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The dopamine transporter gene influences alcohol withdrawal seizures
January 04, 2008* The intensity of alcoholism is typically defined by the severity of alcohol tolerance and/or withdrawal.
* Scientists investigated the role of polymorphisms of the dopamine transporter (DAT1) gene in withdrawal.
* Four polymorphisms - the DAT1-VNTR, rs27072, rs27048, and rs2963238 - appear to alter the risk of alcohol-withdrawal seizures.
The physiological component of alcoholism is defined by tolerance and/or withdrawal: the more severe the dependency on alcohol, the more severe the clinical complications, such as greater intensity and/or complications of alcohol withdrawal. A new study of polymorphisms - two or more mutually exclusive forms or alleles - within the dopamine transporter (DAT1) gene has shown that four of them are associated with withdrawal seizures.
Results are published in the January issue of Alcoholism: Clinical & Experimental Research.
"People with alcoholism continue to die because of complications related to withdrawal symptoms, mainly delirium tremens - delirium associated with visual hallucinations - and /or seizures," said Philip Gorwood, professor of psychiatry at INSERM and corresponding author for the study. "Benzodiazepine has helped to prevent such severe complications, but there are still some patients - approximately three percent - for whom prevention is difficult because we have few cues to detect which ones are highly vulnerable. One approach is to look at the genetic vulnerability of the patient as part of a gene/environment interaction, which helps to distinguish patients who may or may not develop the phenotype, in this case the 'storm' triggered by an acute interruption of alcohol consumption."
Frédéric Limosin, professor of psychiatry at the University of Reims, France agrees that alcoholism must be regarded as a complex disorder arising from a combination of genetic and environmental factors.
"Alcohol can enhance dopaminergic activity in mesolimbic mesocortical circuits, thought to be important for reward and reinforcement behaviors," he said. "Thus, among the different candidate genes, those acting in the dopaminergic pathway may be more specifically involved. Several previous studies have found an association between some polymorphisms of the DAT gene and the occurrence of withdrawal seizures in alcohol-dependent patients. Results from this study could help identify patients at high risk of developing this complication, and/or to prevent the seizures more efficiently."
"If a marker is going to be used for clinical purpose, it is important that we use the marker that is really involved, not a neighbour which is only partially involved," explained Gorwood. "This is why we decided to look at a large sample of patients experiencing withdrawal seizures, also seven other makers in the DAT1 gene, as well as potentially confounding factors like gender, severity of dependence, and the presence of other complications."
Gorwood and his colleagues examined 250 alcohol-dependent subjects (175 men, 75 women) recruited from three university hospitals in Paris suburbs, of whom 24 percent exhibited withdrawal seizures. All participants were genotyped for the variable nucleotide tandem repeat (VNTR) of the gene that encodes DAT1, as well as for seven single nucleotide polymorphisms (SNPs) encompassing the DAT1 gene. Severity of alcohol dependence was also measured.
Results linked four polymorphisms - the DAT1-VNTR, rs27072, rs27048, and rs2963238 - to an altered risk for withdrawal seizures.
"As the authors state, the physiopathology underlying this association between polymorphisms of the DAT1 gene and the occurrence of withdrawal seizures in alcohol-dependent subjects remains unclear," said Limosin. "One hypothesis is that the DAT1 polymorphisms could modulate neuronal excitability, and therefore be associated with a reduced seizure threshold during alcohol withdrawal. Another hypothesis may be based on the relationships that exist between dopamine and other neurotransmitters, notably glutamate through N-methyl-D-aspartate (NMDA) receptors. It will be necessary to realize further studies, such as experimental studies, to better characterize the underlying biochemical mechanisms at work."
Alcoholism: Clinical & Experimental Research
"People with alcoholism continue to die because of complications related to withdrawal symptoms, mainly delirium tremens - delirium associated with visual hallucinations - and /or seizures," said Philip Gorwood, professor of psychiatry at INSERM and corresponding author for the study. "Benzodiazepine has helped to prevent such severe complications, but there are still some patients - approximately three percent - for whom prevention is difficult because we have few cues to detect which ones are highly vulnerable. One approach is to look at the genetic vulnerability of the patient as part of a gene/environment interaction, which helps to distinguish patients who may or may not develop the phenotype, in this case the 'storm' triggered by an acute interruption of alcohol consumption."
Frédéric Limosin, professor of psychiatry at the University of Reims, France agrees that alcoholism must be regarded as a complex disorder arising from a combination of genetic and environmental factors.
