February 25, 2004

It's the Dosage: Salk Study Shows How Drugs of Abuse Work

Salk News

It’s the Dosage: Salk Study Shows How Drugs of Abuse Work

La Jolla, CA – Researchers at the Salk Institute and the University of Geneva have discovered a novel mechanism to explain how the drug of abuse GHB affects the human nervous system. GHB is also known as the “date rape” drug.

The research demonstrates how the dosage of a chemical can significantly alter the functions of a nerve cell receptor, and provides insight into the design of treatments for addictions to GHB and other drugs of abuse. The study appears in the February edition of Nature Neuroscience.

GHB, short for gamma-hydroxybutyrate, was declared illegal in the United States in 2000 after a number of deaths and severe nervous reactions from the drug were reported. GHB also has been implicated in cases of “date rape,” causing complete amnesia in the victim. It is unknown how addictive GHB is, but it is abused to produce feelings of extreme pleasure and euphoria. This drug acts in the reward center in the brain located in an area of the limbic system associated with producing the rewarding effects a person experiences in drug abuse.

Paul Slesinger, assistant professor in the peptide biology laboratory at Salk, Christian Lüscher of the University of Geneva, and colleagues studied two types of nerve cells in the brain?s reward center, one that transmits the neurotransmitter dopamine and another that transmits a neurotransmitter called GABA. Since dopamine works to inhibit euphoric sensations while GABA stimulates them, these nerve cells work in concert to control reward center activity.

The researchers found that specific types of receptors on the GABA nerve cells in the reward center were targeted by GHB at low doses of the drug. At higher doses, the same drugs triggered receptors on the dopamine nerve cells, inhibiting the reward center and acting as anti-addiction chemicals. This dose-dependent activity stemmed from two types of ion channels, called GIRK, that responded to different doses of GHB. Low doses of GHB activated the more sensitive GIRK channels, which triggered the GABA nerve cell activity associated with euphoria. Higher doses activated the less-sensitive channels on dopamine cells and inhibited the euphoria-producing nerve cell activity.

“Scientists have long been puzzled over how GHB can produce pleasure and euphoria, yet anti-addiction treatments produce opposite effects using the same drug acting on the same type of nerve cell receptor,” Slesinger said. “This study shows that key nerve cells of the reward center differ in their sensitivity to GHB. This information could be used to design anti-addiction drugs.”

Slesinger and his team are now looking at how to selectively manipulate the receptors and channels to counteract addictive behavior, and at the cell signaling pathways that lead to addiction. They are also investigating other parts of the brain, where these receptors and channels may play a role in memory and other mental functions.

The Human Science Frontier Project, Strasbourg, France, supported Lüscher and Slesinger’s research.

The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. Jonas Salk, M.D., founded the institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.

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