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Drugs to treat cocaine abuse?

The authors of a new study in Biological Psychiatry explore pharmacological strategies for reducing cocaine self-administration in animals that may have implications for treating cocaine dependence in humans.

Glutamate is the primary excitatory neurotransmitter in the brain, which has been implicated in drug addiction. Metabotropic glutamate receptors (mGluRs) represent a family of G-protein coupled receptors that modulate glutamate transmission.

Glutamate is an important neurotransmitter involved in learning and memory. Today, these receptors are considered to be promising targets for drug discovery, with therapeutic potential to treat various neurological and psychiatric disorders, including drug addiction.

Scientists from The Scripps Research Institute examined whether dysregulation of mGluRs function is a factor in escalating cocaine self-administration in rats. Rats with a history of daily short (1 hour) or long (6 hours) access to cocaine were tested for differences in cocaine consumption after receiving treatment with LY379268, an mGluR2/3 agonist, and MTEP, an mGluR5 antagonist.

They found that the capacity of LY379268 and MTEP to diminish cocaine use changed into opposite directions during development to addiction. LY379268 became more effective, whereas MTEP lost its effect in cocaine dependent rats (long-access). These behavioral changes were paired with distinct changes in the function of mGlu2/3 and mGlu5 receptors.

Dr. Yue Hao, corresponding author of this study, explains their findings: "We provide novel evidence that during the transition from 'casual' cocaine use to addiction, dysregulation develops in both mGlu2/3 and mGlu5 function as reflected by enhanced mGlu2/3 activity and decreased mGlu5 expression." These data suggest that changes in the function of mGlu2 and mGlu5 receptors may play a role in the transition to cocaine addiction.

According to the authors, these new findings identify mGlu2/3 receptors as a particularly promising treatment target for severely cocaine-addicted individuals.

In contrast, the treatment target potential of mGlu5 receptors may be limited to early stages of cocaine abuse.

"This type of study highlights an aspect of the complexity that may be associated with the pharmacotherapy of treating cocaine dependence. All types of cocaine use may not be alike," comments Dr. John Krystal, Editor of Biological Psychiatry. "Cocaine exposure to different extents may produce different adaptations in the brain systems. The different profile of the effects of mGluR2/3 agonists and mGluR5 antagonists is interesting and it should stimulate further research."

Notes to Editors:

The article is "Behavioral and Functional Evidence of Metabotropic Glutamate Receptor 2/3 and Metabotropic Glutamate Receptor 5 Dysregulation in Cocaine-Escalated Rats: Factor in the Transition to Dependence" by Yue Hao, Rémi Martin-Fardon, and Friedbert Weiss. The authors are affiliated with the Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California. The article appears in Biological Psychiatry, Volume 68, Issue 3 (August 1, 2010), published by Elsevier.

The authors' disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, M.D. is Chairman of the Department of Psychiatry at the Yale University School of Medicine and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available at

Full text of the article mentioned above is available upon request. Contact Maureen Hunter at to obtain a copy or to schedule an interview.

About Biological Psychiatry

This international rapid-publication journal is the official journal of the Society of Biological Psychiatry. It covers a broad range of topics in psychiatric neuroscience and therapeutics. Both basic and clinical contributions are encouraged from all disciplines and research areas relevant to the pathophysiology and treatment of major neuropsychiatric disorders. Full-length and Brief Reports of novel results, Commentaries, Case Studies of unusual significance, and Correspondence and Comments judged to be of high impact to the field are published, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Concise Reviews and Editorials that focus on topics of current research and interest are also published rapidly.

Biological Psychiatry ( is ranked 4th out of 117 Psychiatry titles and 13th out of 230 Neurosciences titles in the 2009 ISI Journal Citations Reports® published by Thomson Reuters. The 2009 Impact Factor score for Biological Psychiatry has increased to 8.926.

About Elsevier

Elsevier is a world-leading publisher of scientific, technical and medical information products and services. The company works in partnership with the global science and health communities to publish more than 2,000 journals, including the Lancet ( and Cell (, and close to 20,000 book titles, including major reference works from Mosby and Saunders. Elsevier's online solutions include ScienceDirect (, Scopus (, Reaxys (, MD Consult ( and Nursing Consult (, which enhance the productivity of science and health professionals, and the SciVal suite ( and MEDai's Pinpoint Review (, which help research and health care institutions deliver better outcomes more cost-effectively.

A global business headquartered in Amsterdam, Elsevier ( employs 7,000 people worldwide. The company is part of Reed Elsevier Group PLC (, a world-leading publisher and information provider. The ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).

Maureen Hunter | EurekAlert!
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