Three neuronal growth factors may be key to understanding alcohol’s effects

Growth factors are a large and diverse group of polypeptides critical for the development of the central nervous system.   A symposium at the June 2005 annual meeting of the Research Society on Alcoholism in Santa Barbara, California focused on three growth factors – i nsulin, brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF) – that may also play an important role in the regulation of the behavioral effects of alcohol .   Symposium proceedings are published in the February issue of Alcoholism: Clinical & Experimental Research.

“Growth factors are proteins that are involved in the development of nerve cells and are also important for keeping the cells alive,” explained Dorit Ron, associate professor of neurology at the University of California, San Francisco and symposium co-chair.  “The growth factors covered in this symposium – insulin, BDNF and GDNF – appear to be able to regulate alcohol’s effects independent of their roles in cell survival.”

Some of the symposium’s key proceedings were:

-   Genetic manipulations of the fruit fly Drosophila melanogaster demonstrate that the insulin pathway controls sensitivity to the intoxicating effects of alcohol.

“The insulin pathway has a crucial role in regulating sugar levels in the blood,” said Patricia Janak, assistant professor of neurology at the University of California, San Francisco and symposium chair, “and malfunctions in the insulin pathway can lead to the development of diabetes.  The insulin pathway can also regulate many other processes, including aging, reproduction and the overall growth of an organism.   Using a fruit fly model, the Heberlein lab at UCSF recently found that blocking the function of brain cells that produce insulin or those that respond to insulin can increase sensitivity to alcohol’s intoxicating effects.  These results show that insulin can modulate behaviors related to the acute effects of alcohol, indicating yet another brain pathway with future pharmaceutical applications for treating alcohol addiction.”

-   Rodent research reveals that low concentrations of alcohol increase the expression of BDNF in the brain in order to regulate alcohol consumption.

“We have found that mice that are allowed to freely consume alcohol have increased expression of the growth factor BDNF in the brain, in a region called the dorsal striatum,” said Ron.   “These are considered ‘low doses’ in that the amount of alcohol consumed by these mice is not visibly intoxicating – the mice do not demonstrate any behaviors associated with intoxication, such as unstable gait – but is comparable to social drinkers.   We believe that BDNF is involved in regulation of alcohol consumption because when we block the ability of BDNF to act, the mice drink more.”

- Amygdalar BDNF regulates alcohol’s anxiolytic effects and preference.

“ Amygdalar BDNF refers to BDNF in a specific region of the brain, called the amygdala,” explained Ron.   “This area of the brain is involved in responses to fearful and stressful events, as well as being part of the brain pathway that deals with rewarding experiences.   Co-author Subhash C. Pandey’s lab from the University of Illinois at Chicago showed that BDNF in this brain region is involved in reducing anxiety – so when you interfere with BDNF in the amygdala, you see both increased anxiety and increased alcohol consumption.”

-   Increases in the expression of GDNF in the ventral tegmental area (VTA) appear to reduce alcohol self-administration in rats.

“The VTA is another brain region involved in the ‘addiction’ pathway,” said Ron, “and we have seen that increasing GDNF in this region decreases alcohol consumption in rodents.”   She explained that this line of research was based on claims that a compound called ibogaine, derived from the African shrub iboga, could stop all drug craving for several weeks in humans who had taken the drug.   Ibogaine has dangerous side effects, however, including hallucinations and death of brain cells in some areas.   “We used rodents to determine that ibogaine increases GDNF in the VTA, which decreased alcohol intake, independent of the negative side effects described above.”

Collectively speaking, said Janak, these findings show that growth factors, which were originally found to support cell survival and development, also have other important roles, including “the brain’s response to alcohol.”

Funding for this Addiction Science Made Easy project is provided by the Addiction Technology Transfer Center National Office, under the cooperative agreement from the Center for Substance Abuse Treatment of SAMHSA.

Articles were written based on the following published research:

Brown, J.; Heberlein, U.; Logrip, M.; Pandey, S. C.; Wolf, F. W.   (January 2006).   BIG news in alcohol addiction: new findings on growth factor pathways BDNF, insulin, and GDNF.   Alcoholism: Clinical & Experimental Research.   30(1):