October 27, 2000

Lovinger receives MERIT grant

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Lovinger receives MERIT grant

David M. Lovinger, Ph.D., has been studying a molecular target of alcohol action in the brain for over a decade. His research contributions were recently rewarded with a Method to Extend Research in Time (MERIT) grant from the National Institutes of Health.

The MERIT award provides up to 10 years of continuous funding without competitive review. The stability of the support will give Lovinger, professor of Molecular Physiology & Biophysics, Pharmacology, and Anesthesiology, the freedom to pursue exciting, but potentially risky aspects of his alcohol research.

“If we find interesting avenues during the course of our proposed research studies, the MERIT award will allow us to explore them without having to constantly worry about renewing the grant,” said Lovinger, who also serves as Kennedy Center deputy director for biomedical research.

Lovinger is interested in understanding how alcohol works in the brain. He and other alcohol researchers hope that their studies will pave the way to the development of drugs to treat alcohol abuse and alcoholism.

Nearly 14 million people in the United States – one in every 13 adults – abuse alcohol or are alcoholic, according to the National Institute on Alcohol Abuse and Alcoholism. Although there are medications used to aid in alcohol withdrawal and lessen alcohol craving, they have limited success, Lovinger said.

“For the drugs that have been tried, the average reduction in alcohol consumption, by any measure, is only about 30 percent,” Lovinger said. “So there’s definitely room for improvement in developing pharmacotherapy that offers a way to reduce alcohol withdrawal symptoms and alcohol craving after withdrawal.”

Lovinger’s MERIT award studies will focus on a particular brain target molecule – the NMDA receptor – that is involved in nerve cell communication.

NMDA receptors respond to the “excitatory” neurotransmitter glutamate to promote the passing of messages from one neuron to the next. They are also involved in synaptic plasticity (lasting changes in neuronal communication), particularly a type called long-term potentiation which is thought to reflect the cellular changes that underlie learning and memory.

“We knew that alcohol, both acute and chronic, produces memory loss, and that it affects synaptic transmission,” Lovinger said. “So the NMDA receptor, with its role in excitatory neurotransmission and learning and memory, seemed like a logical target for alcohol action.”

Lovinger and his colleagues were among the first to show that alcohol inhibits the function of NMDA receptors at concentrations of alcohol that are reached in the brain during intoxication.

“The findings set off a whole subfield of research on the effects of alcohol on this receptor and the relationship of those effects to the many facets of alcohol abuse and alcoholism,” he said.

The NMDA receptor is put together from several different protein parts, or “subunits,” and one NMDA receptor is not necessarily exactly the same as another. In the course of their research, Lovinger and his colleagues discovered that NMDA receptors containing a subunit called “NR2B” were particularly sensitive to alcohol, compared to receptors that did not have this part.

The current studies will address the importance of particular NMDA receptor subunits in intoxication.

“We want to know if the alcohol sensitivity of the NR2B subunit makes a difference in the animal,” Lovinger said.

His group will use mice that are missing a different subunit (NR2A) to address this question. Mice lacking the NR2A subunit will usually incorporate only the NR2B subunit into their NMDA receptors.

The researchers will examine NMDA receptor function in isolated neurons and in brain tissue using electrophysiological techniques. They will perform behavioral studies to assess the consequences of acute alcohol exposure in these mice. They expect these mice to be more sensitive to alcohol, Lovinger said.

Other studies will focus on what makes the NMDA receptor sensitive to alcohol. “We think there will be some sort of alcohol binding pocket on the receptor,” Lovinger said.

Defining the molecular basis for alcohol’s inhibition of the NMDA receptor will guide development of drugs that counter its effects.

In addition to its role in the acute effects of alcohol, the NMDA receptor has also been implicated in the chronic effects of alcohol as well as in fetal alcohol syndrome, Lovinger said.

“The NR2B subunit is predominant in the fetal brain,” he said. “And since that subunit is especially sensitive to alcohol, fetal alcohol exposure could produce strong inhibition of NMDA receptors in the fetus and impair brain growth processes that depend on the function of these receptors.

“The overall question of how alcohol works in the brain is an extremely challenging scientific question,” Lovinger said. “It’s exciting work to be doing.”

Other VUMC faculty members currently funded with MERIT awards are: Albert H. Beth, Ph.D., professor of Molecular Physiology & Biophysics; Alan D. Cherrington, Ph.D., Charles H. Best Professor of Diabetes Research and chair of Molecular Physiology & Biophysics; Dr. Daryl K. Granner, Joe C. Davis Professor of Biomedical Science and director of the Vanderbilt Diabetes Center; Elaine Sanders-Bush, Ph.D., professor of Pharmacology; Conrad Wagner, Ph.D., professor of Biochemistry; and Michael R. Waterman, Ph.D., Natalie Overall Warren Distinguished Professor of Biochemistry and chair of the department.