This is an archive page. The links are no longer being updated.
Date: March 14, 1996 For Release: 5:00 E.S.T Contact: NIDA/Mona W. Brown or Sheryl Massaro (301)443-6245
Researchers funded by the National Institute on Drug Abuse, National Institutes of Health, report important findings that have significant implications for the development of medications to treat cocaine addiction. Researchers at the Yale University School of Medicine in New Haven, CT have found that activation of the brain's D1 dopamine receptor system can suppress cocaine seeking in drug-experienced animals, whereas activation of the D2 dopamine receptor system can trigger cocaine seeking. This makes D1 receptor stimulation a potential target for the development of anti-cocaine addiction medications.
Alan I. Leshner, Ph.D., Director of NIDA, said, "These and other recent findings are finally enabling us to strategically develop effective medication treatments for cocaine addiction based on basic science. Because of the tremendous impact of cocaine addiction on the health of the public, NIDA has designated the development of a cocaine treatment medication as its top priority. This study helps move us forward in identifying target systems in the brain and in producing medications that would stop cocaine seeking behavior, interfere with and block craving, and prevent relapse to cocaine use after treatment."
The study, "Opposite Modulation of Cocaine-Seeking Behavior by D1- and D2-like Dopamine Receptor Agonists," was conducted by David W. Self, Ph.D., William J. Barnhart, B.A., David A. Lehman, B.A., and Eric J. Nestler, M.D., Ph.D. and is published in the March 15 issue of Science.
"Our work was based on the increasing knowledge of the molecular and cellular basis of cocaine addiction. This research illustrates how a strong foundation of basic neuroscience can facilitate the development of new and effective treatments for addictive disorders," said Dr. Nestler, the Elizabeth Mears and House Jameson Professor of Psychiatry and Pharmacology, and Director of the Division of Molecular Psychiatry, at the Yale University School of Medicine.
Activation of the brain's dopamine pathways is critically important to cocaine's effects. Dopamine, a chemical messenger in the brain, acts on nerve cells possessing specialized dopamine receptors, which are present in the brain in a variety of forms. Building on this knowledge of different types of receptors, the researchers tested the ability of compounds that selectively stimulate specific dopamine receptors to reinstate self-
administration of cocaine in animals who had stopped seeking this drug. In this study, rats were allowed to self-administer intravenous cocaine for 2 hours and then saline was substituted for 2 hours during which time the self-administration behavior progressively diminished, a behavioral phenomenon known as extinction. The researchers found that when a D2-like agonist (a drug that mimics dopamine's effects on the D2 receptor) was administered to these animals, a dramatic increase in cocaine- seeking behavior was observed, while administration of a D1-like agonist had no effect.
Importantly, the researchers further tested whether the D1- like or D2-like agonists could block the effects of cocaine on reinitiation of cocaine use. In these rats, providing a small priming dose of cocaine causes an increase in cocaine-seeking behavior. While pretreatment with D2-like agonists in these animals caused dramatic potentiation of cocaine's priming effects, pretreatment with D1-like agonists completely prevented cocaine's ability to reinstate cocaine use. The research clearly shows that D1- and D2-like receptor agonists produce opposite effects, and suggests that D1-agonists might be useful in treatment of cocaine addiction.
"This study demonstrates an important dissociation between D1- and D2-like receptor mediated processes in cocaine-seeking behavior. We think that D1-like and D2-like dopamine receptors are involved in very different aspects of the addicting properties of cocaine. Whereas the D2-like receptor mediates the drive to take more cocaine, the D1-like receptor may affect some aspect of satiety or satisfaction," said Dr. Self, Assistant Professor of Psychiatry at Yale University.
Previous NIDA-funded research attempting to identify a medication for successful treatment of cocaine addiction has focused more heavily on dopamine receptor antagonists, which can block some of cocaine's acute reinforcing properties. However, these antagonists are associated with unpleasant and potentially serious side effects, particularly after repeated administration. They also have proven to be ineffective in numerous clinical trials. Other work has focused on D2-like agonists, but the present study raises the concern that such drugs could actually increase cocaine craving and aggravate the addiction.
The present research was conducted at the Connecticut Mental Health Center, a collaborative program of the State Department of Mental Health and Addiction Services and Yale University. Funding was provided by NIDA, the primary federal agency responsible for basic, clinical, and applied research designed to improve and develop new strategies to deal with the health problems and issues associated with drug abuse and addiction. The development of new medications for treating drug addiction is a major part of NIDA's efforts.