The Addicted Brain (14 page)

Because of the long-lasting changes in receptors (and presumably many other proteins), the brains of addicts will function differently for a long time.
²
In fact, imaging studies clearly show long-lasting changes in brain function in addition to changes in protein levels
.
Figure 7-3
shows that taking cocaine for a long time causes significant changes in energy metabolism (a measure of function) in the brain. Levels of energy metabolism (indicated by light areas in the image) are compared in a normal subject, a cocaine user who has not taken cocaine for 10 days, and one who has not taken cocaine for 100 days. It is clear that even after 100 days of abstinence, the brain has not returned to normal.

Figure 7-3. Energy metabolism is changed in abstinent cocaine abusers for months. The more lightly colored areas are regions of higher energy metabolism. The changes are notable in the frontal lobes, the brain regions where impulses are regulated. These experiments were carried out using PET scanning after injecting a radioactive form of glucose. The regions with higher levels of radioactivity show the brain regions where metabolism and neuronal activity are higher. (Courtesy of NIH/NIDA and adapted from
Time Magazine
, page 45, July 16, 2007.)

Many investigators have also found changes in animals’ dopamine receptors and transporters after administering drugs. These studies often used another breakthrough technique referred to as
in vitro labeling autoradiography of receptors
, which was developed in the author’s laboratory at The Johns Hopkins University School of Medicine in the late 1970s.
³
When the same results are found using different techniques, species, and approaches, there is much greater confidence in the results.

This is an interesting question, but the answer is not yet known. Levels or amounts of protein are interesting and informative because more protein results in more function, less protein results in less function, and also because changes in proteins point out where the effects of drugs are taking place. How do changes in proteins occur? It is perhaps obvious that the levels or amount of any given protein in the brain (or in any organ) are due to a balance between the synthesis and degradation rates of the protein. Protein levels can increase due to an increase in synthesis or to a decrease in degradation, or both. All proteins “turn over,” meaning that they are used, worn out, and then replaced by new protein.
⁴
Let’s consider this in a more graphic fashion. If we were able to label every protein molecule in our brain at any given moment with a small flag, we can watch this turnover and replacement because the new proteins will not have a flag. The time it takes for half of the flagged proteins to be replaced by new ones is called the
half life
. Every protein has an existing synthesis rate and degradation rate, and drugs can change them.

The time that it takes a protein to reach a new level after a change in synthesis or degradation depends on the
speed
of the changes in synthesis or degradation. For example, proteins that increase their levels more quickly are synthesized more quickly, degraded more slowly, or both. This is interesting because we scientists think we know something about protein synthesis and degradation and therefore have some ideas about why some protein changes in the brain can last a long time. Moreover, and importantly, we can examine whether there are worthwhile experiments where we can reduce recovery time for addicts by creating conditions in the brain where proteins change their levels more rapidly! For example, if D2 dopamine receptors are resistant or slow to change their levels in drug addicts, as experiments show, then their synthesis rate might be relatively fast and their degradation rate relatively slow. Thus, we can begin to think about whether or not we can control synthesis or
degradation rates, perhaps by new medications. If we could normalize D2 receptor levels more quickly, would this help the addict recover more quickly? As intriguing as this sounds, the technologies currently available in protein biochemistry are not yet advanced enough to produce a medication that would be
selective
in changing the synthesis or degradation of a single protein such as D2 receptors. But, it is useful that we have some general idea as to what controls the levels of D2 receptors in brain and this knowledge might be helpful in the future. However, this general answer about synthesis and degradation is not good enough. We need to find out more about why certain, specific brain changes are so long lasting.

There are other possible answers to this question. Gene expression, which ultimately influences the synthesis rates of proteins, and can be altered by drugs, might be altered for a long time by drugs. This could occur because of epigenetic changes or by long-lasting changes in levels of transcription factors, which regulate genes (
Chapter 5
, “The Dark Side Develops!”).

Discovering that drugs change the brain for a long time is one of the most important discoveries in the field. Even though we still don’t know how to treat the brain so that the changes revert to normal more quickly or even how to prevent the changes, this knowledge has a big impact in many ways.
First
, it helps us understand the problem of drug addiction in a basic and mechanistic way. The duration of the changes explain why drug addiction appears to be chronic, and it seems likely that a lack of appreciation of this contributes to relapse.
Second
, it defines a critical problem in the research laboratory—how exactly do the changes occur and how can we block or reverse them? If we can block or reverse the brain processes that underlie addiction, then we can treat addicts better.
Third
, just knowing that the brain is
changed for a long time tells addicts that recovery is going to be a slow process, lasting months. If they know that they will be vulnerable for a long time after cessation, they will hopefully be more vigilant and stay away from drugs during this dangerous time.
Fourth
, the addict’s support system, which is usually made up of friends, family, and treatment providers, now know that vulnerability to relapse lasts many months and the addict will need a support system that extends in time. Novel treatment paradigms that provide long-term support might be needed.
Fifth
, lawmakers and policy makers that regulate treatment and payments for treatment are now informed that this brain disorder/illness lasts a long time. Would you want reimbursement from insurance for only one day of antibiotics if a known type of infection takes seven days to eliminate? Of course not. Hopefully, not all effective long-term treatments have to be expensive. As you can see, understanding and dealing with the long-term effects of addiction is challenging on many fronts!

