From Mouse to Man

What the latest basic science research is telling us about the human mind

A new target for alcoholism treatment; the N-type calcium channel.

A new target for alcoholism treatment
Hello and welcome to a new blog; From Mouse to Man. I'm your host, Dr. Phil Newton from the University of California at San Francisco. I'll be bringing you some of the latest developments from the world of basic research and trying to translate their implications for human mental health.

I'll ease myself into the blogging process with a blatant plug; I have a new paper out today that I think has some interesting treatment implications for human alcoholism. The problem with alcohol is that we really don't understand how it works. Pick any other abused drug; nicotine, cocaine, heroin, methamphetamine, cannabis and scientists can tell you how it works, the receptors it sticks to in the brain. This information can then be used to develop treatments for addiction to those drugs. For example, heroin addiction is often treated by substituting heroin for methadone; a less potent, slower acting drug. Methadone binds to the same receptor in the brain as heroin, easing craving but without the big highs and lows associated with heroin. Later on during treatment, patients may be prescribed naltrexone (ReviaTM) which blocks those receptors that heroin would otherwise bind to, meaning that if patients relapse then heroin it won't have any effect.

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Unfortunately and perhaps surprisingly, this sort of information just isn't available for alcohol. No-one really knows definitively how alcohol works, making rational drug design very difficult. Our group at the Ernest Gallo Clinic and Research Center has spent a number of years working on a molecule that we think might be an important player in mediating the effects of alcohol. This molecule, called the N-type calcium channel, is a molecular switch that controls the release of messenger chemicals called neurotransmitters. Alcohol stimulates the release of neurotransmitters and heavy alcohol exposure causes the production of more N-type calcium channels. We found previously that genetically engineered mice which lack N-type calcium channels are remarkably resistant to alcohol and drink less of it. This lead us to speculate that blocking N-type calcium channels might prevent some of alcohols effects and reduce drinking.

We partnered with Neuromed Pharmaceuticals (Vancouver BC) who supplied us with NP078585, a drug that blocks N-type calcium channels. We tested the drug on mice, which can be trained to seek out places where they have previously been given alcohol, much like a favorite bar. When we gave mice NP078585, they no longer sought out their favorite bar. We found something similar with rats, who drank less alcohol when given NP078585.

One of the most troubling symptoms of alcoholism is the high rate of relapse, with stress being one of the leading causes. Rats too will seek out alcohol in times of stress, but not, we found, when treated with NP078585. This treatment had another potentially beneficial effect; it substantially reduced the drunkenness caused by administration of an intoxicating dose of alcohol.

This study suggests that drugs like NP078585 might create a "positive feedback"; reducing the desire of human alcoholics to drink, lessening their rates of relapse once sober and reducing the effects of alcohol should they relapse. Our group is expanding these studies to determine whether derivatives of NP078585 might be suitable for human trials.

As excited as I am about this work, I'm not getting carried away. We're still a long way from a treatment that could be used in people and of course there is no guarantee such a treatment will work. Nevertheless, the pharmaceutical industry is actively developing drugs that block N-type calcium channels so there is a real chance we could find out. Hopefully we can deliver some good news for the treatment of a devastating disease that currently has few effective treatment options.

The full paper, entitled "A Blocker of N- and T-type Voltage-Gated Calcium Channels Attenuates Ethanol-Induced Intoxication, Place Preference, Self-Administration, and Reinstatement" is in the November 5th version of the Journal of Neuroscience.

A University of California feature on the findings is here 

 

Philip M. Newton, Ph.D. is a Neuroscience Lecturer at Swansea University Medical School in the United Kingdom.

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