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Science Forum Index » Life Extension Forum » Serotonin receptor linked to severity of withdrawal
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| Kofi |
 Posted: Wed Jul 21, 2004 9:26 am |
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http://www.sciencedaily.com/releases/2004/07/040708014126.htm
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Source:
Oregon Health & Science University
Date:
2004-07-08
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Scientists Find Gene Influencing Drug Withdrawal
PORTLAND, Ore. -- One of the genes that influences drug physical
dependence and associated withdrawal has been identified at Oregon
Health & Science University.
The gene, Mpdz, is involved in physical dependence on a class of drugs
known as sedative-hypnotics, which are widely used for their euphoric
and sedative effects. Drugs in this class include alcohol, inhalants,
barbiturates, benzodiazepines, like Rohypnol or roofies, and some other
club drugs.
Scientists in the Portland Alcohol Research Center (PARC) and the
Department of Behavioral Neuroscience, OHSU School of Medicine, found
Mpdz using mice bred to possess a region of a chromosome known to be
associated with a predisposition to physical dependence and withdrawal
from sedative-hypnotics like alcohol and barbiturates. During the
four-year search, the scientists narrowed the initial field of more than
1,000 candidate genes to only five genes, and finally to one.
We know that a host of biological and environmental factors interact in
a complex manner throughout the addictive process to influence drug use
or abuse. We think that physical dependence on sedative-hypnotic drugs
and associated withdrawal episodes constitutes a motivational force that
perpetuates drug use or abuse and contributes to relapse, said Nikki
Walter, research associate in behavioral neuroscience and a study
co-author.
Now that we have identified one of the key genes, we can begin to study
how this gene regulates brain circuits involved in drug dependence and
withdrawal, said Kari Buck, Ph.D., associate professor of behavioral
neuroscience and senior author of the study, which appears in the
current issue of the journal Nature Neuroscience.
The discovery also is more evidence that drug and alcohol dependency is
genetically determined. Previous OHSU studies have shown that genetics
greatly influence alcohol and drug addiction and withdrawal.
There are a lot of reasons why people drink or use other drugs and a
variety of reasons why they lose control, Buck said. For some of those
people, it may be that theyıre seeking the high of alcohol and drugs
like it, while some people might be seeking a mental escape from their
current situation. This report focused on withdrawal because it can
motivate a person to continue drug use and abuse, and contribute to the
downward spiral of addiction.
The study focused on a chromosomal region previously shown to affect
both alcohol and barbiturate dependence and withdrawal. Using inbred
mouse strains that differ in drug withdrawal severity, the researchers
developed recombinant mice to narrow the region of mouse chromosome 4
that accounted for the withdrawal phenotype to an interval containing
only five genes.
So for the five genes we found were expressed, we tested them for
variations between strains that differ in drug withdrawal severity.
These can be differences among individuals at the sequence level and/or
at the level of expression how much of the protein they have in their
brain, said Renee Shirley, Ph.D., research associate in behavioral
neuroscience and a study co-author.
Out of the five candidate genes, only one, Mpdz, had nucleotide
differences that changed amino acid sequence. Similarly, Mpdz was the
only one that differed in its expression, she added. Its expression also
correlated with the severity of withdrawal among a panel of inbred mouse
strains, which provided further support that this gene is a drug
withdrawal gene.
Mpdzıs protein product interacts with serotonin receptors in nerve cells
in the brain. Serotonin receptors have been implicated in alcohol and
drug addiction, as well as some psychiatric disorders. The human form of
the Mpdz gene also interacts with serotonin receptors. We know that
there are different versions of the human Mpdz gene, but we donıt yet
know if these differences are functionally relevant at the protein level
or at the level of behavior, Buck said.
To determine susceptibility to withdrawal in mice, researchers measured
the severity of convulsions using a well-established behavioral test.
They found that the greater the expression of Mpdz, the less susceptible
the mice were to drug withdrawal seizures.
However, Mpdz does not regulate seizure susceptibility in general
because its status is genetically correlated with seizures induced by
some, but not all, drugs. There are a lot of questions to pursue with
this gene, a lot of questions we can now begin to answer, Shirley said.
As Mpdzıs protein interactions, neural circuits, withdrawal-regulating
mechanisms, and contribution to continued drug abuse and relapse are
uncovered, new pharmaceutical therapies could be identified, Buck said.
For those people who are susceptible to drug withdrawal and are being
treated for drug abuse, therapies focused on this gene and/or proteins
it interacts with could make sense.
Buck added: Itıs very possible that by increasing our understanding of
how Mpdz acts in the brain, we can begin to develop alternative and/or
complementary drug therapies and interventions for individuals.
Other study collaborators were: Matthew Reilly, Ph.D., PARC, the
Department of Behavioral Neuroscience, OHSU School of Medicine; and
Christoph Fehr, M.D., Department of Psychiatry, University of Mainz,
Germany. The study was supported by the National Institute on Drug Abuse
and the National Institute on Alcohol Abuse and Alcoholism, the National
Institutes of Health.
Editor's Note: The original news release can be found here.
------------------------------------------------------------------------
This story has been adapted from a news release issued by Oregon Health
& Science University.
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