The Addicted Brain (6 page)

Experiments of this type are not done in humans for ethical reasons, unless there is a patient with some severe and debilitating disorder that has not responded to other treatments. Dr. Robert Heath and his colleagues at Tulane in New Orleans put electrodes into the brains of human patients in the 1950s, and they had several important goals. They wanted to cure or ameliorate severe mental illness by direct electrical stimulation of the so-called pleasure centers. At that time, there were few treatment options for such patients.

In an interesting case, one of Heath’s patients self-stimulated the septal region of his brain about 1,500 times per hour, showing that
this can be a powerful and even consuming effect—this brings to mind the heroin addict quoted in the first paragraph of this chapter. The patient was reminded of and discussed sex during the stimulations. When stimulations were in a different region, the midbrain, the patient had happy thoughts that were not sexual. Other studies resulted in patients describing many different sensations and feelings, such as general pleasure, a sense of well-being, a positive change in mood, pleasant sensations in various body parts, relief from anxiety, and euphoria. What an amazing result!

Overall, the work of Heath and others indicated that there were pleasure or rewarding centers in humans’ brains and in animals’ brains as shown by Olds and Milner. The notion that the brain is the organ of pleasure as well as pain was here to stay.

A useful procedure used today in humans is called deep brain stimulation (DBS), which is not necessarily associated with drugs and pleasure. In this procedure, neurosurgeons implant electrodes into the brains of patients with a battery-powered generator that produces electrical pulses (see
Figure 3-2
). It has been found that stimulation of the electrodes can relieve symptoms of chronic pain, major depression, Parkinson’s disease, and other disorders. Of course, it depends where the electrodes are implanted, and different sites are used for different disorders. This treatment is relatively new because the first use for DBS was approved by the FDA in only 1997. It is interesting that the mechanism of DBS is still not thoroughly understood. It won’t surprise you to learn that DBS is being discussed as a treatment for addictive disorders. Promising results have been obtained in animal studies where DBS seems to reduce an animal’s interest in self-administering drugs.

Figure 3-2. Deep brain stimulation is an important therapeutic technique used today that can treat serious neurological disorders. An electrode is placed in the brain region (the thalamus is shown here) that has been found to alleviate certain symptoms. A lead is attached to the electrode and the extension wires are threaded under the skin to a pulse generator that provides the stimulation. The pulse generator is placed under the skin in a region where it can be calibrated and serviced safely. The stimulator is turned on to alleviate various symptoms. (From
http://www.medicinenet.com/script/main/art.asp?articlekey=56945
, with permission, accessed December 28, 2010.)

Following the discovery by Olds and Milner, many thousands of papers have been published on the topic. Electrical stimulation reinforcement, as it came to be called, has been reported in many species examined including not only mammals, but also some fishes and even snails. It is often a robust and powerful effect. In one report, rats pressed levers for stimulation for almost 20 straight days, producing about 29 presses per minute! Self-stimulation has also been connected to food and water intake. At some sites in the brain, the rate of
self-stimulation increased with food deprivation and decreased after a meal. Other sites were found to produce varying levels of stimulation as a function of water deprivation. These results supported the idea that there are powerful systems in the brain that reinforce behaviors such as taking food and water. These rewards, as well as those for mating, are critical for our survival as individuals and for survival of the species.
²
It only makes sense that the brain has evolved so as to have a preeminent influence over our survival.

Now for the final piece! We know from the previous chapter that drugs are self-administered, and now we know that certain parts of the brain support electrical self-stimulation. A logical question is this: Are they two completely different entities, or are they connected? In other words, do they access the same thing in our brains? Do the same brain regions mediate both processes?

As it turns out, the two different activities
are
related, and a relatively simple experiment shows this. Rats were allowed to learn to electrically self-stimulate their brains until their lever pressing responses were stable. Then the electrical current was varied until the
threshold
was established. The key to understanding this experiment is to understand thresholds. The threshold is the lowest level of electrical current that will elicit self-stimulation. If less current is used, the rats won’t realize that a stimulation has occurred. If the threshold current or more current is used, then the rats recognize it as stimulating. There are established procedures for reliably measuring thresholds.

At this point the self-stimulating rats were injected with varying doses
³
of cocaine, and the thresholds of electrical self-stimulation were determined for each dose of cocaine. It turns out that the threshold for self-stimulation varied according to the dose of cocaine given to the rat. The more cocaine that was given, the lower the threshold became. The threshold was lowered significantly at around
the dose of cocaine that caused behavioral effects (see
Figure 3-3
), and this same result was found when other addicting drugs were used in the experiment.

Figure 3-3. Electrical self-stimulation can be studied by varying the amount of electrical current that is passed through the electrode. Obviously, if the current is reduced to a very low level, there will be no self-stimulation because the animal won’t recognize it. The threshold is the lowest level of current that will result in self-stimulation (refer to
Figure 3-1
). An injection of cocaine will lower the threshold! It is as though the drug, by itself, provides some stimulation to the brain region already, and not as much electrical current is needed. Thus, drugs affect the same, endogenous, reward systems that have been identified by electrical self-stimulation. (Reprinted from Elsevier Books, George F. Koob, Michel Le Moal,
Neurobiology of Addiction
, 23-67, Copyright (2006), with permission from Elsevier.)

