Much of NIDA's cocaine treatment medication research is directed toward finding compounds that counteract the specific changes that cocaine causes in the brain. Scientists know that cocaine affects the brain's dopaminergic pathways-areas that use the chemical dopamine to transmit messages between brain cells. They have found that cocaine prevents the reuptake, or retrieval, of dopamine by the brain cells that release it. The resulting flood of dopamine overstimulates the receptor molecules to which dopamine binds, an effect that scientists believe may account, in part, for cocaine's addictive effects.
Over the last few years, researchers have identified several kinds of dopamine receptors, each possessing distinct molecular properties and having different anatomical distributions within the brain. Scientists hope to identify potential targets for new cocaine treatment medications by determining whether some types of dopamine receptors play a larger role than others in producing cocaine's addictive effects.
NIDA-funded researchers at The Scripps Research Institute in La Jolla, California, have reported that one of these receptors, known as D-3, looks particularly promising as a target for cocaine treatment medication development.
"It looks like a pretty good bet," says Scripps researcher Dr. George F. Koob about the D-3 receptor's potential as a target for cocaine therapies. In animal experiments, Dr. Koob and Dr. S. Barak Caine found that the D-3 dopamine receptor appears to be a central factor in cocaine use.
The researchers reported that rats that had access to cocaine on a daily basis took less of the drug when given compounds that selectively bind to D-3 receptors. The rats in the study were trained to self-administer a cocaine solution intravenously. After baseline rates of cocaine use were established, the researchers added various dopamine agonists, compounds that bind to and stimulate dopamine receptors, to the rats' cocaine source.
Drs. Koob and Caine found that agonists with high affinities for D-3 receptors reduced cocaine intake more effectively than did agonists with low affinities for D-3 receptors. In fact, the higher an agonist's affinity for the D-3 receptor, the more effective it was at reducing cocaine self-administration.
The researchers hypothesize that D-3-selective agonists may reduce cocaine intake by enhancing cocaine's reinforcing properties. In this view, the rats took less cocaine because, when combined with the D-3 agonists, a smaller dose of cocaine felt the same as their "regular" dose. They believe,however, that much remains to be learned about the role that the D-3 receptor plays in cocaine reinforcement.
The researchers also examined whether the rats would self-administer the D-3 agonists in the absence of cocaine-a step necessary to determine the agonists' abuse potential. Ideally, therapies for drug abuse should have little or no abuse liability. They found that the rats self-administered only very high doses of the high-affinity D-3 agonists-the doses of these compounds that reduced cocaine intake were not self-administered. This is important, says Dr. Koob, because it suggests that, at therapeutic levels, D-3 agonists would have low potential for abuse.
NIDA officials say that they are encouraged by Dr. Koob's findings. "We're excited about his work, and we're hoping to follow it up in the context of our preclinical cocaine treatment discovery testing program," says Dr. Carol Hubner of NIDA's Medications Development Division (MDD). Dr. Hubner notes that some of the compounds that Dr. Koob studied have entered MDD's preclinical drug discovery program.
Dr. Koob reports that new research from his laboratory, done in collaboration with Drs. Jean-Charles Schwartz and Pierre Sokoloff in Paris, and Dr. Larry Parsons, a NIDA postdoctoral fellow, confirms these earlier findings. "We have tested new agonists that are even more selective for the D-3 receptor and have observed an even greater reduction of cocaine intake in rats," he says. He adds that his new research also has defined more precisely the area of the brain at which the D-3 receptor mediates cocaine abuse.
"We believe that the site of action of the D-3 receptor is localized to the shell of the nucleus accumbens," he says. The D-3 receptor's localization to this structure, which lies on the underside of the midbrain, has important implications for cocaine treatment medication development, he says.
Because D-3 receptors are concentrated in an area of the brain associated with emotional and endocrine functions and not in areas that regulate motor functions, he says, therapies targeted at D-3 receptors specifically may reduce cocaine intake without producing motor side effects. Other medications that target dopamine receptors nonspecifically have been shown to cause side effects that are similar to the movement disorders associated with Parkinson's disease.
"We don't expect that there would be any parkinsonian side effects with medications that specifically target the D-3 receptor," says Dr. Koob.
Sources
- Caine, S.B., and Koob, G.F. Modulation of cocaine self-administration in the rat through D-3 dopamine receptors. Science 260:1814-1816, 1993.
- Caine, S.B., and Koob, G.F. Pretreatment with the dopamine agonist 7-OH-DPAT shifts the cocaine self-administration dose-effect function to the left under different schedules in the rat. Behavioral Pharmacology 6:333-347, 1995.