Another thing to remember about signaling in the brain is that circuits and signaling pathways are not static. Levels of neurotransmitters, receptors, transporters, and other proteins can change in response to various stimuli! In other words, the brain has flexibility in its structure, biochemistry, and responses. This flexibility, or the ability of the brain to change in response to stimuli, is called
plasticity
,
which is seriously important. It underlies learning and adaptations to changes in environment, and it can be caused in many ways including repeatedly taking a drug. Plasticity underlies addiction, and a key goal of research into drug addiction focuses on discovering and understanding the nature of these plasticities. Plasticity in response to drugs is described further in
Chapter 5
, “The Dark Side Develops!”
This chapter describes the basic brain machinery for chemical neurotransmission and how drugs interfere in that process. Directly or indirectly, drugs can do the same thing that neurotransmitters do, such as stimulate receptors, or they can block functions, such as cocaine blocking the transporter for dopamine. When drugs are in the brain, the brain cannot control the drugs like it can control neurotransmitters. Drug action in the brain is more under the control of the drug user. This is a significant part of why drugs basically can
take over
the brain. In the next chapter, we see that drugs, because of this aberrant behavior, can produce significant effects in the brain.
1
The discovery of chemical neurotransmission is an interesting story. A major part of the discovery is due to Otto Loewi, a German Jewish scientist and refugee working at NYU. He carried out a definitive experiment in 1921 that has become famous, along with the anecdote of how it happened. It was known that if you stimulated the vagus nerve leading to the heart, the heart’s beating slowed. But Loewi extended this and took some of the fluid from the slowing heart and applied it to another heart, and found that it also slowed! He correctly proposed that a chemical substance was released from the stimulated vagus nerve onto the heart muscle, which resulted in a slowing of the beating of the heart. This substance in fact turned out to be acetylcholine, the first accepted neurotransmitter. An interesting part of this story is that the idea for the experiment came to him in his sleep one night, and in his dreamy state he wrote it down on a scrap of paper on his nightstand. In the morning, much to his horror, he
couldn’t read his writing, nor could he remember the dream! Luckily, the next night he had the same dream, and this time he got out of bed and immediately went to the laboratory and did this definitive experiment. Thirteen years later, he was awarded the Nobel Prize for his “dream experiment!”
2
The following is a brief summary of the history of the dopamine story and drug addiction. It is a personal communication from Dr. Roy Wise, a longtime, productive researcher in this field.
The earliest work was by Olds (a) who showed that nonselective drugs like chlorpromazine and reserpine (whose effects included a blunting of dopamine’s effects) antagonized electrical brain stimulation reward. Stein generated a theory of reward that proposed that norepinephrine was the key neurotransmitter, but this was not supported by subsequent data (b, c). When selective dopamine antagonists became available, they, and selective destruction of dopamine-containing neurons showed effects on reward. This implicated dopamine and not norepinephrine or other neurotransmitters in brain stimulation reward (d, e). Pickens and Harris were the first to suggest that the substrates of brain stimulation reward and psychostimulant reward were perhaps the same (f).
Yokel and I (g) and Davis and Smith (h) were the first to show that amphetamine lost its rewarding action if the dopamine system was selectively blocked, and de Wit and I (i) and Risner and Jones (j) showed the same result with cocaine. Roberts showed that selective dopamine (but not norepinephrine) lesions disrupted cocaine reward (k). These were the first studies to show that dopamine function was necessary for cocaine and amphetamine reward. Yokel and I then showed that a dopamine agonist, apomorphine, (a compound that directly stimulated dopamine receptors) was self-administered (g, l), which confirmed that dopamine activation was also sufficient for drug-related reward. Ritz et al., (m) took the story further by showing that the initial site of action of cocaine and the psychostimulants—specifically for their rewarding and reinforcing actions—was the dopamine transporter rather than some other site. Initial work in knockout mice suggested that cocaine might still be rewarding in animals lacking the dopamine transporter (n), but more recent work questions this finding and shows, rather, the opposite (o).
