The Addicted Brain (8 page)
We need to keep in mind that the normal brain requires the three Rs—
r
elease of neurotransmitter,
r
eceptor activation by neurotransmitter, and
r
emoval of neurotransmitter. When any of these are disturbed, you can get toxicity or disease of some kind. Despite this, it is important to remember that helpful therapeutic drugs and medications also target these processes with much benefit. For example, certain antidepressants block the reuptake of serotonin, thereby prolonging the action of serotonin in the synapse.
Now we can begin to put all of this together and consider how drugs of abuse affect the brain. Abused drugs can distort the functions of neurotransmitters by mimicking or blocking neurotransmitters in
uncontrolled
ways. This distorts our behaviors that are regulated by the brain and alters our sensations.
Uncontrolled
means that the brain itself doesn’t have any mechanism to regulate them.
Because abused drugs in the brain are chemical signals, they are similar to neurotransmitters. But they are different from neurotransmitters in important ways. Neurotransmitters and the brain have co-evolved over eons of time, and they coexist quite peacefully. Neurotransmitters are beautifully regulated by the brain. When their levels are low, they are synthesized. When made, they are safely stored in vesicles. When needed, they are released from specific neurons. After they are released and stimulate receptors, their action is terminated by breakdown, diffusion, or reuptake. Drugs of abuse, on the other hand, get into the brain and affect neurotransmission, but the brain does not have ways to handle or terminate their actions! Drug levels in the brain are under the control of the drug taker and not regulated by synthetic enzymes or release or reuptake in the
brain. Drugs are not easily removed from receptors like neurotransmitters, and therefore the actions of drugs persist in time far longer than those of neurotransmitters. Drug-induced signals can be greater than those produced by neurotransmitters and last longer as well. Thus, it is not surprising that drugs can overpower the brain. They are much like a Trojan Horse. They enter the brain by natural processes, but when in the brain they create havoc!
Dopamine-containing neurons (or dopaminergic neurons) are critical for addiction to occur, particularly to psychostimulant drugs such as cocaine.
2
Many different drugs, although they might act at many different sites and produce many different effects, share the same effect in that they cause a release of dopamine. When dopaminergic neurons are activated and an action potential develops, the electrical impulse moves down the axon into the nerve terminal, and dopamine is released from the nerve terminal. It then diffuses across the synaptic cleft and stimulates dopamine receptors. The action at receptors is terminated by removing dopamine from the cleft by the dopamine transporter, which then transports dopamine from the synaptic space back into the nerve terminal. That is the normal progression of events.
Now enter cocaine! Cocaine blocks the dopamine transporter and the uptake of dopamine.
3
Because it blocks the removal of dopamine, dopamine levels in the synapse rise sharply, thereby prolonging and enhancing the process of dopamine-mediated neurotransmission. The brain itself does not have a mechanism to shut down cocaine’s actions. It can’t be removed by uptake or broken down in the brain, although drugs are removed from the brain and blood by metabolic breakdown in the liver. However, this process in the liver is very slow (sometimes hours) compared to the time of
neurotransmission, which is a fraction of a second. So the intense and prolonged stimulation of dopamine receptors continues for as long as the drug user uses the drug. This level of stimulation probably rarely, if ever, occurs under normal circumstances. Somehow, this prolongation and intensification of dopamine receptor stimulation is key for the addictive process (see
Figures 4-4
and
4-5
). Excess dopamine has been associated with increased reward or motivation.
Figure 4-4. The dopamine nerve terminal and cocaine.
This diagram (partly repeated from
Figure 4-1
) shows the three steps of neurotransmission on the left: (1) release of dopamine from vesicles into the synaptic cleft, (2) interaction with receptors, and then (3) removal of dopamine from the synapse by reuptake. On the right side of the diagram, note that cocaine disrupts this three-step process and blocks the reuptake by blocking the dopamine transporter. This causes dopamine levels to increase at the receptors and to increase signaling. The brain can’t control this problem, because it does not have a way to remove cocaine. (Reprinted from
Trends in Neurosciences
, Vol. 14, M.J. Kuhar, M.C. Ritz, and J.W. Boja, “The dopamine hypothesis of the reinforcing properties of cocaine,” pp. 299-302, Copyright [1991], with permission from Elsevier.)
Figure 4-5. Cocaine blocks the dopamine transporter and extracellular levels of dopamine in the brain increase sharply. The horizontal-axis shows the time after a cocaine injection, which was given at about 1½ hours (vertical arrow). The vertical axis shows the levels of dopamine in the brain region called the striatum relative to the time before the cocaine injection. The highest curve shows dopamine levels after an injection of 30 mg/kg of cocaine, the next lower curve after an injection of 10 mg/kg, and the next lower curve after an injection of 3 mg/kg. The lowest curve shows dopamine levels after no injection and is a continuation of the baseline. Dopamine levels rose about ninefold (to 900 percent of control) after an injection of 30 mg/kg. This is an experimental confirmation of the idea shown in
Figure 4-4
. This figure shows data from one of the first experiments of this type and was produced by Dr. Jay Justice and his colleagues. (Reprinted from
European Journal of Pharmacology
, Vol. 139, W.H. Church, J.B. Justice Jr., and L.D. Byrd, “Extracellular dopamine in rat striatum following uptake inhibition by cocaine, nomifensine and benztropine,” pp. 345-348, Copyright [1987], with permission from Elsevier.)
