The Addicted Brain (13 page)
A more recent view is that dopamine tells us or signals to us what is
salient
, meaning what is arousing or alerting, and this is linked to motivation.
12
Dopamine alerts us or arouses us not only to the availability of food and sex, but also to impending danger and pain. According to this idea, the salience due to dopamine can be considered an alerting sensory act like tasting or listening. From this point of view, drug users are not simply seeking pleasure, and the lack of pleasure in addiction has been observed and reported by addicts.
Drug addiction is obviously a powerful brain disorder that can drive our behavior in spite of personal distress and negative consequences. Drugs are powerful partly because the brain does not have mechanisms to control their levels and drugs can therefore overpower the brain. But it is hypothesized that drugs are also powerful because of the parts of the brain that they act in. For example, cocaine blocks the removal of dopamine from the synapse by blocking the dopamine transporter, thereby increasing dopaminergic neurotransmission. This happens in dopaminergic neurons (mesolimbic neurons) that are part of circuits in the brain associated with feeding, sex, and other important life-sustaining processes. Therefore, the constant “battering” of the dopamine system in the brain by repeated cocaine use causes adjustments and adaptations over time in a brain system driving vital behaviors. However, these systems, even though altered by drugs, can still profoundly influence our behavior, although in an altered and abnormal way. Dopamine is not only involved in pleasure, but also in alerting and motivation. A difference is that the object of desire now becomes cocaine (or another drug) instead of a natural reward. From this perspective, drug addiction is a disorder or disease of motivation. Other neurotransmitters such as glutamate and acetylcholine are also involved in drug addiction.
1
There are several excellent and relatively recent review articles summarizing the data showing a role for dopamine in natural rewards such as sexual behavior and feeding. These include Baskerville, T.A. and A.J. Douglas. “Dopamine and Oxytocin Interactions Underlying Behaviors.”
CNS Neurosci Ther,
16:92–123, 2010. Pfaus J.G. “Pathways of Sexual Desire.”
J Sex Med,
6:1506–1533, 2009. Kelley, A.E. “Ventral Striatal Control of Appetitive Motivation.”
Neurosci Behav Rev,
27:765–776, 2004.
Carlezon, W.A. and M.J. Thomas. “Biological Substrates of Reward and Aversion.”
Neuropharmacol
, 56 suppl 1:122–132, 2009. Peeters, M. and F. Giulliano. “Central Neurophysiology and Dopaminergic Control of Ejaculation.”
Neurosci Biobehav Rev
, 32:438–453, 2008.
2
Bello, N.T. and A. Hajnal. “Dopamine and Binge Eating Behaviors.”
Pharmacol Biochem Behav
, 97: 25–33, 2010.
3
Examples of these studies can be found in Cheskin L.J. et al. “Calorie Restriction Increases Cigarette Use in Adult Smokers.”
Psychopharmacology,
179:430–436, 2004. Carr, K.D. et al. “Chronic Food Restriction in Rats Augments the Central Rewarding Effect of Cocaine...”
Psychopharmacology
, 152: 200–207, 2000. Carroll, M.E. “Interactions between Food and Addiction.” In Niesink, R.J.M., Jaspers RMA, Kornet L.M.W., and J.M. van Ree (eds) “
Drugs of Abuse and Addiction: Neurobehavioral Toxicology
.” CRC, Boca Raton, pp 286–311,1998.
4
Summarized in D.J. Linden
The Accidental Mind
, Harvard University Press, 2007. page 162.
5
Paper in
PLoS ONE
, 3(1): e1506, January 2008. doi:10.1371/journal.pone.0001506.
6
Zhou Q.Y. and R.D. Palmiter. “Dopamine-Deficient Mice Are Severely Hypoactive, Adipsic, and Aphagic.”
Cell
, 83:1197–1209, 1995.
7
Neurons containing the neurotransmitters GABA or acetylcholine are important for addiction to alcohol or nicotine. (Interestingly, these influence the release of or the action of dopamine in the nucleus accumbens.)
8
The Kalivas model deals with glutamate-containing neurons that project from the prefrontal cortex to the nucleus accumbens and that regulate dopamine release. Dopamine facilitates learning of adaptations to important stimuli. This prefrontal cortex neural
pathway regulates seeking behaviors such as drug addiction, and it is impaired by drug use. Repeated cocaine use results in molecular changes in this pathway. A recent review is Kalivas, P.W. and C. O’Brien. “Drug Addiction as a Pathology of Staged Neuroplasti-city.”
Neuropsychopharmacology Reviews
33:166–180, 2008.
9
Koob, G.F. and M. Le Moal.
Chapter 6
, “Nicotine.”
Neurobiology of Addiction,
Elsevier, 2006.
10
Volkow, N.D. et al. “Imaging Dopamine’s Role in Drug Abuse and Addiction.”
Neuropharmacol
, 56 (Suppl 1) 3–8, 2009.
11
Badgaiyan, R.D. et al. “Dopamine Release During Human Emotional Processing,”
Neuroimage
, 47:2041-5, 2009. Martinez, R.C. et al. “Involvement of Dopaminergic Mechanisms in the Nu-cleus Accumbens Core and Shell Subregions in the Expression of Fear Conditioning,”
Neurosci Lett
, 446:112–116, 2008. Levita, L. et al. “Nucleus Accumbens Dopamine and Learned Fear Revisited: A Review and Some New Findings.”
Behav Brain Res,
137:115–127, 2002.
12
Berridge, K.C. “The Debate over Dopamine’s Role in Reward: The Case for Incentive Salience.”
Psychopharmacol
, 191:391–43.1, 2007.
“Before I started drugs, I did great. I never had a hang-up like this. I can’t seem to get over wanting drugs, no matter how hard I try. I stay away from the stuff for weeks, but it doesn’t seem to make a difference. I keep going back.”
Why is drug addiction so long lasting? Just because drugs exert
powerful
actions in the brain doesn’t mean that their effects should last a
long time
. But they do! How do we study this?
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) scanning
1
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
”).
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
.)
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.
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.)
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.
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.)
