Research on Cocaine - Archives - National Institute on Drug Abuse

146
<strong>Research</strong> Findings
NIDA-Supported Scientists Identify Receptor Associated with
Cocaine Abuse
By John A. Bowersox, NIDA Notes Contributing Writer
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 <strong>Research</strong>
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.
Volume 10, Number 5 (September/October, 1995)
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 selfadminister
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