Looking at the Drug Users Brain

Brain imaging is a remarkably powerful tool that enables us to peer inside the skull and brain (see Figure 7-1), and measure various quantities associated with neurotransmission and drugs. There are various types of imaging that tell us different things. Positron Emission Tomography (PET) scanning1 can measure both the levels of some proteins (such as receptors) and their levels of activity as well as glucose metabolism in certain regions (see "PET Scanning").

PET Scanning

Positron Emission Tomography (PET) is an imaging technique that produces a three-dimensional picture of the distribution of a radioactive substance in the body. If the substance is preferentially bound to some receptor, for example, then the distribution of radioactivity shows the distribution and quantity of the receptors. If the radioactivity reflects metabolism, then the distribution of radioactivity shows areas that are highly metabolic or functional. PET is one of the most important research tools available today. It allows us to look inside the body for important molecules and processes without invading the tissues of the body. PET can also be combined with other powerful imaging techniques such as CT and MRI to provide even more information.

Annihilation Image Reconstruction

This schematic shows how PET scanning works. If a radioactive substance that emits positrons and binds preferentially to D2 dopamine receptors, for example, is injected into a subject, then the substance will settle onto D2 receptors in the brain. As the positrons are emitted during radioactive decay, they encounter electrons, and, being antiparticles, they annihilate each other and produce gamma radiation (see lower left) that is detected by a ring of detectors arranged around the head. The information about the annihilations is then processed and sent to a computer where the spatial distribution of the radioactivity (and the receptors) is reconstructed.

Image adapted from "Positron Emission Tomography," in http://en.wikipedia.org/wiki/Positron_emission_tomography, accessed November 18, 2010.)

Coronal Plane

Coronal Plane

Horizontal Plane

Figure 7-1 Understanding brain images. Imaging machines look inside the head and brain and display slices of the brain. The schematic on the left shows three different ways or planes that the human brain can be sliced in. Sometimes structures of interest are better seen in one plane or another. Brain imaging instruments look at slices of the brain and reconstruct them so that the details of structure (or function) can be seen, as on the right. The images on the right were obtained using magnetic resonance imaging (MRI). Although the schematic images on the left show only the brain, the actual brain images shown on the right include the skull, eyes, nose, and other tissues, which are more realistic. The PET images shown in Figures 7-2 and 7-3 are horizontal sections that reveal the distribution of radioactivity in slices of the brain. (Adapted from http://faculty.washington.edu/chudler/slice.html.)

Horizontal Plane

Horizontal Section
Sagittal Section

Figure 7-1 Understanding brain images. Imaging machines look inside the head and brain and display slices of the brain. The schematic on the left shows three different ways or planes that the human brain can be sliced in. Sometimes structures of interest are better seen in one plane or another. Brain imaging instruments look at slices of the brain and reconstruct them so that the details of structure (or function) can be seen, as on the right. The images on the right were obtained using magnetic resonance imaging (MRI). Although the schematic images on the left show only the brain, the actual brain images shown on the right include the skull, eyes, nose, and other tissues, which are more realistic. The PET images shown in Figures 7-2 and 7-3 are horizontal sections that reveal the distribution of radioactivity in slices of the brain. (Adapted from http://faculty.washington.edu/chudler/slice.html.)

Studies using brain-imaging techniques have shown that continued use of drugs causes long-lasting changes in brain chemistry and function. For example, dopamine receptors, specifically the D2 type of receptor, are decreased in the brains of drug abusers who take cocaine, methamphetamine, alcohol, or heroin. When an established addict stops taking cocaine or some other drugs, the D2 dopamine receptor levels do not immediately increase to normal (see Figure 7-2). In fact, they remain suppressed for months and months, and this has proven to be the case in several studies. The low levels of the receptors have suggested that the dopamine system is dysfunctional or under-functioning in these people. In other studies, low D2 levels were also found in obese subjects, echoing the importance of dopamine in "natural" rewards, and that drugs insert themselves in circuits for natural rewards such as feeding. Thus, low levels of D2 dopamine receptors are a suggestive marker for increased vulnerability to drug use, and perhaps other addictive behaviors as well.

Because of the long-lasting changes in receptors (and presumably many other proteins), the brains of addicts will function differently for a long time.2 In fact, imaging studies clearly show long-lasting changes in brain function in addition to changes in protein levels. Figure 7-3 shows that taking cocaine for a long time causes significant changes in energy metabolism (a measure of function) in the brain. Levels of energy metabolism (indicated by light areas in the image) are compared in a normal subject, a cocaine user who has not taken cocaine for 10 days, and one who has not taken cocaine for 100 days. It is clear that even after 100 days of abstinence, the brain has not returned to normal.

4 months

Normal

1 month

4 months

Normal

1 month

Figure 7-2 Levels of D2 dopamine receptors in a normal brain (top), a brain from a cocaine user after one month of withdrawal (middle), and a brain from a cocaine user after four months of withdrawal (bottom). Each row shows two different slices of brain from the same subject and comparisons are made by examining the images in each column. The bright areas in the image show the places where D2 dopamine receptors are the highest—the larger the brighter area, the greater the number of receptors. For example, consider the left column that shows the same brain levels from three individuals, one with no drug history and two users. The top image from an individual with no drug history has the most receptors, the middle image from a user abstinent for one month has many fewer receptors, and the third or lowest level shows perhaps a slightly higher level compared to the middle image. But it is clear that even after four months of abstinence, D2 dopamine receptor levels are not back to normal. The images are from PET scans of D2 dopamine receptors, which were first carried out by a team of which the author was a member. (Adapted from "Figure 2" from Volkow et al. "Decreased Dopamine D2 Receptor Availability Is Associated with Reduced Frontal Metabolism in Cocaine Abusers," Synapse, 14:169-177, 1993, with permission of John Wiley & Sons, Inc.)

Cocaine abuser 100 days after abuse stops

Figure 7-3 Energy metabolism is changed in abstinent cocaine abusers for months. The more lightly colored areas are regions of higher energy metabolism. The changes are notable in the frontal lobes, the brain regions where impulses are regulated. These experiments were carried out using PET scanning after injecting a radioactive form of glucose. The regions with higher levels of radioactivity show the brain regions where metabolism and neuronal activity are higher. (Courtesy of NIH/NIDA and adapted from Time Magazine, page 45, July 16, 2007.)

Many investigators have also found changes in animals' dopamine receptors and transporters after administering drugs. These studies often used another breakthrough technique referred to as in vitro labeling autoradiography of receptors, which was developed in the author's laboratory at The Johns Hopkins University School of Medicine in the late 1970s.3 When the same results are found using different techniques, species, and approaches, there is much greater confidence in the results.

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