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Opposing Responses in Brain Sparked by Cocaine

A single exposure to cocaine activates different brain systems that can enhance both the pleasurable and unpleasant effects of psychoactive drugs, according to new research studies with rats. The dual effect may explain why some people become addicted to drugs while others do not, the scientists say. It appears to result from cocaine's effect on two parallel, but opposing brain circuits.

In some people, the two opposing processes may develop at different rates, and if the drug-aversion circuitry predominates, it may protect some individuals from becoming addicted to drugs of abuse, said Howard Fields, MD, PhD, UCSF professor of neurology and physiology. Fields is Director of the Wheeler Center for the Neurobiology of Addiction and an investigator in UCSF's Ernest Gallo Clinic and Research Center where the study was carried out.

Identifying what accounts for the opposing actions of the two brain circuits could lead to medicines that treat addiction by changing the balance between the two pathways -- strengthening the drug-aversion response and, in effect, weakening its addictive potential, Fields said.

Different neurotransmitters may act in the two circuits and would be likely targets for such treatment, he said.
The study is being published online the week of March 29 by the Proceedings of the National Academy of Sciences (PNAS). Fields is senior author of the paper.

Fields and his colleagues used a drug to block activity in the ventral tegmental area of the brain, or VTA, where dopamine neurons have been shown to be active in learning and memory processes involved in addiction. The drug blocked cocaine's ability to boost morphine's rewarding effect, as well as cocaine's enhancement of an unpleasant effect of another drug, demonstrating that the two opposing brain circuits involve the VTA.

The study involved "place conditioning," in which the animals are allowed to express either an attraction or aversion to two differently colored and textured chambers where they have received one of two drugs or a placebo.

Before the rats were introduced to the training environments, they were injected with a dose of cocaine. They were then placed in one chamber or the other. One group was then injected with morphine over a two- to four-day period, while another group received a related drug called a kappa-opioid receptor (KOR) agonist which produces an unpleasant or aversive effect.

Rats tend to return to sites where they have received morphine and to avoid sites where they received a KOR agonist. That is what occurred in this study, except that the single cocaine exposure significantly increased both their attraction to the sites where they had received morphine and their aversion to the sites where they had received the KOR agonist.

While cocaine is known to enhance the pleasurable effects of morphine, this is the first study to show that it can also increase sensitivity to an aversive drug.

Although the two reactions were strong and opposite, they occurred at different times, with the increased morphine preference occurring between the first and fifth days after cocaine injection, while the KOR aversion spike took place between the fifth and tenth days after cocaine injection. The different time courses and opposite behavioral effects indicate the two reactions are carried out through different nerve pathways in the brain, Fields said.

The scientists speculate that the KOR avoidance mechanism may be a "compensatory" effect that regulates the addictive power of psychoactive drugs.

"The brain circuitry that enhances avoidance may help protect people from being overwhelmed by a single highly rewarding substance like cocaine or alcohol." Fields said.

"All people are stimulated by different food, drinks or chemicals, but if there were no natural checks on the growth of rewarding power over repeated exposure to any single stimulant, people could become stuck on any single highly rewarding thing they might encounter -- for instance, chocolate -- and become consumed with the pursuit of it. They would lose their ability to adapt to a changing environment and respond to new rewards."

Lead author on the paper is Joseph A. Kim, a postdoctoral scientist at the Gallo Clinic and Research Center. Co-authors are Gregory O. Hjelmstad, PhD, also at the Gallo Center, and Kelly Pollak, currently a medical student at Oregon Health Sciences University.

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