New understanding of the changes in brain chemistry caused by chronic cocaine use has suggested a novel treatment that could reduce the intense craving that forms the core of cocaine addiction.
"Our studies show that administration of an existing drug – n-acetyl cysteine, which is used to treat cystic fibrosis and several other disorders – reverses the changes in brain chemistry that appear to cause cocaine craving," said David A. Baker, a post-doctoral fellow in the laboratory of Peter W. Kalivas at the Medical University of South Carolina.
Baker presented the latest results from the Kalivas group's studies of the effects of cocaine in a region of the brain called the nucleus accumbens, which has been associated with motivation, at the annual meeting of the American College of Neuropsychopharmacology in San Juan, Puerto Rico. The initial studies were done in rats, but the results have been so promising that Kalivas and his colleagues are designing experiments to see if this effect carries over to humans.
Previous studies have found that cocaine addiction interferes with the levels of the common neurotransmitter glutamate in the nucleus accumbens. Normally, the neurons are bathed in high levels of glutamate, which tends to reduce their sensitivity so that they fire less frequently. When cocaine is withdrawn after repeated exposures, however, glutamate levels plunge to about half their normal level. During the withdrawal stage, injections of small amounts of cocaine produce large increases in glutamate concentrations, but only for short periods.
The Kalivas group has located a novel target of cocaine's action: a special protein complex, called the cysteine-glutamate antiporter, that pumps glutamate out of the interior of neurons and into the region between them. Most neurotransmitters are ejected into the synapse between two neurons when the neuron fires. However, Baker and Kalivas have determined that more than 60 percent of the extracellular glutamate is produced by antiporters that are located along the sides of the neurons outside the synaptic region.
"It appears that cocaine treatments reduce glutamate levels by suppressing anti-porter activity," says Baker, "and treatment with n-acetyl cysteines not only restores glutamate to normal levels but also prevents glutamate levels from spiking following subsequent cocaine injections."
Cocaine's effect on glutamate levels in the nucleus accumbens have been associated to cocaine addiction through the reinstatement paradigm in rats, which many researchers think is the best animal model for drug-induced craving and relapse in humans.
In this animal model, rats are trained to self-administer cocaine injections by pressing a lever. Once a rat's behavior becomes stable – in about two weeks –the cocaine is replaced with saline causing withdrawal. It generally takes a rat two to three weeks before they stop pressing the lever in hopes of getting more cocaine. If the rats are given a single injection of cocaine, they begin the lever-pressing behavior again. Similarly, extreme stress can cause a rat to return to lever pressing.
Previous studies have shown that blockage of glutamate receptors in the nucleus accumbens before administration of cocaine prevents the rats from returning to lever pressing. This is interpreted as preventing a return of cocaine craving. In the current study, post-doctoral fellow Krista McFarland found that treatment with n-acetyl cysteine had the same preventative effect.
The study was supported by funds from the National Institute on Drug Abuse and the National Institute of Mental Health.
The American College of Neuropsychopharmacology (ACNP) is a professional organization of some 600 leading scientists that was founded in 1961. Members are selected primarily on the basis of their original research contributions to the field of neuropsychopharmacology, which involves the evaluation of the effects of natural and synthetic compounds on the brain, mind and human behavior. The principal functions of the College are research and education. ACNP's annual meeting is limited to participants from around the world who have made major research or clinical contributions in the field.
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