The Addicted Brain (12 page)
A few experimental findings can be mentioned to support this. Food intake is associated with a release of dopamine in the nucleus accumbens, a place in the brain involved in addiction. In bulimic subjects, for example, dopamine metabolites in the brain fluids, which reflect the amount of dopamine used at the synapse, suggested
a reduced activity of dopaminergic neurons in subjects with this eating disorder. Another more complicated kind of evidence comes from molecular biology and genetics. It has been discussed how important the dopamine transporter is for normal dopaminergic neurotransmission. Like many proteins, there are several naturally occurring variants of the transporter gene that are inherited by various individuals. One molecular variant of the dopamine transporter is more often found in people who binge, suggesting a genetic linkage between the dopamine system and binge eating (see the next section, “
The Dopamine Transporter Is Connected to Binge Eating
”). Other work in animal studies have related compulsive eating with dopamine,
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and D2 dopamine receptors are reduced in both humans and animals that are obese.
The Dopamine Transporter Is Connected to Binge Eating
Genes are the units of heredity that determine the features of our bodies. Also, genes can undergo mutations, and, as you know, some mutations are not friendly and can produce disease, whereas others have only neutral or subtle effects. The collection of genes in our chromosomes is called the genome, and each of us, because of the way in which we inherit genes from our parents, have unique genomes, but of course we share many features of our family’s genome.
There are genetic mutations that result in rearrangements, deletions, or even in repetitions of parts of the genome. One situation where there are repetitions of genes is referred to as a variable number tandem repeat (VNTR). This means that different individuals can have different or variable numbers of genes that are repeated. In other words, I might have nine copies of the dopamine transporter gene lined up in a row next to each other (that is what tandem means), whereas you might have ten copies. In the schematic that follows, you can see four different tandem repeats where a gene (the elongated rectangle) is repeated six, four, three, or five times.
This is important because the number of repeats can affect the way the gene is expressed, which can have effects on human health. In other words, someone with nine repeats instead of ten might be more susceptible to a health problem. Also, it is important because the VNTRs can be used as genetic markers to study heritability patterns.
In a study of patients with a binge-eating disorder, it was determined that the fewer number of VNTRs was found more frequently in the subjects with the binge-eating disorder (Shinohara et al.
J Psychiatr Neurosci
29:134-137, 2004). Thus, a modification of the transporter gene has significant effects on our eating and presumably drug-taking behavior. (Schematic from
http://en.wikipedia.org/wiki/Variable_number_tandem_repeat
, accessed September 27, 2010.)
Regarding interactions between eating and taking drugs, Drs. Ken Carr, Marilyn Carroll, David Gorelick, and others have shown in animals and humans that caloric restrictions (in other words, dieting) result in greater drug intake.
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For example, in humans, dieting was associated with a small but significant increase in nicotine delivery by cigarette smoking.
Regarding sexual behavior and dopamine, it has long been known that, for example, injections of dopamine-related drugs into the hypothalamus of laboratory animals can influence the interaction between male and female rats and the number of ejaculations produced by the male. Another experiment has associated sexual activity with dopamine in the nucleus accumbens, a brain region well known to be connected to drugs. The far left side of
Figure 6-2
shows the
dopamine levels in the brain of a male animal when he is undisturbed in his home cage during the first 20 minutes of the experiment. When you transfer the animal to the test chamber, the levels rise slightly, and they rise slightly again when he is placed in the cage together with a receptive female. But dopamine levels go way up with copulation (shown as male and female together, around 90–120 minutes), and after the female is removed, dopamine levels decline. Because dopamine levels go up in the same brain region when we take drugs (for example, refer to
Figure 4-5
in
Chapter 4
), the brain, in a sense, sees drugs and sex as the same. Drugs are as powerful as sex and some drug users report that the rush from taking some drugs is like a whole body orgasm. Quite amazing (also refer to
Figure 4-5
)!
Figure 6-2. Mating results in dopamine release. Dopamine levels (a measure of dopamine release by neurons), indicated by “dialysis output” on the vertical axis, increased when the male rat was placed in a novel chamber and again when a receptive female was introduced. A subsequent copulation resulted in a sharp increase of dopamine release. Dopamine levels returned to normal after the female was removed from the chamber. Dopamine levels also went up in the brain after rats received an injection of cocaine (refer to
Figure 4-5
). From the point of view of the brain and the neuron receiving dopamine, the brain doesn’t know whether the animal had cocaine or copulated. (Adapted from J.G. Pfaus, G. Damsma, G.G. Nomikos, D.G. Wenkstern, C.D. Blaha, A.G. Philips and H.C. Fibiger. Sexual behavior enhances central dopamine transmission in the male rat.
