The Addicted Brain (4 page)
Because the drug self-administration paradigm has been so successful, it is a trusted model for human addiction. It is used to determine if new drugs or medications are potentially addicting. For example, if some compound X affects the brain, it is reasonable to see if it is self-administered. If it is, then it has to be considered as a potentially dangerous and addicting substance.
Because of the robust self-administration of drugs in both animals and humans, there seems no other explanation than the fact that animals and humans share some property in the brain that makes the sensation produced by these drugs desirable. In other words, there seems to be some hardwiring in the brain that is shared by both humans and animals that facilitates drug addiction. The danger of addiction is a biological vulnerability that both humans and animals share. Some see this as evidence that widespread drug-using behavior in humans cannot be simply explained as a moral weakness because a biological basis for it exists.
Looking back, it shouldn’t be surprising that at least some animals share an interest in drugs with humans. In 1871, Darwin made some interesting observations that are humorous and enlightening.
On Booze, Men, and Monkeys
“Many kinds of monkeys have a strong taste for tea, coffee, and spirituous liquors: They will also, as I have myself seen, smoke tobacco with pleasure. Brehm asserts that the natives of north-eastern Africa catch the wild baboons by exposing vessels with strong beer, by which they are made drunk. He has seen some of these animals, which he kept in confinement in this state, and he gives a laughable account of their behaviors and strange grimaces. On the following morning, they were cross and dismal;
they held their aching heads with both hands and wore a most pitiable expression. When beer or wine was offered them, they turned away with disgust, but relished the juice of lemons. An American monkey, an Ateles, after getting drunk on brandy, would never touch it again, and thus was wiser than many men.” (From Charles Darwin’s
On The Descent of Man
, Penguin Classics, pp. 23–24)
Today Google, YouTube, and other websites permit all of us to see what our forefathers must have noted in nature: wallabies munching opium-ripe poppies, tree shrews seeking out fermented palm nectar, and even more examples of animals taking advantage of human brews carelessly left sitting around. Unfortunately for modern man, however, the attraction to alcohol, like attraction to food, can go awry in a world where both are easy to get.
What if every lever press doesn’t result in a drug hit, but rather about every third? As psychologists have discovered, and as any gambler knows, an occasional payoff serves as a stronger reinforcement of a given behavior than does an entirely predictable payoff.
Experiments on food reinforced behavior in the 1950s showed this nicely. Rats traversed a runway to get food as a reward. One group was given a food reward every time they moved down the runway. In another group, there was a reward only about 30 percent of the time. Both groups learned to run down the runway in expectation of a reward. Then the food reward was eliminated for both groups, but they were still allowed to run down the runway in search of it. Now you would expect that the rats wouldn’t give up immediately. They would continue down the runway in subsequent trials even if they were disappointed the previous time, and that’s just what they did. Now here’s the interesting part. The animals that received rewards only 30 percent of the time persisted in the runway behavior
much longer than the rats that were rewarded each and every time (see
Figure 2-2
). They tried for a longer time. A nonregular reward was more reinforcing and shaped seeking behavior more strongly than the regular reward, whereas actually, the opposite might be expected. We seem to want rewards that have been uncertain or not regular more than we do certain, regular ones!
Figure 2-2. Nonregular or uncertain rewards are more addicting or reinforcing. Rats were trained to run down a runway for food. One group was rewarded with food every time, and another group was rewarded only 30 percent of the time. Then the food reward was removed completely. The group of rats that had been rewarded each and every time (100 percent of group) gave up or extinguished their running behavior more readily than the rats receiving a reward only 30 percent of the time. The 30-percent group persisted in running down the runway for longer times and more trials, even though there were no rewards. (Adapted from Figure 4.25 from
Psychology
, First Edition, by Henry Gleitman. Copyright © 1981 by W.W. Norton & Company, Inc. Used with permission of W. W. Norton & Company, Inc.)
This has important implications in our everyday life, where, for example, we may want to shape the behavior of a pet. Suppose a dog begs for table food, and you restrain yourself but nevertheless give in every so often. Although you tell yourself that you don’t do it all the time, and you think you are doing well, you are in fact making it harder for the dog to stop begging. We can easily think of similar scenarios with children, students, and so on. This should give us insight into our own behaviors. Is this why some of us find gambling such a persistent urge?
The animal model of drug self-administration (see
Figure 2-1
) has been critically important for research in drug addiction. Interestingly, our appreciation of the model has continued to evolve. By extending and examining the model more closely, you can study additional aspects or phases of drug addiction. These include: the initiation of drug taking or the rate at which an animal learns to self-administer it; the maintenance of drug taking, which is the phase where the lever pressing has been learned and is stable or relatively unchanging; the extinction of drug taking, which occurs when the lever pressing no longer produces a drug reward and the lever pressing gradually stops; and the relapse to drug taking, which is either stress, cue (see the following sidebar), or drug-induced, and occurs when an extinguished subject begins to seek drugs again. These four phases are different and can rely on different processes in the brain. Moreover, certain medications can be more effective in treating one phase compared to the other phases. Thus, the tools for searching for medications and treatments are becoming more sophisticated.