(a) J. Olds, K. F. Killam, P. Bach y Rita,
Science,
124, 265 (1956). (b) L. Stein,
J Psychiat Res
8, 345 (1971). (c) S. K. Roll,
Science,
168, 1370 (1970). (d) A. S. Lippa, S. M. Antelman, A. E. Fisher, D. R. Canfield,
Pharmacology Biochemistry and Behavior,
1, 23 (1973). (e) G. Fouriezos, R. A. Wise,
Brain Research,
103, 377 (1976). (f) R. Pickens, W. C. Harris,
Psychopharmacologia
12, 158 (1968). (g) R. A. Yokel, R. A. Wise,
Science
187, 547 (1975). (h) W. M. Davis, S. G. Smith,
Journal of Pharmacy and Pharmacology,
27, 540 (1975). (i) H. de Wit, R. A. Wise,
Can J Psychol,
31, 195 (1977). (j) M. E. Risner, B. E. Jones,
Psychopharmacology,
71, 83 (1980). (k) D. C. S. Roberts, M. E. Corcoran, H. C. Fibiger,
Pharmacology Biochemistry and Behavior,
6, 615 (1977). (l) R. A. Yokel, R. A. Wise,
Psychopharmacology
(Berl),
58, 289 (1978). (m) M.C. Ritz et al., 1987. Science 237: 1219–1223. (n) B. A. Rocha et al.,
Nature Neuroscience,
1, 132 (1998). (o) M. Thomsen, D. D. Han, H. H. Gu, S. B. Caine,
J Pharmacol Exp,
Ther 331, 204 (2009).
3
The dopamine transporter (DAT) is known as the initial site of action of cocaine that produces the addicting properties of the drug. This was shown more or less definitely in a paper in 1987 using “receptor binding,” a technique that reveals the initial site of action of drugs. The problem before that was that cocaine has many actions. It not only inhibits the uptake of dopamine, but it also inhibits the uptake of serotonin and norepinephrine, two additional neurotransmitters. Moreover, cocaine produces a local analgesia by blocking sodium channels in nerves, and it has other actions, too. So, which is the site that makes cocaine an abused drug? A team at the National Institute on Drug Abuse, lead by Drs. Mike Kuhar and Mary Ritz, compared the capability of cocaine and several cocaine analogs to inhibit the uptake of neurotransmitters with the capability of these chemicals to be self-administered (SA) by animals. The drugs that were potent at the DAT were the ones potent in drug SA, and the drugs weak at DAT were the ones weak in SA. This correlation was strong and statistically valid. There was other existing evidence for this at the time, but this binding experiment solidly confirmed the idea. The reference is Ritz M et. al. “Cocaine Receptors on Dopamine Transporters Are Related to the Self-Administration of Cocaine.”
Science,
237: 1219–1223, (1987).
4
An example of a study with animals showing that compounds with a faster onset of action were better reinforcers is Kimmel H et al.
Pharmacol Biochem Behav,
86:45–54, 2007. An example of a study with human subjects showing that the rate of entry of cocaine into the brain determines its reinforcing (addicting) effects, as described in the text is Volkow N.D. et al.
Life Sciences
, 67:1507–1515, 2000.
5
Ibid.
6
This idea derives from studies of the sensory systems in our bodies. Many highly technical experiments on vision and touch show that individual neurons in the periphery and brain respond to
changes
, either increases or decreases, in stimuli. For example, this can be seen in the responses of ganglion cells in the retina, in cortical neurons responding to mechanoreceptors, and in rapidly adapting mechanoreceptors in skin. Details of these studies can be found in a textbook such as Kandel et al.,
Principles of Neural Science
, Third edition (Appleton and Lange, 1991). While the rush derived from drugs has not yet been subjected to such careful scrutiny, it seems reasonable to propose that a drug-induced high or rush is due to
changes
in the basic sensations.
Tim, an Iraq veteran who lost both legs in a roadside ambush where most of his buddies died, has been taking drugs for years. He’s been diagnosed with Post-traumatic Stress Disorder (PTSD) and uses several drugs, including alcohol, to help him relax and sleep. He is distressed that he has gradually needed more and more drugs to get to sleep, even for a short time. This has added to his troubles because of the increasing cost, and searching for drugs seems to dominate his activities. He is beginning to worry that he is addicted.
