Gotta Have More and More

One of the hallmarks of addiction is tolerance to the addicted substance. It means that more and more drugs are needed over time to produce the same response, or that the same dose of drugs now produces a lesser response. If you originally got high on one pill of a drug, with continued use it might take three times as much drug to get a similar high. So addiction is not only the compulsion to keep taking the drug, but also, in many cases, the compulsion to take more and more drugs to get the same response. A basis of tolerance is at least partly due to changes in the molecules of synaptic transmission. Tolerance is well documented in humans for many drugs. For some drugs, at least part of tolerance is due to the fact that the liver adapts and metabolizes the drug faster. However, many changes in the brain are also needed to explain tolerance. Dr. Bill Dewey, Professor at Virginia Commonwealth University, along with others, have described how tolerance has many different mechanisms in different tissues. It is more appropriate to talk about many different kinds of tolerances, rather than just one tolerance.

With psychostimulants such as cocaine or amphetamine, a reverse tolerance or sensitization can occur. The same dose of drug now produces a greater response instead of a lesser response, and this has been studied in animals. Both tolerance and sensitization are regarded as adaptations of the brain3 to repeated drug taking.

What Is Happening in the Brain?

The brain is the organ of behavior, and if we have a compulsive drug-taking habit, then that compulsivity is based in the brain. We know from the previous chapter that drugs of abuse change chemical signaling, and this chapter explores how chemical signaling can change gene and protein expression. Because we have directly measured gene expression in the brain, we know that drugs do in fact produce such changes.

Every cell in our body, including neurons in the brain, has a nucleus that contains chromosomes. Each chromosome has a number of genes, which are made up of stretches of deoxyri-bonucleic acid (DNA) (see Figures 5-2 and 5-3), and genes are units that code for a particular protein. Proteins in the body produce obvious traits such as hair color or the particular sound of our voice.

Figure 5-2 The DNA in our genes code for specific proteins. This simple figure is one of the most important. It shows that DNA, which is the material that contains our genes in the chromosomes, is the template on which messenger ribonucleic acid (mRNA) is made. In turn, mRNA is the template on which proteins are made. A mutation in our genes, which is a change in the structure of our DNA (see Figure 5-3), leads to a changed protein, which might or might not be functional. The proteins in our body are ultimately responsible for how we look and behave. Something that is not shown schematically is how the activity of the gene is regulated. Special proteins, called transcription factors, bind to the DNA and regulate the levels of mRNA and protein that are produced. Neurotransmitters can regulate the activity of transcription factors. Thus, drugs can alter gene expression and ultimately protein levels.

Figure 5-3 The helical structure of DNA. The DNA molecule is composed of two similar and complementary strands that bind together. The strands are like a twisted ladder (helix), where the rungs are the special chemicals or bases that make up the genetic code. The names of the bases are abbreviated as A, T, C, and G. A gene is a length of DNA that ultimately produces a protein. By complementary, we mean that Gs and Cs always match up and As and Ts always match up. Each group of three bases make up a codon that codes for a specific amino acid. So, all of the proteins in our body are specified by the codons in our genes. A mutation occurs when one of the bases is changed, for example, a G to a C. This changes the protein that is made by one amino acid, but that can be significant in some cases. (Adapted from: http://en.wikipedia.org/wiki/File:Dna-SNPsvg, accessed January 24, 2011.)

mRNA

> Protein

Figure 5-3 The helical structure of DNA. The DNA molecule is composed of two similar and complementary strands that bind together. The strands are like a twisted ladder (helix), where the rungs are the special chemicals or bases that make up the genetic code. The names of the bases are abbreviated as A, T, C, and G. A gene is a length of DNA that ultimately produces a protein. By complementary, we mean that Gs and Cs always match up and As and Ts always match up. Each group of three bases make up a codon that codes for a specific amino acid. So, all of the proteins in our body are specified by the codons in our genes. A mutation occurs when one of the bases is changed, for example, a G to a C. This changes the protein that is made by one amino acid, but that can be significant in some cases. (Adapted from: http://en.wikipedia.org/wiki/File:Dna-SNPsvg, accessed January 24, 2011.)

But the effect of most genes and their proteins are more subtle and do not produce an obvious or visible trait. Rather the proteins might help the brain function in several different ways: by facilitating chemical neurotransmission in certain parts of the brain, by changing the number of synapses in certain places, or by changing energy metabolism. The point is that proteins determine how the brain (and the individual) functions or at what level it functions. A major reason why protein levels change is because of changes in the activity of genes or in gene expression. Changing gene expression ultimately has an effect somehow, somewhere. And, as we have said, drugs of abuse cause changes in gene expression that, in the end, result in a behavioral state characterized by the urge to find and take more drugs!

