A new study focusing on the differences between alcohol-dependent and non-dependent brains could bring scientists closer to developing more personalized treatments for alcoholism and alcohol-use disorder.
Scientists at the Scripps Research Institute, led by TSRI Prof. Marisa Roberto, had previously discovered that alcohol increases neuronal activity in an area of the brain called the central amygdala (CeA). However, when they compared brain activity in alcohol-dependent and naive rats, the researchers the found that the activity was triggered by two completely different brain signaling pathways.
Within the amygdala, the central nucleus (CeA) plays a critical role in alcohol dependence. When it is impaired in human alcoholics, the CeA causes negative emotional states, and increases motivation to drink, according to the researchers.
The findings were published in The Journal of Neuroscience.
By giving naive rats a dose of alcohol, the researchers engaged proteins called calcium channels and increased neuronal activity. Neurons fired as the specific calcium channels at play, called L-type voltage-gated calcium channels (LTCCs), boosted the release of a neurotransmitter called GABA. Blocking these LTCCs reduced voluntary alcohol consumption in naïve rats.
But in alcohol-dependent rats, the researchers found decreased abundance of LTCCs on neuronal cell membranes, disrupting their normal ability to drive a dose of alcohol’s effects on CeA activity. Instead, increased neuronal activity was driven by a stress hormone called corticotropin-releasing factor (CRF) and its type 1 receptor (CRF1). The researchers found that blocking CeA CRF1s reduced voluntary alcohol consumption in the dependent rats.
Studying these two groups sheds light on how alcohol functionally alters the brain, Roberto explained.
“There is a switch in the molecular mechanisms underlying the CeA’s response to alcohol (from LTCC- to CRF1-driven) as the individual transitions to the alcohol-dependent state,” she said.
The cellular and molecular experiments were led by TSRI Research Associate and study first author Florence Varodayan. The behavioral tests were conducted by TSRI Research Associate Giordano de Guglielmo in the lab of TSRI Associate Professor Olivier George.
Roberto hopes the findings lead to better ways to treat alcohol dependence. While alcohol use disorder appears to have many different causes, the new findings suggest doctors could analyze certain symptoms or genetic markers to determine which patients are likely to have CRF-CRF1 hyperactivation. They could benefit from the development of a new drug that blocks that activity.
Doctors could choose the most effective therapies based on a patient’s genetic content or other molecular or cellular analysis.
The study was supported by the National Institutes of Health