The Addicted Brain (11 page)

When the brains from addicts that have died are analyzed (referred to as postmortem studies),
⁵
there are many biochemicals whose levels are changed. It still is not clear which chemicals and brain regions are the most significant for drug addiction, but we have many hints. It is likely that changes in many chemicals and many neurons (as opposed to one chemical in one neuron) are required for the addiction process. So, although we don’t know the full story, we have at least the beginnings of a story.

Postmortem studies have been carried out in several species including man. In general, the results point out many neuroplastic changes that amount to significant impairments in neuronal function. Receptors, such as D2 dopamine receptors and glutamate receptors, signaling proteins, proteins involved in energy metabolism, and proteins involved in cell structure were found to be changed by drug use.
⁶
Proteins are large molecules that are chains of amino acids and can have many uses in the cell, from being receptors to being transporters. But, the exact proteins that are changed might depend on the drug that is studied. This approach to looking at multiple brain changes in biochemical assays is somewhat easier and cheaper than imaging approaches, which usually focus on just one biochemical, such as a dopamine receptor, at a time.

Although studying the effects of drugs on human brains is a direct approach to the problem, there are limitations with studying humans. One is that most drug users are multi-drug users, so we don’t know which drug is producing the effects. Also, drug users are not noted for taking good care of their health and perhaps the poor health is producing the changes in the brain and not the drugs. Yet another issue
is that many drug users have a simultaneous diagnosis of a mental disorder, and maybe the mental disorder is producing the changes. So, in any study of drug users, these problems have to be addressed, and this is done by selecting a control group who has similar problems without the drug use, as best as we can. As a result, caution is essential when interpreting the results. For these and other reasons, studies with animals are helpful because we can control many more factors, such as lifetime nutrition and drug use, than we can in humans.

It isn’t surprising, given that drugs change the biochemical makeup of the brain and that drugs change the electrical and metabolic activity patterns in the brain. This was clearly shown by Dr. Linda Porrino and her colleagues who analyzed glucose utilization in monkeys after a few initial doses of cocaine and after many doses (chronic) of cocaine. Glucose utilization is relevant because the parts of the brain that use more glucose do so because they are more active and therefore need more energy. The brain slices shown in
Figure 5-5
have dark regions showing where glucose utilization was high. Note that the area of high glucose utilization was enlarged in the slice from an animal treated chronically with cocaine compared to the slice from an animal with only an initial experience with the drug (see
Figure 5-5
). It is as though drugs take over more and more of the brain gradually, and their influence spreads.
Figure 5-5
shows only one slice of brain but the study revealed that many regions of the brain responded to drugs by enlarging the regions of glucose utilization. This is a nice demonstration of the power and influence of drugs on the brain, and, ultimately, on behavior.

Figure 5-5. More and more drug taking changes more and more of the brain. Slices of brain show regions of high glucose utilization by the dark color. Glucose utilization, or energy consumption, by the brain increased in specific areas (that are identified) after chronic cocaine administration. See text for more details. Caud = caudate nucleus, Put = putamen, NAcS = nucleus accumbens shell, NAcC = nucleus accumbens core. These brain regions are important in drug addiction. (From L.J. Porrino, H.R. Smith, M.A. Nader and T.J. Beveridge. “The Effects of Cocaine: A Shifting Target over the Course of Addiction.”
Prog in Neuropsychopharmacol and Biol Psychiat
, 31:1593-1600. Copyright [2007]), with permission from Elsevier.)

Addiction occurs after repeated drug taking. This is so because chronic drug taking alters chemical neurotransmission and cellular signaling, which in turn changes the brain by altering gene expression and the proteins that are made. As drug taking continues, the drug begins to influence larger and larger portions of the brain. When the drug is no longer present, the changed brain is out of balance and withdrawal symptoms occur. Repeated drug taking also produces the adaptive changes of tolerance and sensitization.

¹
This is summarized from a
New York Times
article that appeared August 30, 2010, and was written by Richard Friedman MD, entitled “Lasting pleasures, robbed by drug abuse.”

²
Plasticity, or neuroplasticity, is the ability of the brain to change in response to a stimulus. In the context here, it is the ability of the functions of the brain to change in response to drugs. Plastic changes can be an increase or decrease in the number of synaptic connections in the brain, or in changes in the levels of important proteins. Tolerance and addiction involve plasticity. Dr. Antonello Bonci and others have reviewed some of the findings on plasticity in Stuber G.D. et al.
Curr Top Behav Neurosci
, 3:3–27., 2010, and in Chen B.T. et al.
Ann N Y Acad Sci
, 1187:129–139, 2010.