Brain Res
, 530:345-348. 1990, with permission from Elsevier.)
In a study of human subjects who had recently fallen in love, there were activations in the ventral tegmental area, part of the dopamine mesolimbic system. In studies of male orgasms, the ventral tegmental area was one of the regions activated.
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In a paper entitled “Prelude to passion; limbic activation by ‘unseen’ drug and sexual cues,” Drs. Anna Rose Childress, Charles O’Brien, and others from the University of Pennsylvania found that there was limbic activation in subjects that received cues about drugs and sex outside of their awareness.
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The brain can receive short signals that are outside of our conscious recognition, and those are referred to as “unseen” cues; the paper shows that brain reward circuitry responds to these unseen cues. This demonstrates an interesting, additional vulnerability of the brain to drugs and other stimuli.
A major point here is that elevations in dopamine and activations of dopaminergic areas are associated with powerful urges, such as the sexual drive to mate, which is critical for survival of the species. The increased dopamine is associated with something that feels good, or with something that you want to do again and again.
Given what has been discussed, it seems justified to propose that the dopamine mesolimbic system is important for survival and is part of “survival pathways” in the brain for both individuals and the species. Without these pathways, perhaps our species would not survive or survive as well. In fact, special transgenic mice have been prepared that do not have dopamine in the brain. When these dopamine-depleted animals are born, they do not move or eat normally and die by four weeks of age.
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If the survival pathways in the brain have more power over behavior than other pathways, and if drugs work by inserting themselves in those pathways, then drugs will have relatively more power over our behavior (see Endnote 2 in
Chapter 4
). Therefore, drugs are powerful at least partly because they work through powerful brain circuits. Although this is a hypothesis and one
can argue about the meaning of the word powerful, this seems to be a reasonable position.
If this hypothesis is true, then it might explain some other puzzling issues. For one thing, if drug addiction is bad, and it obviously is, then why hasn’t it been weeded out by evolution? Given the survival hypothesis, it hasn’t been weeded out because it is intrinsically connected to survival functions like eating and mating. Addiction hooks into mechanisms for natural rewards, and genetic mutations that blunt addictions would have a negative survival impact.
One can argue that all parts of the brain and their functions are just as critical for individual and species survival as the mesolimbic dopamine system, but this doesn’t seem to be true. When it comes to survival of the species, sex is the main factor. For survival of the individual, it seems there are many factors but food is definitely a major one. Loss of movement, sensory detection, and focus are also critical for survival, but you can argue that they are a means to locate and get to food. Also, people survive with losses of many of these functions. In any case, there are many important parts of the brain but the dopamine mesolimbic system, along with additional connecting neurons in the circuitry, seems to be paramount for basic survival brain functions.
But it wouldn’t be accurate to imply that dopamine and its neurons are the sole, powerful players here for all drugs. Dopamine is a major player for drugs such as opiates and psychostimulants, like cocaine and amphetamine. But there are other neurons, circuits, and neurotransmitters in the picture that we have not mentioned or explored.
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For example, Dr. Peter Kalivas, his colleagues, and others have shown that molecular changes in a neuronal pathway from the prefrontal cortex to the nucleus accumbens core underlie cocaine seeking, and this circuit uses the neurotransmitter glutamate.
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It is not just the effects of drugs on a given neurotransmitter, but also the impact of drugs on the specific circuits, brain regions, and their functions that
are important as well. Dopamine was used as an example to bring out the idea that the specific functional pathways in the brain that drugs attack are at least partially responsible for the power of drugs.
But it is interesting to consider other drugs, because it is sometimes possible to relate their actions to the action of dopamine in the nucleus accumbens and to circuits containing dopamine. Self-administration of nicotine, which mimics the neurotransmitter acetylcholine, and acts at receptors for acetylcholine, also results in an increase in the release of dopamine in the nucleus accumbens, a drug reward area. Thus, the mesolimbic dopaminergic pathway is involved with nicotine/smoking even though the directly affected neurotransmitter is acetylcholine and not dopamine. But, nicotine probably uses additional mechanisms and pathways.
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Although dopamine has been implicated in the addicting action of many drugs, not all drugs have been conclusively connected to dopamine at this time.
This is a question with which scientists have struggled. It’s been said that dopamine is associated with pleasure or reward. After all, it looks that way, and brain imaging studies in humans, for example, have associated dopamine levels with the high and euphoria produced by the drug.
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But, dopamine is not just there for pleasure! Addicts are not in a constant state of pleasure, and animal studies show that dopamine levels increase in the face of fear.
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So the concept of what dopamine does has had to evolve.