Volume 13, Number 2 (July, 1998)
Brain Scans Open Window to View Cocaine's Effects on the Brain
By Neil Swan, NIDA NOTES Staff Writer
New NIDA-funded research supports a widely held theory that cocaine-induced euphoria is precipitated by blocking the normal flow of the chemical messenger dopamine in the brain. The findings also help clarify why cocaine addicts "binge" on the drug. A related study by the same research team challenges another theory about where in the brain this dopamine action occurs.
Dopamine is a neurotransmitter, a chemical that carries messages from one nerve cell, or neuron, to another or from one functional section of the brain to another. This neurotransmitter is associated with body movement, awareness, judgment, motivation, and pleasure. Researchers believe it is responsible for the addictive effects of drugs such as cocaine.
Dopamine flows from neurons into the synapses, or spaces between neurons, to form a temporary link that serves to transmit signals between neurons. Then, normally, after it has transmitted its signal to the neighboring neuron, it vacates these spaces, returning to the same neuron that released it in a recycling process called reuptake. Dopamine moves from the synaptic gap back inside the neuron by attaching to "transporter" molecules on the neuron's surface.
|Cocaine in the Brain|
The neurotransmitter dopamine transmits brain signals by flowing from one neuron into the spaces between neurons and attaching to a receptor on another neuron. Normally, dopamine then is recycled back into the transmitting neuron by a transporter molecule on the surface of the neuron. But if cocaine is present, the drug attaches to the transporter and blocks the normal recycling of dopamine, causing an increase of dopamine levels in the spaces between neurons that leads to euphoria.
Cocaine, however, attaches to the same transporter binding sites as dopamine. This means that, when cocaine is introduced, dopamine cannot bind to the dopamine transporter and is stranded in the synapses. Thus, cocaine's blocking action leads to an increase of dopamine levels in the synapses that, scientists believe, normally produce feelings of pleasure. Cocaine's action intensifies these feelings into euphoria, studies show.
Now, Dr. Nora Volkow of NIDA's Regional Neuroimaging Center at Brookhaven National Laboratory in Upton, New York, has provided visual evidence to confirm this theory of how cocaine blocks the reuptake of dopa-mine. Dr. Volkow used brain images to show that, in cocaine addicts, dopa-mine is directly involved in the euphoria that reinforces the drug abuser's desire to take drugs.
"The results affirm the theory that dopamine transporter blockade plays
a crucial role in the rewarding and reinforcing properties of cocaine in humans," she says, adding that this role may explain why cocaine addicts sometimes binge uncontrollably.
Dr. Volkow theorizes that cocaine binging may result from the corruption of primeval survival-of-the-species urges that are controlled by dopamine. Dopamine activity is known to control urges to begin - and to repeat - acts that are necessary for survival such as eating, drinking, and engaging in sex. Satisfying these urges results in pleasure or gratification. "Pleasure is
a natural reinforcer to increase the probability that a species will engage
in a given behavior and continue that behavior," she says. Once these urges have been satisfied, the body's normal response is satiety or "that's enough." Repeated cocaine use, however, turns off this normal satiety response so that users continue craving and drug seeking behavior, she suggests. This short-circuiting of the satiety response could explain why cocaine abusers binge even in the face of powerful negative side effects, she adds.
"When satiety is suppressed, the pleasurable properties of cocaine serve as a trigger for activating brain pathways that will then maintain the drug-consuming behavior," she concludes.
Dr. Volkow used a brain imaging technology called positron emission tomography (PET) to study 17 long-term users of cocaine. She found that the intensity of the cocaine-induced high or euphoria that the volunteers reported was related directly to cocaine's ability to block the dopamine transporter system.
Using intravenous injections of cocaine at doses comparable to those typically used by abusers, Dr. Volkow found that cocaine blocked between
60 percent and 77 percent of the dopamine transporter binding sites in the brains of the addicts. She found that at least 47 percent of the binding sites had to be blocked by cocaine before the volunteers said they felt a drug-induced high.
A related study by Dr. Volkow measured drug responses of cocaine addicts and of nonaddicted volunteers who had not developed craving for the drug. In that study, she used PET imaging to compare responses to intravenous administration of methyl-phenidate, a stimulant drug that, like cocaine, increases synaptic levels of dopamine.
Many researchers have theorized that elevated dopamine levels associated with the reinforcing effects of cocaine occur in the brain region called the nucleus accumbens. However, Dr. Volkow found that cocaine-dependent volunteers experienced decreased, not increased, levels of dopamine release, compared to nonaddicted volunteers, in the striatum, where the nucleus accumbens is located. Instead, addicts' response to methylphenidate was greater than that of nonaddicts in the thalamus, a brain region that carries sensory signals to the cerebral cortex. This thalamic response in the cocaine addicts was associated with cocaine craving and was not seen in nonaddicted volunteers. "Thus, our findings challenge the notion that addiction involves an enhanced dopamine response to cocaine in the striatum," Dr. Volkow reports. The data suggest that the brain's thalamus region may have an addiction-related role in dopamine levels and functions, she says.
Volkow, N.D., et al. Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386:827-830, 1997.
Volkow, N.D.; Wang G.-J.; Fowler, J.S.; Legan, J.; Gatley, S.J.; Hitzeman, R.; Chen, A.D.; Dewey, S.L.; Pappas, N. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature 386:830-833,
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