³
Ibid.

⁴
Normally, changes in gene expression are defined by changes in the level of mRNA, which is made directly from DNA (see
Figure 5-2
). However, for the sake of simplicity, we often define proteins as the product of gene expression.

⁵
Endnote 1 in
Chapter 2
, “Hardwired: What Animals Tell Us About the Human Desire for Drugs,” describes how human subjects in research protocols must be protected against risk. These rules apply even in postmortem studies. For example, the identities of the subjects must be concealed in any discussion of or publication of data from the use of the brain tissue.

⁶
For example, see Hemby, S.E. “Cocainomics: New Insights into the Molecular Basis of Cocaine Addiction.”
J Neuroimmune Pharmacol
, 5:70–82, 2010. Flatscher-Bader T. et al. “Comparative Gene Expression in Brain Regions of Human Alcoholics.”
Genes Brain Behav
, 5 (Suppl 1):78–84, 2006.

Arla, like other members of her family, is a bright, attractive, and successful person. She’s always been popular and a leader in many activities. As you might expect, she’s confident of her abilities and feels that she can succeed at anything she really tries. But, she has a secret and a worry. She has been taking opiate drugs, at first for pain from a root canal, for many months. She has come to crave the high and has discovered that even though she really wants to and tries to stop, she relapses to drug use after a couple of weeks at most. She is beginning to worry that she might need help stopping, but she doesn’t really want to admit this, because it seems like a failure. She can’t believe that her urge is so powerful.

Why are drugs so powerful that some people lose control of their actions to some degree? People can become sociopaths, liars, and destructive to their loved ones, all in a compulsion to find and take drugs. Certainly this does not happen to everyone who tries drugs, but it happens to enough people that it is considered a national problem. Note that this is not asking why drugs
cause
addiction, but rather why is addiction itself so
powerful
. This is an important question that we haven’t fully answered, but we do have some ideas about it.

One reason that drugs are so powerful has been described in
Chapter 4
, “The ABCs of Drug Action in the Brain.” They enter the brain and dominate the process of chemical neurotransmission, and the brain by itself doesn’t have any ways to fight that domination.
Drugs, therefore, can “push the brain around” and override natural processes. But we think there might be other reasons as well. There are some additional hypotheses about the power of drugs that are based on specific circuits and brain regions that contribute to our survival and living. Neuronal circuits that contain dopamine are good examples of this.

The dopaminergic mesolimbic system, which is an important substrate for drugs in the brain, evolved in our brains over many millions of years. Why is it there, and what exactly does dopamine do? The answers to these questions have developed over the years and are probably not yet complete. An early view was that release of dopamine was like turning on a switch that told you when something felt good and should be repeated. In other words, dopamine is rewarding because it makes us feel good when we have a nice meal or make love. Dopamine is also reinforcing because it motivates you to repeat certain actions, such as eating and sex, which are important for survival—not only for the survival of the individual, but also for the survival of the species!

There is abundant evidence that dopamine is associated with fundamentally important actions, such as food intake and mating.
¹
Figure 6-1
shows a schematic of the human brain and neuronal pathways that contain dopaminergic neurons. The names of the anatomical regions are unfortunately a bit arcane, and derive from historical discoveries and Latin. But decades of scientific work has shown that these dopamine-containing neurons are involved in many functions surrounding feeding and sexual behavior.

Figure 6-1. Brain dopamine (DA) systems. Three major systems contribute to sexual arousal and desire, including the mesolimbic and mesocortical DA system. This system has DA-containing cell bodies in the ventral tegmental area (VTA) with terminals in the nucleus accumbens (NAcc) (and other limbic regions) and medial prefrontal cortex (mPFC), respectively. Other DA systems shown include the diencephalic system and the nigrostriatal system. The tuberoinfundibular DA system controls hormone release from the anterior pituitary gland. These systems control attention and motivation related to sexual and feeding stimuli and are also involved in the regulation of mood and emotions, attention, motivation, reward and reinforcement, and the actions of cocaine. SN = substantia nigra; mPOA = medial preoptic area. (From “Figure 3” from Pfaus, James G., “Reviews: Pathways of Sexual Desire,”
Journal of Sexual Medicine
, Copyright © 2009. Reprinted with permission of John Wiley & Sons, Inc.)