Nov. 12, 1998 ATLANTA, GA -- Researchers at Yerkes Primate Center have demonstrated that the same neurochemical changes in the brain that occur with cocaine use can also be triggered by environmental stimuli, without the presence of cocaine at all. This is significant in understanding why recovering addicts experience overwhelming "cravings" when they see a crack pipe or some other environmental link to their habit -- a craving so strong it often sends them into relapse.
Dr. Leonard Howell will present his findings at the annual meeting of the Society for Neuroscience on Tuesday, November 10 at 1:00 pm in Anaheim, CA. Dr. Howell's study lends support to the notion that the behavior of drug abusers is driven by biology rather than merely a weakness of willpower. The ultimate goal of these studies is to find a treatment to prevent even the desire for cocaine -- not just block the effect of cocaine once it has been ingested.
The neurochemical changes in the brain that occur directly after cocaine use include a sharp increase in dopamine levels. This increase is believed responsible for cocaine's euphoric effects because dopamine is the most important neurochemical in the brain's "reward system," which is involved in normal pleasurable activities like eating and sex.
Scientists have known for several years that cocaine binds to a molecule called the dopamine transporter, thus preventing it from performing its usual job -- which is to remove dopamine from its site of action after initial release. "So, with cocaine, you're prolonging and magnifying the effects of a neurotransmitter that's naturally in the brain and which is integral in the reward process," says Dr. Howell.
With this knowledge in hand, Dr. Howell set out to measure exact levels of dopamine increase in monkeys that work for cocaine by pressing a lever (called a self-administration model). In each one-hour session, the animals worked for four 15-minute intervals. During the entire work sessions, a red light is on. (The animal learns to link the sight of the red light, a neutral stimulus, with availability of cocaine.) Each time the animal has pressed the lever 20 times, a white light is flashed. At the end of the 15 minute interval, the animal gets one injection of cocaine, during which the white light is again flashed. The cocaine is the primary reinforcer; because the white light is paired with the pleasurable feeling of cocaine, the light becomes reinforcing in it own right.
"It's classical Pavlovian conditioning," says Dr. Howell. "When you pair neutral stimuli, here the red and white lights, to the the cocaine, the stimuli become conditioned reinforcers." To quantify just how much of a reinforcing effect these drug-paired stimuli had, Howell measured dopamine levels in the caudate nucleus of the brain, an area involved in reward.
"In the first 15 minutes, while the animal was still drug-free but the white light was flashed every 20th lever-press," says Howell, "the monkey's dopamine levels increased by 70% from normal levels. It was amazing to see how, without any drug at all, the brain chemistry changed so drastically." Of course, as the animals are given the cocaine four times during the session, the dopamine levels go up even higher. This is called a "direct pharmacological effect," explains Dr. Howell, "but clearly the first 15 minutes can't be explained by the cocaine." It proves that something in the environment can trigger changes in the brain similar to what a small dose of the drug can do. "Seeing the white light may be analogous to the animals getting a little dose of cocaine," he says. In effect, Dr. Howell has found a way to induce craving in an experimental animal model.
The goal of the work at Yerkes is to find a medication that could be given to the animal to prevent the dopamine levels from increasing during that first critical 15 minutes. If a medication could do that, it may prevent the strong desire for cocaine experienced by most drug addicts when they get out of a treatment clinic and return to the same neighborhood and friends that were very much a part of their drug experience. Without such medication, says Dr. Howell, "drug abstinence is much more difficult for these addicts once they return home." It's like trying to avoid temptation while living in the constant presence of the white light.
Why does dopamine increase even in the absence of cocaine? Since the dopamine transporter is not being blocked, there must be something else activating the neurotransmitter, upstream of the transporter. Dr. Howell's next step is to determine what influences dopamine activity in the brain under normal circumstances. This could provide a brand new target for treatment medications, rather than those currently used, which attempt to block the action of cocaine. But blocking its action still doesn't stop the craving for the drug. Those medications only work once cocaine has been ingested, which is rarely the most effective strategy with a population of drug abusers. "We want to find something so people won't even want to use it in the first place," says Howell.
Dr. Howell believes a potential new target for curbing drug abuse may be the next port of call upstream of the dopamine transporter -- the serotonin system. Scientists already know that the neurotransmitter serotonin somehow regulates dopamine. Prozac (fluoxotine), for instance, works by elevating serotonin and is clinically effective in treating depression. Dr. Howell plans to to test his monkeys with a pre-treatment of Prozac and related drugs that block the serotonin transporter, to see if the initial rise in dopamine in the self-administration task can be blunted. After that, he'll attempt to identify the specific serotonin receptor subtypes that are involved and their functions.
As a complement to looking at specific neurotransmitters in a certain region of the brain, Dr. Howell is also looking at the brain as a whole using PET imaging. PET measures the pattern of blood flow in the brain, indicating which parts of the brain are being activated for any given task. In another first, Dr. Howell has trained monkeys to perform drug self-administration while they are being imaged in a PET scanner. "No one has ever tried to train monkeys for this before, because they thought it was too difficult," says Howell. "But we thought it was important to do the images in awake animals. Drugs in an anesthesized brain act differently than in an awake brain." Also, voluntary self-administration of a drug can have markedly different neurochemical effects compared to passive drug administration.
The PET images are just beginning to be analyzed and Dr. Howell is optimistic about the information that can be gleaned. "We have two systems working together beautifully which we'll overlap to give a whole picture of the brain. This will help us map out which basic systems in the brain respond to psychostimulant drugs, to enable development of medications," says Dr. Howell. One can also use PET imaging to identify long-term changes in brain function due to chronic drug use in humans. Also, having unstressed, awake monkeys trained to perform motor tasks while being scanned will be extremely useful for a host of other fields, including Parkinson's disease studies.
The study is being funded by grants from the National Drug Abuse at the National Institutes of Health.
The Yerkes Regional Primate Research Center is the oldest scientific institution dedicated to primate research. Its programs cover a wide range of biomedical and behavioral sciences.
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