Cocaine addiction linked to a glutamate receptor

Addiction researchers have paid increasing attention to the neurotransmitter glutamate in the past year or two. Now a Swiss-based team has found that mice lacking a glutamate receptor not previously considered significant in the past do not become dependent on cocaine.Equally important, the mutant mice appear to be otherwise normal, retaining an interest in natural rewards such as food and water. This makes the receptor (mGluGR5), for which a human homolog is known to exist, a prime target for developers of anti-addiction drugs. The finding, reported in the September Nature Neuroscience, is one more piece of evidence that glutamate, a neurotransmitter central to learning and memory, is also central to addiction. "What we're saying is that the concept of dependence is a learning process which is mediated by glutamate," says François Conquet, from GlaxoSmithKline R&D at the Institut de Biologie Cellulaire et de Morphologie in Lausanne, Switzerland, and the papers senior author.Conquet hastens to point out that the findings do not imply that a single gene is responsible for addiction. "You have a complex situation where you have different contributors to this process," he says. "We have found that one piece of the mechanism can be blocked, and by blocking this piece you significantly affect the system. The system itself is made of, I don't know, maybe hundreds of pieces."Conquet calls the work "a novel concept," and others agree. "This is an elegant study with surprising findings," says Stanislav Vorel, who shortly plans to join Eliot Gardner's medication development lab at the National Institute of Drug Abuse in Baltimore, Maryland, to work on the glutamate system.Vorel and his colleagues at the Albert Einstein College of Medicine in New York published a study in the May 11 Science showing that electrical stimulation of the brain's chief memory structure, the hippocampus, could cause relapse in rats that had previously kicked the cocaine habit."One reason mGluR5 is an attractive candidate for developing therapy against addiction is that this receptor is relatively prevalent in the nucleus accumbens, a brain area commonly implicated in drug addiction," Vorel notes. The nucleus accumbens is part of the brain circuit involved in pleasure, reward, and motivation, where the chief neurotransmitter is dopamine.In the past decade, addiction researchers have zeroed in on this reward pathway, looking for ways to interfere with the addiction process. But both the dopamine reward and the glutamate learning circuits underlie much of human life. Finding drugs that work on addiction without hampering the essential jobs these systems perform is a challenge.Potential therapies based on dopamine and glutamate are being examined in labs all over the world, but a medication that is both effective and safe has yet to surface. "We think that this is a better target to use to treat drug dependence because you don't affect the natural reward system," says Conquet. "The paper is important in that it reveals yet another gene that seems to be important for cocaine addiction, but it makes an already-large list bigger," says Eric Nestler, a molecular biologist and addiction expert at the University of Texas Southwestern Medical Center in Dallas.Nestler reviewed recent findings tying addiction to learning and memory in June 22 Science. One question, he points out, arises in all studies of mouse mutants that are missing a gene. "Is this a developmental consequence of the knockout? Is the knockout abnormal in some way, does it have abnormal circuitry in the brain caused by the absence of the mGluR5 receptor?"Even if absence of the receptor affects only cocaine taking in the adult, many issues remain, Nestler points out. "We need to know how it interacts with cocaine. Where is the receptor located, which part of the circuit contains the receptor, and why is loss of that receptor in the circuit so important for cocaine's ultimate behavioural effects? Those are important areas of investigation that are now needed in order to understand this finding."

Cocaine addiction linked to a glutamate receptor

A previously overlooked glutamate receptor expands our understanding of the neurological basis of learning and addiction.

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