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Drug therapies could counter alcohol withdrawal

PULLMAN – The U.S. government estimates that nearly 20 million Americans suffer from alcoholism. About one in four receives treatment for this disabling addictive disorder, but nearly half of those treated will experience a relapse within three months.
Why it is so hard to stop using alcohol and what can be done to help those struggling to quit are questions at the heart of Washington State University researcher Brendan Walker’s work.
Walker, an assistant professor and neuroscientist in the Department of Psychology, has been awarded a five-year, $1.65 million grant from the National Institute on Alcohol Abuse and Alcoholism to study how chronic exposure to alcohol affects the structure and chemistry of the brain, producing neuroadaptations that contribute to depression and anxiety during withdrawal from alcohol.
Walker’s goal is to develop new drug therapies that will support patient treatment compliance and long-term recovery.
The opposite of “happy” endorphins
Alcohol-induced depression and anxiety can persist long after a person has ceased drinking, and in a vicious cycle many alcoholics seek relief from these symptoms by resuming the habit.
“If you’re trying to stop using drugs or alcohol, you are going to be in withdrawal and potentially you will have depression and decreased mood,” said Walker. “That negative state motivates you to resume excessive alcohol use.”
In general, an elevation in mood produced by alcohol use is followed by a compensating decline. After prolonged exposure to alcohol, a person’s baseline emotional state drops.
“Our set point for mood is shifted down,” said Walker. “If you stop using drugs, you’re down, and even if you are using drugs you’re not getting to where you were.”

Walker believes the neurotransmitter dynorphin may contribute to the mood-altering effect.

It works in the brain similarly to the more familiar endorphin, which produces a feeling of well-being commonly referred to as a “runner’s high,” only dynorphin has the opposite effect.

“Like endorphins, dynorphins are opioid peptides, but endorphins make you feel good and dynorphins make you feel bad,” Walker said. “So the theory I am investigating is that dynorphins are recruited during [alcohol] dependence and keep you in this really down, depressed, negative mood state.
“What I am trying to do is block those dynorphins, basically trying to block that down state so people don’t have to excessively use drugs or alcohol.”
A different direction in drug therapy
There are three drug therapies approved by the U.S. Food and Drug Administration for treatment of alcoholism. Walker believes his research will eventually lead to a fourth pharmacologic option.
Disulfiram, also known as Antabuse, works as a deterrent by causing a severe adverse physical reaction when the person taking it consumes alcohol.
Acamprosate reduces the physical distress and emotional discomfort people often experience when they stop drinking. This drug focuses on glutamate, one of the chemicals in the brain that transmits signals between neurons and cells, but according to Walker the precise way it works is still a subject of research.

Naltrexone blocks the effects of endorphins, so drinking no longer produces an elevation in mood.

Walker is approaching the problem from a different angle. He believes that a drug, or combination of drugs, that blocks the binding of dynorphin to its receptors can facilitate sustained recovery by easing the negative mood state that afflicts people when they stop drinking.
“In conjunction with those pharmacotherapies that target the other aspects of addiction and dependence, treatments can be designed that can assist an individual during those critical times that are likely to promote relapse,” he said.
Academic and private research into new drug therapies is the precursor to clinical trials conducted by drug companies and the National Institutes of Health and upon which final FDA approval is based.

“I am the on the pre-clinical side,” said Walker. “You have to have a good idea, backed up by substantial evidence, before you get to the next step.”

Inspired to help by friends’ sad histories
Walker’s interest in alcohol and drug abuse treatment goes back to the 1980s, when he was a teenager growing up in the Hollywood Hills of Los Angeles. A number of friends and acquaintances got involved with drugs and alcohol. Some died as a result, and others never graduated from high school.
“It was very sad,” said Walker. “I think that the initial impetus (for choosing this field of research) was to try and help people who are being plagued by this problem.”
With this grant, Walker is in a position to do just that.
The National Institute on Alcohol Abuse and Alcoholism, an agency of the National Institutes of Health, supports and conducts biomedical and behavioral research on the causes, consequences, treatment and prevention of alcoholism and alcohol-related problems.
Walker received his Ph.D. in behavioral neuroscience from the University of California, Santa Barbara. Following postdoctoral studies with George Koob in the Committee on the Neurobiology of Addictive Disorders at the Scripps Research Institute in La Jolla, Calif., he worked as a staff scientist in the institute’s Department of Molecular and Integrative Neuroscience on topics related to alcohol dependence, negative affect and adolescent alcohol exposure.
In 2008 Walker joined the psychology faculty at WSU, where he founded the Laboratory of Alcoholism and Addictions Neuroscience.

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