Another drug that disrupts normal neurotransmission is morphine, which is an opioid or opiate drug. Morphine stimulates receptors in the brain for the neurotransmitters enkephalins and endorphins. Morphine does not do anything to the uptake, diffusion, or metabolism of a neurotransmitter. Rather, it stimulates receptors. Actually, most drugs work by doing something to receptors, either stimulating them or inhibiting them. When the drug user injects or takes morphine orally, it goes from the blood to the brain where it stimulates the receptors that are there for endorphins and
enkephalin. However, the brain does not have a way to remove or stop the action of morphine like it does for enkephalin and endorphin (which is by diffusion and breakdown by peptidases). Morphine is metabolized in the body, but the process is slow compared to the time for a natural neurotransmission event, so the time course of neurotransmission is greatly distorted by the drug! Again, neurotransmission at opioid synapses is greatly enhanced and prolonged by morphine (and other opiate drugs) to a degree that might never occur naturally. Morphine taken by the user commandeers opioid neurotransmission in the brain. Because it makes the user feel good, he or she will control the levels of drug in the brain according to how he or she feels and how much drug is available. It is interesting that morphine, through some neuronal circuit, also increases dopamine levels.
So what does all this mean? One interesting implication is that the abuse of drugs and addiction has a physiological basis in the brain. It involves a significant change in neurotransmitter function in specific brain regions. Because drug abuse and addiction have a physiological bases, rather than a mystical or spiritual one, it is unlikely that these disorders are due to a fatal flaw in moral character or a lack of self-control. This is important to emphasize because therapeutic medications generally target physiologic processes also. Therefore, medications can be developed for drug users, and, in fact, many helpful medications to combat drug abuse are currently in use.
The speed at which drugs enter the brain seems critically important. When drugs enter the blood stream, they reach the brain by the regular circulation of blood. However, just reaching the brain is not the only factor in producing actions in the brain. The rate or speed of drug entry into the brain has been shown to be important.
When a drug is taken by mouth, it gets into the stomach and then is absorbed into the blood. This route is a slow route for drugs compared to other methods of drug delivery. Direct injection of drug into blood (intravenously) can produce quick effects, much faster than by the oral route. Snorting drugs into the lungs or smoking are also fast because the absorption of drugs from lung to blood is quick as well. This is relevant because drugs that enter the brain faster produce a greater or more intense
rush
than drugs entering more slowly. Methods that produce a greater rush and high have a greater addiction liability. This has been shown in both animal
4
and human studies and seems well established. One study
5
showed that smoking 50 mg of cocaine produced a high in less than 1 minute, but taking 96 mg intranasally didn’t produce an equivalent high even after 5 minutes. Understanding this helps us understand the overall process of addiction and suggests also that potential medicines for drug users, particularly those medicines with some drug-like properties, might be best if they enter the brain slowly to avoid being highly addicting themselves!
Why is the rate of entry of a drug into the brain important? Again, we think it is because of the way the brain is constructed, functions and has evolved. Our senses, which include, for example, hearing, smelling, and seeing, are obviously critical for survival. But it is not only the simple
detection
of sounds, odors, and objects that are critical, but also the
rate of change
in these sensations that contributes to our survival.
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When a sound suddenly changes in volume, or when an object moves, it becomes more noticeable. In other words,
changes
in our environment are more readily detected in our awareness! We all have been at loud parties where we adapt to the music and racket. But, if there is a sudden change in a particular sound, such as a new record being played, or a loud announcement, we hear it and attend to it. If we are looking at a landscape, we might not notice an animal or person in the scene until it moves, and we know that lying still can
help us evade detection. So, our senses are geared to detect changes in environment more readily than slow or unchanging scenes. You can easily imagine that this has survival advantage because sudden threats or treats will be picked up and acted on. Changes in sensations are more readily detected, and faster changes are detected faster!
This applies to drug taking because drugs that enter the brain more quickly produce greater changes in our sensations than drugs that enter more slowly. In other words, a greater rush is produced when drugs enter the brain faster or at a greater rate, and getting a rush or high is often the reason for taking drugs. Drugs can enter the brain and be detected faster for at least two reasons. One is that, because of the chemical structure and solubility of some substances, they can more easily penetrate into the brain. The second is that humans can control the rate at which they take the drug. Smoking crack cocaine gets cocaine into the brain faster than swallowing it. Injecting a drug into the blood stream gets the drug into the brain faster than swallowing or snorting it. Therefore, smokable or injectable forms of drugs have a greater danger of producing abuse or addiction.
The way the brain functions and has evolved plays an important role in how drug users select drugs and the methods they use to administer the drugs. This explains why the brain loses control over drug-influenced chemical signaling and how the brain has a natural vulnerability to addiction.