drugs "dock" on these opiate receptors and act to stop pain.

Other researchers examined brain regions that were rich in opiate receptors and found that they also contained a substance that would bind to opiate receptors. In 1973 John Hughes and Hans Kosterlitz in Aberdeen, Scotland, showed that pig brains contained two similar small molecules that acted much like morphine when they were extracted, purified, and injected into lab animals. The shapes of these previously unknown molecules were shown to resemble closely the opiates from poppies and other narcotic drugs created by human chemistry. Named enkephalins, meaning "in the head," they unfortunately proved to be addictive, just like morphine: the effect of the purified enkephalins in animals would lessen unless increasingly higher doses were used.

Years before, Choh Hao Li, at the University of California in San Francisco, had looked at a substance he purified from a gland at the base of the brain. Li believed that this pea-sized gland, called the pituitary gland, might have a substance that aided the body's handling of fat (fat metabolism). Because the gland is so tiny, Li used material from 500 camels to find and purify a single molecule. But this molecule did not do much in his experiments on fat metabolism. Puzzled by his lack of results, he put the molecule in storage.

Sometimes, science involves luck and timing. But it always requires a prepared mind to recognize the significance of a finding and how to fit it in to an existing or developing theory. When Li read of the work on the brain's own opiates, he retested his molecule. He found that it, too, could lessen the perception of pain. This was a bigger messenger molecule, more closely resembling other messenger molecules, called hormones, that come from the pituitary. The small enkephalin molecules are similar in size to many neurotransmitters in neurons. Many hormones come from the pituitary, rather than the small, enkephalin molecules in neurons.

Li's molecule obviously was doing something other than handling fat. Scientists quickly renamed Li's hormone endorphin, meaning "the brain's own morphine." Endorphin lasts longer when injected than the much smaller enkephalins, which are nearly instantly broken down by the body. Yet it, too, is addicting. The discovery of the brain's own opiates has not yet led to the design of painkillers that are free from addicting qualities. But it has deepened researchers' understanding of how the brain works, especially at the level of molecular signals.

Experiments throughout the 1970s and 1980s mapped out an opiate-rich circuit within the brain. Many of the areas loaded with the enkephalins or endorphins correspond to regions known to carry pain messages, and to control the brain's ability to acknowledge pain, or to ignore it. And parts of this opiate circuitry overlap with the brain's reward pathways.

Imaging the Living Brain

By 2000 researchers had confirmed that the findings about brain chemistry and addictions in rats apply to brain chemistry and addictions in humans. The same areas mapped in the rats light up when the brains of humans, either using or recovering from addicting drugs, are scanned. Positron emission tomography (PET) is a technique that shows the use of energy by the brain. PET scans can show differences in brain activity in the reward circuitry when cocaine is taken, compared to a normal pattern of brain activity. Also, PET scans suggest that the drug ecstasy can alter the workings of a transmitter called serotonin in the brain of someone who takes the drug repeatedly. In fact, PET scanning reveals that dopamine, the messenger molecule of the reward circuit, is involved in nearly all addictive behaviors that scientists examine. Even alcoholics and obese people have a detectable difference in their dopamine activity on PET scans.

Now that scientists can see inside a living, working human brain, they are trying to uncover the details of addiction. Craving for a drug once addiction develops turns out to be a separate phenomenon, and one that may be key to interrupting the process of addiction.

Surprisingly, rats that were once addicted to cocaine did not re- lapse when stimulated in the reward area of the brain. Instead, findings reported in 2001 show that the hippocampus region of the brain, involved in forming memories, was crucial for seeking more drug. The hippocampus, with its rich connections to the reward centers, and the cerebral cortex—the outer region of the brain—may be prompting the drug-seeking behavior.

The brain remains the most complicated frontier for advancing our comprehension of ourselves. Formulating new models, and revising prior ones, will help those who seek release from addictive behavior.

see also Brain Chemistry; Brain Structures; Drug Testing in Animals: Studying Potential for Abuse; Drug Testing in Humans: Studying Potential for Abuse; Imaging Techniques: Visualizing the Living Brain.

WANT TO KNOW MORE?

For an illustration of PET scans, check out the National Institute on Drug Abuse's site, at http://www.drugabuse.gov/Teaching3/teaching3.html, slide 10 and 11. Another good web site is Brookhaven Lab's site, at http://www.bnl.gov/pet/ studies.htm.