The Addicted Brain (15 page)
4
Kuhar, M.J. “Measuring Levels of Proteins by Various Technologies: Can We Learn More by Measuring Turnover?”
Biochem Pharmacol
, 79:665–668, 2010.
5
Nader M. et al. “PET Imaging of Dopamine D2 Receptors During Chronic Cocaine Self-Administration in Monkeys.”
Nature Neurosci
, 9:1050–1056, 2006.
“Why me, Doc? Why am I the one hooked on drugs in my family? Why do I have all this trouble? Maybe I’m a bad seed...” Conversations like this can be common between drug users and their doctors. Understanding why someone is a drug user is a complex and important problem.
Drug users are a diverse population of individuals, and drug abuse, in general, is a complex process. But, key questions are the following: What traits or characteristics do drug users share? Can we identify groups or individuals that will become addicts or are in danger of becoming addicts? It would be a great thing if we could, because then we could target these people for prevention and treatment. Targeting just this group would likely save lots of money and possibly be more effective because the efforts would be focused rather than broadly aimed and widespread.
It turns out that we have studied drug users and addicts and have identified factors that are more common among them than among the general population. These factors contribute to the vulnerability to becoming a drug user. At the outset of this discussion, we can say that we don’t know enough about vulnerability to precisely predict who will become an addict and who won’t. There is no mathematical equation that we can use! Rather, vulnerability studies provide more of a
probability
of becoming a drug user. In general, the more
vulnerability factors that a person possesses, the greater the likelihood that he or she will become an addict—but again, there is no certainty. Nonetheless, someone with vulnerability factors should be interested in this topic in order to assess what he or she needs to do to avoid becoming involved with drugs. It can be scary for many to face this, but understanding vulnerability is one of the best ways to prevent drug use and become a healthier person in general.
There are a large number of factors that contribute to vulnerability (see
Figure 8-1
), and some of the most critical ones are discussed here. The first ones are the biological factors, which help us address a key issue: Is it in my genes? If so, will I become a drug user no matter what I do?
Figure 8-1. Overall vulnerability to drug use comes from several interacting factors. Let’s consider three factors in becoming a drug abuser. First, there is the drug, which might or might not be addicting (hence the + or –), but for our discussion it is an addicting substance. Then there is the person who has a genetic basis that might or might not (hence the + and –) support drug taking. Lastly, there is the complexity of the environment, in which there might be drugs and various factors that might or might not support drug taking. Thus, the overall vulnerability can be high or low depending on each factor and how they add up or interact. On the right, the range of possible outcomes are listed. Treatment should address all of the factors. (Adapted from“Figure 1” from O’Brien, CP. Review: Evidence-Based Treatments of Addiction. “Philos Trans R Soc Lond.”
B Biol Sci
. 363(1507):3277–86, Oct 12, 2008, with permission.)
After a person’s first exposure to a drug, his or her biological makeup plays a major role in determining whether he or she will become a drug abuser. Because a person’s biological makeup is determined by genes, there has been a focus of research on genes that are involved in drug abuse. Studies of genes have developed exponentially over the last couple of decades. Many of these studies rely on mutations that we carry and they can be identified by amazing, high-throughput technologies.
Tracking Genes
Understanding genes, their mutations, and how they are used gives us an appreciation of how genetic studies are carried out in addiction and even in other diseases.
Imagine your ancestors, many, many generations ago. You have many men and women in your ancestral tree and the further you go back in time, the more there are. Over time, mutations occur in various genes, and if they are not fatal, then they are passed on from generation to generation. Some of the mutations might be small without any functional effect, or some might have an effect that reduces function but is not fatal. The mutations that are not fatal are passed down and—here is the critical part—they can be detected as markers of heredity. In other words, if a group of people have the same mutation that is not found throughout the population, then chances are that the members of the group share a common ancestor. Because they share the same mutation, they also share and express the effects of that mutation, which, for example, might be a slightly increased liking (or vulnerability) for certain kinds of drugs.
The following schematic shows DNA in the well-known shape of a double helix.
The genetic markers that are used in studies of heritability are often single nucleotide polymorphisms (SNPs). Genes consist of strings of molecular units called nucleotides. Nucleotides come in four varieties, which differ from each other only in the subunits known as bases. Each nucleotide is named after its base: adenine (A), thymine (T), cytosine (C), or guanine (G). At many locations in the human genome, the nucleotide string that makes up a particular gene is identical in everyone. That is, if you start at one end of the gene and count off the nucleotides in order along one of the two DNA strands, the result is the same—for example, AAGGGATCCAC. At certain places along the string, however,
some people have one nucleotide and others have a different one
—for example, AAGGAATCCAC, instead of
the more common sequence. Such a variation is a SNP (also see the next sidebar “
Genome-Wide Association Studies [GWAS]
”). (Adapted from
http://en.wikipedia.org/wiki/File:Dna-SNP.svg
, accessed on November 23, 2010.)