After someone has been an addict, does his or her brain ever normalize? This is one of the most important questions in the field. Some believe that at least some of the changes caused by drugs last forever, which if true, will impact treatment. Although evidence is still accumulating, there are some findings that we can examine. Twelve-step programs such as those used by Alcoholics Anonymous and Narcotics Anonymous assume that addicts have a chronic disease and chronic vulnerability. Using this assumption, these programs suggest that addiction is never cured, but can be treated by avoiding drugs. This is perhaps the safest approach to treatment. These programs have an effective track record with effective procedures. Perhaps some brains carry a chronic vulnerability that can’t be completely reversed, and perhaps some can be changed by treatment. Additional research is needed to discuss this question in a more informed way.

An interesting study by Dr. Michael Nader and his colleagues at Wake Forest University looked at the recovery of D2 dopamine receptors in the brains of five monkeys.
⁵
When the animals self-administered cocaine for some time, their levels of D2 receptors dropped as expected (low D2 levels reflect a propensity to take drugs). The receptor levels were then monitored after cessation of cocaine use for the next 12 months. In three of the five animals, the receptors returned to normal levels by three months (this seems to be faster than it happens in humans). But in two of the monkeys, the levels did not return to normal even after 12 months! So there were individual differences in the monkeys in that some reverted to normal and some didn’t. This is just like humans. Individual differences in human drug users have long been noted as important. Based on this study’s results, you see that all drug users are not the same and treatment has to be flexible to take into account individual differences.

Here is an anecdote from my own history. As a young man, I smoked tobacco for years. But, when a relative died of lung cancer, I decided to stop smoking—and much to my surprise (it shouldn’t have been)—I craved tobacco for a long time! The second six months of abstinence produced worse craving than the first six months (at least it seemed that way). I especially craved when others smoked after a meal, which was the time when I enjoyed smoking the most. Sometimes I would even get up and leave the table so I wouldn’t be affected by others’ lighting up. After about a year, the craving for tobacco began to reduce, and after about 18 months, I experienced no craving at all. Today, many years later, smoking bothers my throat and lungs and leaves me coughing, and I consider myself totally cured of that addiction. Because of this, I feel that addiction is curable (at least in my case). Still, I can’t be absolutely sure that there isn’t some residue of change left in my brain that somehow increases my vulnerability to relapse. If there is some lasting change in my brain, it doesn’t seem significant at all. Take note, however, that this single story does not minimize the fact that many drug users might crave for longer times or might never stop taking drugs.

Drugs change the biochemical makeup of the brain for a long time, and the changes persist long after one stops taking drugs. This presumably explains why drug addiction appears to be a chronic and relapsing disease. Laboratory research has shown that this finding can be understood in terms of drugs causing changes in levels of functionally important proteins. The mechanisms that drugs might use can include epigenetic changes or other changes in gene regulation. However this limited understanding needs substantial improvement. The realization that the brain changes for a long time has had a major impact on our goals and methods for developing and delivering treatments. Because the duration of the changes might be different for different drug users, the ability of an individual drug user to recover from addiction might require a custom-made treatment program.

¹
The development of PET scanning as we know it today took more than half a century. The concept of emission and transmission tomography was introduced by David Kuhl and Roy Edwards in the late 1950s. Tomography is producing images of sections of the body through the use of any kind of penetrating wave (such as gamma radiation). Michel Ter-Pogossian and Michael E. Phelps at Washington University School of Medicine, and Gordon Brownell and Charles Burham at Mass General, also made significant advances in PET technology. However, it was Al Wolfe and Joanna Fowler at Brookhaven National Labs that contributed to the acceptance of PET by the development of 2-fluorodeoxy-D-glucose—a chemical that is used to measure metabolism in the brain. They, along with Abass Alavi at the University of Pennsylvania, showed how PET can be used to monitor activity in the brain. PET scanning of receptors in the brain was developed at Johns Hopkins in the early 1980s by a team lead by Henry
Wagner. Mike Kuhar, the author, was a senior member of the team who had carried out receptor imaging in the brain by a different but invasive approach called autoradiography. He brought that skill to the PET team.

²
For review, see Volkow N. et al. “Imaging dopamine’s role in drug abuse and addiction.”
Neuropharmacol,
56 (Suppl) 1:3–8, 2009.

³
Receptor autoradiography is a procedure that visualizes drug receptors in slices of brain with the microscope. Being able to see receptors and where they are is an immense help in determining what drugs might be doing in the brain and how the brain adjusts to repeated drug taking.

Human interest stories about scientists can be fascinating. James Watson’s “Double Helix” was quite popular. Sometimes scientists, being human, forget who did what and how things were done. In a book called
Molecules of Emotion
(New York: Scribner, 1997), the author confuses the order in which things were done and who did the developmental work in receptor autoradiography. In fact, the home department of the senior developer was not even correct in the book. The autoradiographic approach to localizing receptors in brain was done by the author (M. Kuhar), a collaborator (H. Yamamura), and a graduate student (W.S. Young III) who are the authors of the relevant papers. Existing notebooks, photography logs, publications, and written recollections of those involved solidly support this. The appropriate publications are Kuhar, M.J. and H.I. Yamamura. “Light Autoradiographic Localization of Cholinergic Muscarinic Receptors in Rat Brain by Specific Binding of a Potent Antagonist.”
Nature
, 253: 560–561, 1975. Young, W.S. and M.J. Kuhar. “Autoradiographic Localization of Benzodiazepine Receptors in the Brain of Humans and Animals.”
Nature
, 280: 393–395 1979. Young, W.S., III, and M.J. Kuhar. “A New Method for Receptor Autoradiography: [
³
H]Opioid Receptors in Rat Brain.”
Brain Research
, 179: 255–273, 1979. Collaborations with others began after the details were worked out by this initial group.