The Addicted Brain (5 page)

Now, let’s return to the animal that has experienced a drug but is currently without it. If stress, such as a foot shock, is present or if the drug is injected, the animal remarkably starts to press the lever that previously resulted in a drug injection. The animal does this even if
no drug is given
by the lever press (see
Figure 2-4
). Previous drug use has conditioned the animal to look for the drug in situations that elicit cravings in humans.

Figure 2-4. Drug self-administration in animals provides a model for relapse in humans. Animals were presented with both a drug-related lever (darker dots) and a nondrug lever (lighter dots). The nondrug lever was rarely pressed as expected (shown on the vertical axis as “responses”). They were trained for 12 days to self-administer cocaine (left half of figure), and drug delivery was accompanied by a cue, which was typically a light and/or a tone. Drug self-administration was stable at about 140 responses (on the vertical axis), except for the first day when the animals were learning. In the second phase of the experiment (right half of figure), animals underwent “extinction training” during which no drug was administered in response to lever presses (E1–E14), and the rate of lever pressing dropped nearly to zero. At the end of this second phase, animals were presented with the cue that had accompanied each drug infusion during self-administration, a mild stressor (typically foot shock), or the drug itself. Each of these stimuli reliably overcame extinction training and the animals pressed the lever, even though no drug was delivered. This reinstatement or reoccurrence of lever pressing is considered to be a bout of drug seeking or relapse. Although this is a complicated experiment, it is clear evidence that stress or a single injection of a drug can stimulate drug seeking in an animal with previous drug-taking experience. This animal model can be used to study relapse. (Adapted from PW Kalivas, Jamie Peters, and Lori Knackstedt. “Animal Models and Brain Circuits in Drug Addiction.”
Mol Interv.
December 2006: 6:339–344.)

In this animal model, it is possible to ask a variety of questions about relapse, and we can begin to consider which medications are best for treating or preventing relapse.

Other models allow us to study additional properties of the brain and of drugs. These models, such as “conditioned place preference” and “drug discrimination,” are technical and sometimes complex but quite useful. These are mentioned only to inform you that the experimental repertoire in drug addiction research is quite rich. In the next chapter, we explore “electrical self-stimulation” and why it is important for this discussion.

The realization that addiction is not only a human vulnerability but is shared by animals is important. Drug abusers were and sometimes still are considered disgusting, moral failures, hardly worthy of help, much less research programs. Their out-of-control drug seeking with its associated crimes and degradations leaves them stigmatized and sometimes abandoned. The drug abusers themselves feel helpless and hopeless. But realizing that addiction is a brain disorder, maybe like a migraine headache or a seizure, is transformative. Now we think that if we can learn enough about the brain, we can more effectively treat addicts, and this is becoming true. The drug users themselves realize that a new realm of treatment possibilities has been opened to them. These include medications and behavioral therapies directed at the brain and how it functions. This is not to say that older, existing programs are not effective. On the contrary, many are effective. However, we are now adding to the options for treatment. One of the most important functions of research is not only to make discoveries, but also to provide hope for the future and hope for treatments that are now lacking.

Animals take drugs in the same way that humans do and are considered as models for human drug use. Because studies of drugs and the
brain are essential, and because many types of studies on humans are not possible, animal models have been used and have been successful.

¹
Under certain, strict conditions, it is possible to carry out research with human drug abusers. The conditions of the experiments must minimize any risk to the human subject. The subjects must be physically fit and offered treatment even if they refuse it. Of course, they must be medically monitored to avoid any unsuspected and damaging effects of drugs. For example, certain doses of certain drugs that can sometimes be toxic must be avoided. Finally, every human experiment must be described in detail in writing in advance, and the description must be studied by an expert committee that can approve the experiment. The safety of human subjects is paramount, and the benefits from the research must outweigh any risks to the subjects. There are federal regulations for the protection of human research subjects (45 CFR 46, 42 CFR 52h, Public Law 103-43) that are strictly enforced. The guidelines for administration of drugs to human subjects can be found at
http://www.drugabuse.gov/Funding/HSGuide.html
.

²
The National Research Council has published the
Guide for the Care and Use of Laboratory Animals,
Eighth Edition (Washington DC: The National Academies Press, 2011), which is strictly enforced at the national level. Any investigator using animals must justify the species and numbers, provide adequate veterinary care, describe provisions for minimizing discomfort and distress, and provide euthanasia if needed.

³
For example, two papers that show this are as follows: Ahmed, SH and George Koob. “Long-Lasting Increase in the Set Point for Cocaine Self-Administration after Escalation in Rats.”
Psychopharmacology
146:303-312, 1999. Paterson, NE and A Markou. “Increased Motivation for Self-Administered Cocaine after Escalated Cocaine Intake.”
Neuroreport
14:2229-2232, 2003.

⁴
See endnote 1.

