Scientists from the USC School of Pharmacy’s Alcohol and Brain Research Laboratory have received two grants of approximately $1.7 million each from the National Institute of Alcohol Abuse and Alcoholism, an organizational component of the National Institutes of Health.
The five-year grants will use novel approaches to investigate the neurochemical systems that serve as targets for alcohol in the brain with an emphasis on identifying molecular sites and mechanisms of alcohol action on neurotransmitter receptor proteins.
The proteins are responsible for fast communications between brain cells.
“The goal of this work is to identify specific targets at which therapeutically relevant pharmacological agents can be directed to reduce social problems, loss of lives and tremendous economic costs resulting from the misuse and abuse of alcohol,” said Ronald Alkana, professor of molecular pharmacology and toxicology in the USC School of Pharmacy.
Alkana serves as principal investigator for the first grant that will utilize increased atmospheric pressure as a tool to identify where alcohol acts on the brain.
Daryl Davies, research assistant professor of molecular pharmacology and toxicology in the USC School of Pharmacy, is the co-principal investigator.
Neurons are cells that receive and transmit chemical and electrical signals, which the brain uses to communicate and carry out its functions.
A chemical messenger � called a neurotransmitter � carries information between the synapses of the neurons by binding to receptor proteins.
Some of these transmitters � like glutamate � stimulate or excite the neuron to fire and send information along to the next neuron.
Other transmitters � like glycine and GABA � inhibit or make it more difficult for the next neuron to fire and send along its information, Alkana said.
“We know that alcohol decreases the effects of excitatory transmitters and increases the effects of inhibitory transmitters,” he said. “Therefore, the overall effect of alcohol on brain function is inhibitory, which means it depresses function in the brain.”
Scientists think that this inhibitory action explains the changes in behavior caused by alcohol, which include symptoms of intoxication like slurred speech and loss of motor control. But they do not know how alcohol causes these changes.
Part of the difficulty in developing an understanding of these mechanisms reflects a lack of tools that can block or antagonize alcohol’s effects, Alkana said.
“Over the past 20 years, our work has shown that increased atmospheric pressure blocks alcohol’s effects at the behavioral and molecular levels,” he said. “From these and other findings, we conclude that atmospheric pressure blocks alcohol by acting directly on the same molecular sites on which alcohol acts, and thus can be used as a tool to help identify these sites.”
The laboratory’s previous findings suggest that there may be two targets for alcohol in glycine receptors. This knowledge might provide insight into how alcohol acts on other related receptors, such as GABA, Alkana said.
“Our goal is to use pressure in combination with a number of other techniques to pinpoint the sites of alcohol’s action in brain receptors and understand how alcohol changes their function,” he said.
The Alcohol and Brain Research Laboratory’s second grant of $1.7 million from the NIAAA focuses on identifying initial molecular sites of alcohol action on P2X receptors.
Davies is the principal investigator of this grant, and Alkana serves as co-principal investigator.
P2X receptors are activated by the neurotransmitter ATP and are widely distributed in the central nervous system. This class of receptors constitutes the most recently cloned superfamily of neurotransmitter receptor proteins found in the mammalian brain, Davies said.
“ATP is an energy source used throughout the body, but has a particularly unique role in the brain,” he said.
“ATP not only mediates pain, long-term memory and eating behaviors, but it also modulates how much of the other neurotransmitters are released. Initial studies from our lab have shown that P2X receptors are also sensitive to alcohol.”
Davies found that alcohol had different, even opposite, effects on different types of P2X receptors.
The grant will exploit these opposite effects by using molecular biological techniques to construct chimeric P2X receptors, which are made up of pieces from various P2X receptors that respond differently to alcohol, he said.
Davies is the only scientist currently funded by the NIAAA to look at the effects of alcohol on P2X receptors.
“It would be extremely beneficial if there was a good pharmacological intervention that could be used in conjunction with behavioral efforts to treat alcoholism,” Davies said.
“Our overall goal,” he added, “is to find sites in the brain that are selective for alcohol and develop a long-term therapy based on the ability to block or manipulate the actions of alcohol on these sites.”