"Alcohol can enhance dopaminergic activity in mesolimbic mesocortical circuits, thought to be important for reward and reinforcement behaviors," he said. "Thus, among the different candidate genes, those acting in the dopaminergic pathway may be more specifically involved. Several previous studies have found an association between some polymorphisms of the DAT gene and the occurrence of withdrawal seizures in alcohol-dependent patients. Results from this study could help identify patients at high risk of developing this complication, and/or to prevent the seizures more efficiently."
"If a marker is going to be used for clinical purpose, it is important that we use the marker that is really involved, not a neighbour which is only partially involved," explained Gorwood. "This is why we decided to look at a large sample of patients experiencing withdrawal seizures, also seven other makers in the DAT1 gene, as well as potentially confounding factors like gender, severity of dependence, and the presence of other complications."
Gorwood and his colleagues examined 250 alcohol-dependent subjects (175 men, 75 women) recruited from three university hospitals in Paris suburbs, of whom 24 percent exhibited withdrawal seizures. All participants were genotyped for the variable nucleotide tandem repeat (VNTR) of the gene that encodes DAT1, as well as for seven single nucleotide polymorphisms (SNPs) encompassing the DAT1 gene. Severity of alcohol dependence was also measured.
Results linked four polymorphisms - the DAT1-VNTR, rs27072, rs27048, and rs2963238 - to an altered risk for withdrawal seizures.
"As the authors state, the physiopathology underlying this association between polymorphisms of the DAT1 gene and the occurrence of withdrawal seizures in alcohol-dependent subjects remains unclear," said Limosin. "One hypothesis is that the DAT1 polymorphisms could modulate neuronal excitability, and therefore be associated with a reduced seizure threshold during alcohol withdrawal. Another hypothesis may be based on the relationships that exist between dopamine and other neurotransmitters, notably glutamate through N-methyl-D-aspartate (NMDA) receptors. It will be necessary to realize further studies, such as experimental studies, to better characterize the underlying biochemical mechanisms at work."
Alcoholism: Clinical & Experimental Research
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Mayo clinic study finds gene bringing together animal and human research in alcoholism
An important genetic study conducted through Mayo Clinic has identified vital new information concerning alcoholism in subjects with European ancestry, according to a recent issue of Alcohol: Clinical and Experimental Research.
New study reveals brain cell mechanism of alcohol dependence
A study released today reveals a cellular mechanism involved in alcohol dependence. The study, in the May 28 issue of The Journal of Neuroscience, shows that gabapentin, a drug used to treat chronic pain and epilepsy, reduces alcohol intake in alcohol-dependent rats by normalizing chemical communication between neurons, which is altered by chronic alcohol abuse.
Scripps Research scientists find seizure drug reverses cellular effects
In the new research, published in the May 28, 2008 edition of The Journal of Neuroscience, the scientists found that gabapentin normalizes the action of certain brain cells altered by chronic alcohol abuse in an area of the brain known as the central amygdala, which plays an important role in fear- and stress-related behaviors, as well as in regulating alcohol drinking. In the study, alcohol-dependent rodents receiving gabapentin drank less alcohol.
Brain DNA 'remodeled' in alcoholism
Reshaping of the DNA scaffolding that supports and controls the expression of genes in the brain may play a major role in the alcohol withdrawal symptoms, particularly anxiety, that make it so difficult for alcoholics to stop using alcohol.
Intensive-care patients with alcohol problems are more likely to require mechanical ventilation
More than 300,000 patients receive mechanical ventilation during intensive care per year in the United States, even though the hospital mortality rate for ventilated patients can approach 50 percent.
The glutamate decarboxylase 1 gene may play a pivotal role in developing alcoholism
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA has been implicated in the development of alcoholism, although the mechanisms through which this occurs are unclear.
Chronic Alcohol Exposure Can Affect Brain Protein Expression
Researchers at the University at Buffalo studying the effects of alcohol on the brain, using zebrafish as a model, have identified several novel central nervous system proteins that are affected by chronic alcohol exposure.
Alcoholism-treatment medication acamprosate may help abstinent alcoholics sleep better
Alcoholics generally don't sleep well. Nor does abstinence improve the situation much. In fact, sleep difficulties during alcohol abstinence may be responsible for a relapse to alcoholism as individuals attempt to self medicate their sleeping problems.
Chronic drinking and smoking cause both separate and interactive brain injury
Most alcoholics in North America are chronic smokers. While much is known about the adverse effects of chronic smoking on cardiac, pulmonary and vascular function as well as the risk for various cancers, little is known about its effects on brain neurobiology and function.
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