A “cue,” in this context, is anything that reminds you of drugs or taking drugs. It can be the sight of a friend that you take drugs with, the place where you have taken drugs, or even something like a white powder whether it is drug or not. The importance of a cue is that it can precipitate a relapse. A cue can trigger a response in your brain that makes you want drugs. Someone who wants to stop taking drugs must learn his or her cues, or danger signs, that lead to craving and more drug taking, and he or she must avoid them or neutralize them in his or her mind.
An example of how this model can be used to explore new ideas is an experiment with CART peptide that comes from the author’s laboratory. CART peptide is a chemical found in brain regions that are
involved in drug abuse, and the effect of CART peptide on drug taking can be explored by using this animal model. If an animal has been allowed to learn the self-administration of cocaine, it can then be forced to give up or extinguish lever pressing by requiring a very large number of lever presses to get a reward. Instead of getting a drug injection for every lever press or for every other lever press, the number of lever presses required to get just one injection of cocaine can be made so great that the animal just gives up pressing. Now, here is the key part. The drugs that the animals like better elicit more attempts to get the drug than other less desirable drugs. The number of presses that the animal makes for a drug before it gives up is a measure of how much the animal wants the drug. Suppose animals are allowed to lever press to get injections of cocaine, and they learn to expect this whenever they press the lever. By withholding the drug injection, the number of presses required before they give up lever pressing can be measured. An interesting experimental result is that if CART peptide is injected into critical brain regions, the animal gives up lever pressing
sooner
(
Figure 2-3
). It appears that the animal is less interested in getting a cocaine reward when it has been given CART peptide.
Figure 2-3. Injections of CART peptide reduce cocaine reward and intake. Animals work to receive injections of cocaine by lever pressing because they find cocaine rewarding and they want it. In fact, they press the lever many times to get a single injection of the drug. Now let’s add another part to the experiment. If a drug-free solution (aCSF) is injected into the brain, the animals can still press for cocaine hoping to get some drug (the number of presses corresponds to the height of the bars in the figure). But if CART peptide (2.5 micrograms) is injected into a part of the brain associated with cocaine use (the nucleus accumbens), then the animal works much less for cocaine as indicated by the shorter bar on the right. You can think of the length of the bar as a measure of cocaine’s desirability to the animal, and an injection of CART peptide reduces the desirability of cocaine and shortens the bar. More details about this kind of experiment are given in subsequent chapters. (Summarized from Jaworski et al.. “Injection of CART Peptide into the Nucleus Accumbens Reduces Cocaine Self-Administration in Rats.”
Behavioral Brain Res
191:266-271, 2008.)
The bottom line of the story is that CART peptide injected into the brain can function to make cocaine less attractive. Perhaps CART peptide is part of a chemical reflex that tries to control the excess brain activity produced by cocaine, and more will be said about this in later chapters. But, wouldn’t it be interesting if medications based on CART peptide could be developed to make cocaine less attractive to addicts? This last question is speculative because we need to learn much more about CART peptide before we think about treating humans, but you get the idea. There are many experiments like this using drug self-administration that generate many new ideas for additional treatments.
You can see how important this drug self-administration model is (and other models, too). By showing that drug addiction is a physiological process based in the brain, we can then search for new medications and treatments for addiction that block or reverse the drug-induced processes in the brain. It provides a rational and physiology-based search for new treatments. We can inject drugs directly into various brain regions or surgically alter those regions to define the parts of the brain that mediate addiction. Of course, it goes without saying, that experiments like this using human beings are grossly unethical and impossible.
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Thus, the animal models make significant progress possible.
Drug abuse is a relapsing disorder. In fact, most drug abusers and addicts have stopped or tried to stop taking drugs, only to eventually relapse. So at any given time, most drug abusers are in fact relapsers. Therefore, it is important to study relapse itself, and this is nicely done in a variant of the self-administration model, as mentioned previously. It works by allowing the animal to learn to self-administer a drug, such as cocaine, until the lever pressing is stable. Then, the drug is withdrawn, and, as expected, the animal gradually tires of lever pressing without a reward and the lever pressing behavior is extinguished. This animal is now an experienced drug user, much like most humans who have used drugs but have stopped. A human in this condition likely thinks about the drug, and when stressed or reminded of the drug, perhaps by some cue, craves the drug and perhaps starts looking for a drug. The cue can be the sight of friends who use drugs, the crack house, or even some white powder that reminds him or her of the drug. Cues and their effects are very interesting and currently studied. For example, Drs. Leslie Lundahl and Chris-Ellyn Johanson recently found that drug-related cues set off cravings in marijuana-dependent subjects.
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Getting even a small amount of the drug (which is a cue) might set off a binge of drug taking. So, as you can see, certain events can trigger craving, drug seeking, and relapse.