⁵
Lundahl LH and CE Johanson. “Cue-Induced Craving for Marijuana in Cannabis-Dependent Adults.”
Exp Clin Psychopharmacol
19:224-230, 2011.

What do drugs do for us? An addict was asked why she injects heroin. Her reply was that it is like a dozen orgasms! Although the effects can vary according to the drug, it is safe to say that drugs can make us feel good, or even wonderful. The concepts of pleasure, reward, and reinforcement are so important for drug abuse that we can’t leave this topic without describing key discoveries about the brain’s own pleasure and reward system. Drugs couldn’t produce reward if these capabilities weren’t already in the brain.

Prior to experiments showing a drug-related reward described in the previous chapter, there were experiments that revealed a naturally occurring reward and reinforcement system in the brain. Given that the brain works partly by electrical activity, it isn’t surprising that these discoveries relied on electrical stimulation of brain regions. If you carry out an action that results in an immediate reward or good feeling, you want to carry out that action again and again, and we all do this every day. The good feelings reinforce (and hence, the idea of “reinforcement”) the performance of the actions that produced them. For example, we get to the dining room in time for meals. We learn, develop habits, and so on, in response to rewards. Given that the brain is the organ of behavior, how do we find out where these rewarding and reinforcing actions reside in the brain and what exactly happens in the brain?

To answer these questions, electrodes can be implanted in the brain, stimulated, and the elicited behaviors can be recorded and measured. However, there is also a procedure called electrical
self
-stimulation, which is the process by which rats (and humans) press a lever that delivers an electrical stimulation to some part of the brain. Yes, lever pressing again! Only this time it is not a drug injection but rather a direct electrical stimulation of the brain that is the result. The fact that the animals press the lever again and again means that there is something positive or good about the result of electrical stimulation. But electrical self-stimulation occurs only when the electrodes are in certain parts of the brain, revealing to us the parts of the brain that are involved in giving us rewards or pleasure. This was an important discovery that was made in the 1950s.

Here’s how it all started. In 1954, two young scientists, Drs. James Olds and Peter Milner, were trying to find out whether electrical stimulation of a part of the brain called the reticular formation would make rats learn faster. In the course of this work, they noticed that some of the rats that were stimulated for a short time quickly returned to the place in the cage where they experienced the stimulation. The rats returned to the place where they were stimulated again and again, as though they wanted more stimulation! This suggested that there was something positive, rewarding, and reinforcing about stimulating the part of the brain containing the electrodes.

A big surprise was that in the animals behaving this way, the electrodes were not in the reticular formation at all, but rather in another area called the septum. A mistake had been made in calculating where the electrodes should have been placed. Wow! It was an accidental discovery in more ways than one. In subsequent experiments, when the rats were given control over their own stimulation, when they were allowed to press a lever to self-stimulate their brains, they did. This was so striking to Olds and Milner, who realized they were on the verge of a discovery, that they dropped their original planned
experiments and decided to study the rewarding and reinforcing properties of the electrical stimulation. They implanted electrodes in various places in the brain to see whether the various brain regions would support lever pressing for electrical stimulation (see
Figure 3-1
).

Figure 3-1. This figure depicts a rat rotating a wheel that results in an electrical stimulation of a specific part of the brain. The wheel that rotates produces the same stimulation as a lever that is pressed, and either can be used. The part of the brain that is stimulated is selected by placing an electrode during sterile surgery with anesthesia. In practice, the electrical stimulator is attached to the electrode into the brain by a loose spring so that the animals can move freely about the cage. By systematically exploring brain regions, a map of the “pleasure” centers, for example, sites where animals will self-stimulate, in the brain has been produced. (From Roberts, A.J., and G.F. Koob. “The Neurobiology of Addiction: An Overview.”
Alcohol Health & Research World
, 21(2): 101–106, 1997. Updated: October 2000.)

By carefully mapping the sites of the electrodes in the brain
¹
, they found that there were several regions in the brain that produced this repetitive, reinforcing self-stimulating behavior, and they sometimes referred to these areas as the pleasure center(s). High rates of electrical self-stimulation were found in the lateral hypothalamus, the medial forebrain bundle, and other areas. These anatomical mapping studies have revealed much about the brain regions involved, but for our purposes, we don’t need to go into that level of anatomical detail. These regions contain many components that are likely stimulated at the same time, and any one of them can be the contributor to the electrical self-stimulation. Later experiments showed that at least one major component of the medial forebrain bundle supporting electrical self-stimulation was the nerve cells, or neurons, that contain the neurotransmitter dopamine. Electrical self-stimulation of the medial forebrain bundle caused a release of dopamine, and chemicals that blocked dopamine blocked electrical self-stimulation. Drugs like cocaine also cause an increase in dopamine, so drugs and electrical self-stimulation have many of the same effects. Neurotransmitters, including dopamine, and their role in the brain are discussed in more detail in the next chapters.