Biology of Cocaine Addiction Studied in Monkey Behavior

The reactions of monkeys to administration of cocaine are providing key insights into the biological foundations of addiction to the drug, said a group of Harvard researchers at the New England Primate Research Center in Southboro, Mass.

Three teams of scientists at the Medical School, led respectively by Roger D. Spealman, professor of psychobiology, Bertha K. Madras, associate professor of psychobiology, and Jack Bergman, assistant professor of psychobiology, are using the primates to study how the behavioral symptoms of addiction are related to the neurochemical effects of the drug.

"We are trying to understand the biological basis for cocaine addiction," said Spealman.

Inhibition of Neurotransmitters

Madras explained that when nerve cells communicate, one nerve ending secretes a chemical, which sets off a sequence of events in an adjacent cell. This sequence must be stopped, Madras said, or the action coded by the sequence will continue indefinitely.

In the case of cocaine use, the sequence is not stopped, Madras said, because cocaine binds to the system that returns the necessary chemicals to the nerve terminal, known as the transporter, and disables it. Consequently, she said, nerves are flooded with chemical messages.

Madras said there is strong evidence that one of the chemicals cocaine binds to is a neurotransmitter called dopamine.

She said that she and co-workers found a strong correlation between drugs which inhibit dopamine transport, such as cocaine, and drugs which inhibit cocaine binding.

Tests on brain tissue using radioligand binding, in which derivatives of cocaine were radioactively tagged to see where they bound to tissue, revealed that those areas in which cocaine bound were rich in dopamine, Spealman said.

Observing Primate Behavior

Bergman said that primates are a good model for studying the effects of self-administration of drugs of abuse. He also said that drugs could be distinguished subjectively from placebos by primates.

"All of our research is done in monkeys or in monkey tissue," said Spealman. One such experiment was the self-administration test, in which the animals were allowed to take cocaine intravenously by performing a specific task.

In other experiments, monkeys were trained to report whether they had received cocaine or a placebo, and also discriminate between different drugs, Spealman said.

Madras said that rather than actually using cocaine, the researchers used an analog of the drug called CFT during experimentation.

"Cocaine is very difficult to work with," she said. Madras said that cocaine dissociates very quickly from binding sites, and that working with it requires a great deal of patience.

She said that in earlier work with the drug, it was found to be the most potent competitor for binding sites of cocaine, and also the best choice for radiolabeling.

"It was a natural," she said.

Therapeutic Goals

Bergman said that the results of their research so far may have several therapeutic uses, for cocaine addicts as well as victims of Parkinson's disease.

Drugs used during the research, many of which were similar in structure or chemical actions to cocaine, could be used to combat the effects of cocaine addiction, Bergman said, because such drugs block the dopamine signal, and thus the ability of cocaine to bind to the transport system.

In addition, Spealman said, cocaine agonists--chemicals that compete for the binding sites of the drug--could be used to alleviate withdrawal symptoms without themselves being addictive.

"These drugs could be used in a similar way to methadone for heroin addicts," Spealman said.

And because cocaine and CFT act on pre-synaptic dopamine neurons, the same neurons that are lost in Parkinson's disease, CFT "may be usable as a marker for Parkinson's," Madras said.

Upon investigation of CFT binding in postmortem tissue in Parkinson's and normal brain tissue, it was found that CFT did indeed affect those areas with large numbers of pre-synaptic neurons.

"It was quite exciting," Madras said, referring to the discovery of CFT's potential for use in Parkinson's research.

Integrated Efforts Praised

The three team leaders all expressed satisfaction at the success in integrating the different aspects of the research.

"The key thing is a coordinated way" of research, Bergman said.

"You get a clearer picture of the effects of cocaine" when the neurochemistry and behavioral aspects of the drug are combined, he added.

Madras also praised the variation in skills and experience of the three teams of the project.

"One of the beauties of a big collaborative group is that it can make an enormous amount of progress as a team," she said.

"Everyone came in with a different set of backgrounds," she added. "It was enormously enjoyable."