Drugs literally dominate the brain because the brain doesn’t have an adequate defense against drugs. But there is more to addiction than that. If a drug is taken once, it distorts the way the brain functions, but is that addiction? No, the development of addiction almost always requires repeated drug taking. That is not to say that a single drug experience cannot be profound. Indeed, drug users have said things such as, “The first time I took heroin I knew it was special for me. With heroin, I could do anything or get through anything.” In fact, sometimes drug users try to re-experience that first, special high or feeling. They are chasing something they might or might not fully experience again. But, they keep trying—with disastrous effects.
A compelling account of the disaster of addiction is given in the book,
Methland,
(Bloomsbury, USA), by Nick Reding. He describes how a highly addictive substance like methamphetamine, called crank or crystal meth, literally took over the economy and social fabric of various, poor Midwestern towns. In some cases, the drug was
given away for people to try, and they returned with a vengeance to buy it. There were the expected stories of users messing up their health, relationships, and jobs. Some turned to making or “cooking” methamphetamine themselves, maybe to save money or to make money by dealing the drug. Unfortunately, it is a dangerous process where the containers can explode. Many injured addicts, people with severe scars from burns or missing fingers from explosions, still learned to hold, light, and smoke a pipe to get the drug. Drug dependence can be unbelievably gripping.
The drive to take drugs is a curious thing. Sometimes it is more of a drive just to take a drug than it is to get high. Drug abusers say that drugs produce euphoria, but for most people, that doesn’t last! Cocaine doesn’t always get them high anymore but they still can’t stop.
1
Initially the high can be better than anything, but after several months, the euphoria can be gone and you are still driven to get drugs even though it is disrupting your life. The state of addiction can be more of a compulsion or a motivation than actually getting high. As the simple choice to take a drug the first time becomes compulsive drug use, many things are happening in the brain.
George Koob, a neuropsychopharmacologist, studies changes in the brain due to drugs and he refers to them as the “dark side” of addiction. He notes that with continued drug taking, deficits develop in the reward system, and brain stress systems become sensitized. This suggests that with more drug use, there is less reward or feeling good, and a greater response to stress. Moreover, he has specified the neuronal pathways and neurotransmitters involved in these processes, which will foster much future research. His work is explored and extended by many researchers.
The addicted brain is like having a drug-craving demon in your brain. But as repeated drug use creates the addicted brain, there is another important demon in the brain called
withdrawal
. Withdrawal occurs
when an individual stops taking drugs and then develops symptoms that are often the opposite of the feelings that the drug produces. For example, an effect of cocaine is mental stimulation, and a symptom of withdrawal from cocaine is depression. Besides making the addict feel terrible, withdrawal is an impetus to relapse to drug use because taking more drugs relieves withdrawal. Fear of withdrawal is also likely to be an impediment to getting treatment. So, withdrawal is a big part of the complex picture that we have been examining. But how does it happen, and how do we think of it?
A relatively simple way to think of addiction and withdrawal is to look at a seesaw (see
Figure 5-1
). Consider that someone is functioning normally and doesn’t have anything to do with drugs. This normal state can be represented by the seesaw that is level or in balance and not touching the ground on either side. But when drugs are taken repeatedly, the brain is battered by changes in chemical signaling and is driven to a new state, one represented by the seesaw pushed down (by the drug) on one side—the brain can change and is capable of plasticity.
2
As drugs push the seesaw down, the brain compensates by pushing in the opposite direction to get the seesaw level and in balance. Taking enough drugs over a long enough period of time results in an accumulation of compensatory changes in the brain, which is addiction. If drug taking stops, the brain’s counterbalancing efforts are unopposed and the seesaw is either pushed up or down on the opposite side. This is where the drug taker can experience unpleasant feelings or physiological symptoms of withdrawal. For some drugs such as alcohol, withdrawal can be medically serious and even life threatening. Withdrawal interferes with everyday tasks and can drive the drug user to do many things, even dangerous and destructive crimes to get more drugs. But, if he or she succeeds in staying away from drugs for a long enough time, the brain readjusts, and the fictional seesaw eventually shifts back so that it is level and balanced, and the original, normal state is regained—at least theoretically. Realistically though, staying away from drugs is not easy to do once you are hooked.