Researchers Shed Light on Molecular Pathways of Alcohol Addiction

By Renee Twombly

Unlike most drugs such as nicotine, cannabinoids, and opioids, alcohol doesn't have a primary "receptor" with which it binds or interacts. "Alcohol is a dirty drug. It targets a lot of things in a very disordered way," says Marisa Roberto, an assistant professor at The Scripps Research Institute.

The Roberto lab is determined to understand the mechanism of action of ethanol in the brain. So far, she has shed light on pathways that alcohol interacts with, providing potential targets that might yield new therapies to treat alcohol addiction and abuse.

Roberto and colleagues have taken a novel approach to understanding alcohol dependence, looking at the cellular effects of the drug and employing both pharmacological and genetic approaches. In the June 17 issue of the Proceedings of the National Academy of Sciences (PNAS), Roberto and colleagues, including first authors Michal Bajo and Maureen Cruz, report their findings of how ethanol and corticotrophin releasing factor (CRF) both affect the neurotransmission of gamma-aminobutyric acid (GABA). Fundamental to the effects of ethanol and CRF (a hormone involved in the stress response) is the intracellular PKC epsilon signaling pathway.

The lab had previously shown that ethanol increases release of GABA in the central amygdala, an important center of the brain critical in mediating fear- and stress-related behaviors, as well as in regulating alcohol consumption. Ethanol increases GABA transmission by activating corticotrophin CRF type 1 receptors, which bind CRF. In the new PNAS study, Roberto and colleagues dug deeper into the mechanisms involved in releasing GABA. "Here we have added another piece of the ethanol story, which could also have relevance for anxiety and substance abuse in general," she says.

One prime candidate was protein kinase C (PKC), which activates the calcium channels on neurons, thus regulating several of the proteins that are involved in the release of GABA. Roberto and colleagues tested knock-out mice lacking the PKC epsilon pathway. "These mice drink less and show less anxiety-like behavior than wild-type mice," Roberto says. A main finding of their study is that ethanol and CRF had no effect on GABA transmission, indicating that both ethanol- and CRF-induced GABA release are mediated by the PKC epsilon pathway. "It really was a clear black and white effect," Roberto says.

"These findings indicate a signaling pathway whereby CRF, most likely acting at presynaptic CRF1 receptors in the amygdala, activates PKC epsilon to stimulate GABA release," Roberto explains. This same pathway may be involved in anxiety and substance abuse, in general, and may also point toward a targeted therapy against PKC epsilon that would control anxiety and alcohol consumption.

"A complete understanding of the cellular and molecular underpinnings of anxiety and drug abuse may require a region-by-region exploration of the many neuronal circuits shown to be involved in these behaviors, but we believe this is one of the important pathways," she says.

"Treatment of alcoholism will probably require a combination of drugs because ethanol affects so many aspects of brain function," Roberto says. In a recent study published in The Journal of Neuroscience on May 28, 2008, Roberto and colleagues found that by inhibiting GABA transmission with the anti-epileptic drug gabapentin (Neurontin™), alcohol-dependent rats drank significantly less, and had less anxiety-like behaviors.

In addition to Roberto, Cruz, and Bajo, the study "Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala" was authored by George R. Siggins of Scripps Research and Robert Messing of the University of California, San Francisco, who provided the knock-out mice. For more information, see http://www.pnas.org/cgi/content/abstract/105/24/8410.

The work was supported by grants from the National Institutes of Health (NIAAA), the Pearson Center for Alcohol and Addiction Research and by Harold L. Dorris Neurological Research Institute grants.

Send comments to: mikaono[at]scripps.edu

"Here we have added another piece of the ethanol story, which could also have relevance for anxiety and substance abuse in general."

—Marisa Roberto