The interaction between drugs and electrical self-stimulation in specific brain regions shows that they both use the same neuronal pathways in the brain. The drugs raise the activity of the pathways so that less electrical current is needed to reach the threshold for electrical self-stimulation—definitely an informative finding about how drugs are working!

To complete the picture, it was found that there are also sites in the brain related to aversion or avoidance.
⁴
Drugs of abuse also have aversive properties, and one can guess that the degree of self-administration is influenced by the ratio of rewarding to aversive properties of the drug. In careful experiments, it has been shown that many drugs such as cannabis, cocaine, alcohol, morphine, and others have aversive properties. Many find the taste of alcohol quite bitter and awful, or the smoke from a cigarette overly nauseating and choking. There is likely to be a tolerance, at least for some drugs, to aversive as well as to rewarding effects of drugs. Unfortunately, the rewarding properties of drugs win out too often.

Among the many parts of the brain, there are several that support electrical self-stimulation. In other words, animals work persistently to get an electrical stimulation of these regions. At least some of these areas are activated by addicting drugs as well. Thus, there are natural, neuronal pathways in the brain that mediate positive feelings and drugs activate some of these same pathways. Drugs act on a brain that is already wired to make us feel good.

¹
A schematic showing the brain regions that support self-stimulation is found in Gardner E.L., “Brain Reward Mechanisms.” In Lowinson J.H., Ruiz P, Millman R.B., Langrod J.G. (Eds),
Substance Abuse: A Comprehensive Textbook,
4th Edition. Philadelphia, PA: Lippincott Williams and Wilkins, pp. 48–97, 2005.

²
From
http://www.hackcanada.com/ice3/wetware/electrical_brain_stimulation.html
, accessed December 23, 2010.

³
The systematic use of varying doses of drugs in scientific experiments is important. In
Figure 3-3
, the doses of cocaine were varied to show that the threshold depended on the dose. If it was not dependent on dose, then the effect would not be due to the drug, but due to some other stimulus, perhaps simply holding and injecting the animals. To
claim cause and effect, different quantities of the drug must be used to show no effect at low doses and a gradual, graded response as the dose is increased. Dose-response studies are a fundamental tool in studies of drugs.

⁴
Spear L.P., Varlinskaya E.I. “Sensitivity to Ethanol and Other Hedonic Stimuli in an Animal Model of Adolescence: Implica-tions for Prevention Science?”
Dev Psychobiol
. Apr;52(3):236-43, 2010. Davis C.M., Riley A.L. “Conditioned Taste Aversion Learning: Implications for Animal Models of Drug Abuse.
Ann N Y Acad Sci
. Feb;1187(2010):247-75. Carlezon W.A. Jr, Thomas M.J. 2009. Biological Substrates of reward and aversion: a nucleus accumbens activity hypothesis.
Neuropharmacology
, 56 Suppl 1:122-132.

The patient told his counselor that he had fallen into addiction by taking more and more drugs over several months. “I used to be able to stop, but now, if I don’t have the stuff, I go crazy. They say it’s in my head, my brain. Somehow it’s changed...” The patient is right. The brain
is
changed, and to understand that, we need to know how the brain works at the basic level.

Our brain directs our body and its behavior by using its basic functional unit, the nerve cell. The nerve cell, or
neuron
, has a cell body with branching arms called dendrites, a longer thread-like part known as an axon, and nerve terminals that are found at the ends of the axon (see
Figure 4-1
, left). The nerve terminal typically abuts another neuron that it will influence by releasing a stimulating chemical. The boundary of the cell is the cell membrane, which keeps the neuron intact.

Figure 4-1. Structure and function of the neuron. The schematic on the left shows the structure of a neuron or nerve cell. It has a cell body with dendrites, and an axon that ends in nerve terminals. In this depiction, the axon is covered by a myelin sheath that assists the movement of the action potential (electrical impulse), but the neurons that we discuss do not always have such a sheath. The nerve terminals sit close to the next neuron in the circuit and abut the dendrites on the next cell. This close apposition of nerve terminals and the next neuron (see right side) is fundamental to the way the brain works.
On the right is a schematic of a nerve terminal containing the neurotransmitter dopamine, which abuts the next cell (post synaptic dendrite). Dopamine is stored in the vesicles, and after an action potential (electrical impulse) invades the nerve terminal, the vesicles merge with the membrane to release dopamine into the synaptic cleft or space. The neurotransmitter diffuses across the synapse and then interacts with the receptors and produces a stimulation (indicated by arrows). Finally dopamine is removed from the cleft by the transporter, which moves it back into the nerve terminal where it is stored in the vesicles again. (The left portion is adapted from
http://en.wikipedia.org/wiki/Nervous_system
. The right portion is 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.)