With great self-awareness at 21, Marc joined Alcoholics Anonymous, admitting he was “so young but so broken.” Marc said he quickly learned he was suffering from an illness and that “…when I took the very first sip of alcohol, set up this craving—this compulsion—to need more...”
Marc not only captured the crippling feeling he experienced, but also a physiological truth about alcoholism: There is a connection in the brain that allows alcohol tolerance, or the need to drink more to get the same effect.
The connection, according to UH College of Pharmacy professor and medicinal chemist Joydip Das, is a protein in the brain called MUNC 13-1 that binds to alcohol. It is possible that the cure to the disease of alcoholism resides inside that protein. If it could be blocked, the tolerance to alcohol could be stymied.
No time like now
The National Institute on Alcohol Abuse and Alcoholism reports approximately 7.2 percent, or 17 million adults in the United States aged 18 and older, had an alcohol use disorder in 2012. Despite increased awareness, countless prevention campaigns, and tighter laws and regulations, a 2015 Centers for Disease Control and Prevention study revealed that excessive alcohol consumption was responsible for an average of 88,000 deaths per year.
To date only three FDA-approved drugs comprise therapeutic alcohol addiction treatment. Disulfiram causes unpleasant reactions in persons drinking, including flushing, nausea and palpitations. Naltrexone blocks receptors involved in the rewarding effects of drinking and the craving for alcohol. Acamprosate is thought to reduce symptoms of protracted withdrawal, such as insomnia, anxiety, restlessness and dysphoria.
“These drugs are only effective modestly and patient compliance is a serious issue because of several adverse side effects, necessitating the developments of newer drugs,” said Das. Current research drug development efforts remain in identifying new alcohol targets.
Most people recognize tolerance as the ability to “hold their liquor.” It’s not the humblebrag it might be intended. Tolerance is considered a major risk factor for alcoholism, as those who are able to drink a lot without feeling the effects tend to drink more than people with low tolerance.
“If a person becomes tolerant of one drink, he will have another and maybe another,” said Das who recently published his findings on curing alcoholism through examining MUNC 13-1, in eNeuro, a journal of the Society for Neuroscience. His co-authors are biologist Gregg Roman of the University of Mississippi and University of Houston psychologist J. Leigh Leasure.
“If we could stop alcohol from binding into MUNC 13-1, it will help problem drinkers in reducing tolerance. If we can reduce tolerance, we can reduce addiction,” said Das whose study focuses on binge alcohol exposure.
The process of MUNC 13-1 binding to alcohol takes place in a brain synapse, where one nerve cell, or neuron, passes a signal to another. Specifically, the binding takes place in the presynaptic space, a much-understudied portion of the synapse mechanism.
During binge alcohol exposure, alcohol creates widespread and long-lasting changes in neural activity, altering both presynaptic and postsynaptic activity.
Thus far Das and company’s work has been done using the Drosophila, or fire fly, genetic model system, a simple model with various similarities. Surprisingly, fire flies have a genetic makeup comparable to humans even though their genome is 1/26th the size.
In fire flies, the activating protein is called Dunc13, the equivalent to MUNC 13-1.
“Reduction in Dunc13 produces a behavioral and physiological resistance to sedative effects of ethanol,” said Das. That makes MUNC 13-1 an important target for developing drugs.
“We need to develop a pill that would inhibit alcohol binding to MUNC 13 and reduce its activity. Based on our results so far, this would likely reduce the formation of tolerance, making it harder to become addicted to alcohol,” said Das.
Welcome news to millions, including people like Marc.
“Even before alcohol was in my life, I suffered from the illness of alcoholism. I had the ‘ism’—was just waiting on the alcohol,” he said.