Despite alcohol being a legal and easily obtainable substance with several negative consequences, the scientific community has not yet fully understood how ethanol produces changes in brain function to promote habitual, uncontrolled use of alcohol and its cravings. A recent discovery by a team of researchers from the University of California, San Francisco (UCSF) sheds new light on the impact of heavy drinking on brain cells. The study, published in the journal Neuron on Sep. 7, 2017, has identified a specific protein which links alcohol abuse and structural changes in the brain.
The research was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Belgian American Educational Foundation. A technique called RNAseq was applied on rodents to search for new proteins which could trigger mTORC1 (mammalian target of rapamycin complex 1) activity in mice brains as a response to alcohol. The normal function of mTORC1 is to control protein synthesis.
A previous research had found that mTORC1 is a key contributor to the development of addiction to drugs such as alcohol, cocaine and morphine. The researchers identified 12 proteins, including prosapip1, which is known to play a part at synapses. Following rodents’ prolonged exposure to alcohol, prosapip1 altered the structure and activity of neurons in the nucleus accumbens (NAc), a brain region controlling reward and satisfaction.
By genetically blocking the production of prosapip1, the researchers were able to significantly reduce alcohol-dependent changes in the brains of mice. Following the genetic changes, mice were given a choice between alcohol and water. The mice in which prosapip1 was blocked showed a reduced preference for alcohol. However, blocking the protein had no effect on the preference for sugar water, normally considered very rewarding by mice. These findings provide new insights into how alcohol triggers long-lasting changes in the brain which can promote heavy drinking behavior.
Significant human cost of alcohol abuse and addiction
According to the 2016 National Survey on Drug Use and Health (NSDUH), an estimated 15.1 million Americans aged 12 or older had an alcohol use disorder (AUD) in 2016, representing 5.6 percent of all people in the age group. This comprises 3.7 million young adults aged 18 to 25, 10.9 million adults aged 26 and older, and an estimated 488,000 youths aged 12 to 17. The NSDUH report also showed that in 2016 an estimated 136.7 million people aged 12 or older reported alcohol use in the past month, representing 50.7 percent of people aged 12 and above.
Dorit Ron, professor and Endowed Chair in Cell Biology of Addiction in UCSF’s Department of Neurology and senior author of the study, states that although the current focus on opioid abuse and addiction is justified, problems related to alcohol abuse and addiction are much bigger. Globally, 3.3 million people die every year from alcohol abuse, which is a “staggering” human cost. “Unfortunately, there are only a few medications on the market to reduce craving and relapse, and none of them work very well,” Ron says. Nearly 88,000 Americans die from alcohol-related causes every year. In 2010, the economic burden of excessive alcohol consumption was $249 billion in the U.S.
The study reveals prosapip1’s role in neural plasticity and identifies how alcohol and other addictive drugs alter brain function. Past research shows that excessive alcohol consumption activates mTORC1 signaling pathways in the NAc of rodents, leading to problematic alcohol drinking. The new study suggests that mTORC1 may cause structural changes in the NAc that strengthen positive links with alcohol, resulting in the cycle of excessive drinking. Blocking mTORC1 activity with rapamycin, a common immunity-suppressing drug, resulted in significantly reduced alcohol consumption among mice without affecting their preference for other rewarding substances.
Way to treat alcohol addiction
Rapamycin’s side effects make it unsuitable to treat AUD in humans. By better understanding the role of mTORC1 in alcohol addiction, scientists in future may be able to search for new, targeted drugs to treat alcohol addiction. According to Ron, in the several years that she has been investigating the molecular neurobiology of alcohol abuse, this is the first time that she has discovered a “signaling molecule that appears to be shared by many drugs of abuse.” She believes that in a way this could be a “gateway” to understanding drug addiction.
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