A powerful study was carried out by Dr. George Uhl and his colleagues at the National Institute on Drug Abuse. They used an approach called
genome-wide association studies
(see the next sidebar “
Genome-Wide Association Studies [GWAS]
), where the genes in drug users are compared to those in non-drug users (or in low-level drug users). After examining the genes in these populations, they found that 89 genes were associated with drug use. Uhl explained further that “unlike cystic fibrosis which is caused by a single (defective) gene, in addiction and a number of complex disorders, many different genes must act together with environmental factors to create the illness. No single gene is likely to have a large effect by itself; it’s the combination of effects that produce...the problem.”
1
Many of these 89 genes were known to be associated with memory formation, receptors, and adherence of neurons to each other. It makes sense that those kinds of genes would be involved in drug dependence, which produces biochemical and functional changes in the brain.
Genome-Wide Association Studies (GWAS)
GWAS is a powerful way to identify genes that are associated with traits or diseases. It depends on having a test population that has the trait of interest (such as drug taking) and a control population that does not have the trait. Then, all the genes in all of the subjects are characterized and the occurrence of genetic markers in the populations are compared.
The genetic markers that are used are SNPs (see previous sidebar, “Tracking Genes”).
Studies can look at hundreds of thousands of SNPs that occur among our approximately 30,000 genes by relatively rapid, computerized techniques.
The variations (SNPs) might or might not make a difference in the way a gene functions. (For example, two similar model cars but with different color are like SNPs where there is no difference in function. But the same model cars with very different sized engines might function differently.) So, SNPs don’t have to be functionally powerful; but they are good markers for studying the heritability of specific genes. Scientists can take advantage of the SNP variations to discover associations between genes and critical traits, such as vulnerability to drug addiction. For example, if a certain SNP occurs more often in drug abusers than in non-drug abusers, then the gene that contains the SNP is said to be associated with, and possibly partly causing, drug addiction. (Adapted from “New Techniques Link 89 genes to Drug Dependence,”
NIDA Notes
, Vol. 22, September 2008.)
There have been interesting new discoveries about the genes related to smoking and the vulnerability for nicotine addiction. As noted, nicotine works in the brain by stimulating receptors for acetylcholine, which are referred to as nicotinic cholinergic receptors. Nicotinic receptors are made up of five separate proteins that bundle together to form a functioning receptor. These proteins, or subunits, have been identified and studied (see
Figure 8-2
); when combined, they create the various subtypes of nicotinic receptors. Surprisingly, there are more than five subunits, but only five are used in any given receptor. When the different nicotinic receptors have different subunits, they might function differently, and different people inherit different subunits from their parents.
Figure 8-2. Nicotine acts at receptors for the neurotransmitter acetylcholine. These receptors, which are ion-gated receptors, are shown from a more sideways perspective in
Figure 4-2
, but from a more top-down view in this figure. These nicotinic cholinergic receptors are composed of five subunit proteins that bundle together to form a circle around a central pore. When acetylcholine or nicotine binds to the receptor proteins (at the places marked with an asterisk), ions (electrical charges) migrate through the pore into the post-synaptic neuron. The receptors can be composed of a variety of different subunits to produce a variety of subtypes of nicotinic receptors. Some of these subtypes are shown in the figure. Receptors comprised of different subtypes might function differently and confer different levels of vulnerability to smoking. (From NIDA Notes, “Studies Link Family of Genes to Nicotine Addiction,” Vol. 22, December 2009.)
Now here’s the relevant part. Studies have linked various subunits to aspects of smoking (see the following sidebar). It is this kind of research that leads to real understandings of the molecules of addiction—and ultimately to improve medications for such addicts. Again, the brain is complex, and having a “bad” subtype does not mean that someone will, without question, have the addiction. But, he or she will have an increased overall vulnerability.
Genetic studies have become amazingly sophisticated, and it is a triumph that many different receptor subunits have been related to aspects of smoking. This sidebar summarizes some of the work in this area relating smoking to nicotinic receptor subunits. Findings such as these can guide our efforts in the search for new medications, and they offer hope that someday we will understand enough about drug addiction that we can develop better medications for treating drug users. (Adapted from NIDA Notes, “Studies Link Family of Genes to Nicotine Addiction,” Vol. 22, December 2009.)