It's the Molecules that Do It

The key to understanding the compulsion to take drugs begins in the synapse and the next or postsynaptic neuron (refer to Chapter 4, "The ABCs of Drug Action in the Brain," Figures 4-1 and 4-4). When drug taking results in either increases or decreases in neurotransmission, gene expression is likely to be altered. As described previously, neurotransmission involves signal transduction, which is the change that occurs in biochemical pathways inside the neuron after a receptor is stimulated. A key feature of this process is the activation of transcription factors by intracellular signaling (see Figure 5-4).

Transcription factors are proteins that interact with the parts of the genes called the promoter that controls whether or not the gene is expressed and makes proteins (see Figure 5-4). Our knowledge of transcription factors and how they interact with genes is growing. You can think of a transcription factor as the hand that touches the door knob (which is analogous to the promoter part of the gene) and turns it; the opening of the door is like an increase in gene expression. An interesting discovery has been that there are some transcription factors that build up in neurons with repeated cocaine administration. For example, Dr. Eric Nestler and colleagues discovered a transcription factor called delta Fos-B, whose levels incrementally increased with each cocaine injection, causing it to become more and more powerful in changing gene expression.

CPl Neurotransmitter

CPl Neurotransmitter

Figure 5-4 Drugs change gene expression by signal transduction. An example of the complex process of signal transduction is shown in this diagram of part of a neuron containing a receptor embedded in the cell membrane. Near the center of the nerve cell body is the nucleus with its DNA/chromosomes depicted as a double-stranded helix. The chromosomes contain the genes, some of which are activated at any given moment. On the top part of the neuron is a transmembrane receptor with a notch in the top. The transmembrane receptor is about to bind a neurotransmitter. When the neurotransmit-ter binds to the receptor, the receptor changes shape and activates a series of processes inside the cell referred to as a cascade, because it is a series of connected steps. The cascade activates other proteins, called transcription factors, which regulate gene expression. In other words, an activated transcription factor can turn on or shut off the expression of genes in the chromosomes. Because drugs can drastically alter the action of neurotransmitters, drugs can drastically alter gene expression through this mechanism. Also, signal transduction can produce epigenetic changes where there are alterations in the copying of the DNA. Changes in gene expression alter the biochemical makeup of the cell and therefore the function of the cell. (Image courtesy Dr. Danton O'Day, University of Toronto Mississauga.)

This understanding of how drugs change the brain has been a major achievement of the last many decades. The goal of research now is to identify the most important genes and the most significant brain regions that cause drug addiction.

An aside is that drugs can also produce other kinds of changes in brain. One of these is phosphorylation, which is adding a phosphate to various proteins, such as the phosphorylation of transcription factors, which can increase their activity. These changes are important for the effects of drugs, but the long-term changes are usually associated with changes in gene expression.

Epigenetic Changes

A change in the production of a protein is almost always due to a change in gene expression.4 Thus far, we have discussed the ability of transcription factors to alter the expression of genes, but another way has been found in recent years. This has been referred to as Epigenetics (see the next section, "Epigenetics: A Way to Change the Brain"). Epigenetic changes occur when the environment (for example, a drug) influences our genes in a lasting way, such that some genes become inactivated, or perhaps more activated. This change in activation occurs by chemically altering the DNA itself or by changing proteins called histones—proteins that control access to a gene. The discovery of epigenetics explains how genetically identical individuals, but who have different experiences, can express different proteins and be different. Genetically identical twins are not always identical in all ways. Moreover, epigenetics explains another way that drug taking can influence gene expression.

Epigenetics: A Way to Change the Brain

An epigenetic change causes a change in gene expression, but it does not involve a mutation which is a change in the sequence of chemical bases in the DNA (see Figure 5-3). Rather, it involves a chemical modification of either the DNA or the proteins surrounding the DNA such that gene expression is changed.

When addicting drugs enter the brain, they alter chemical neurotransmission (Figure 5-3), and produce epigenetic changes that influence gene expression, and hence modify the biochemical makeup of the brain.

This figure shows the unraveling of a chromosome near the bottom and how DNA is stored in the chromosome. The DNA, which contains our genes, is wrapped around proteins called histones to provide an efficient storage of the DNA in the tiny nucleus of the cell. Near the top is the standard, double stranded model of DNA. Epigenetic modification includes two main mechanisms. One is methylating the DNA, which changes its ability to make protein, and the other is modifying the histones, which change the way DNA is accessed and translated into protein. Both procedures can be affected by drugs. (From http://www.lexic.us/definition-oi/epigenetic, accessed on January 15, 2001.)

In any case, mechanisms aside, it is clear that drug taking can influence the biochemical makeup of the brain. This is the molecular heart of addiction.

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