Alcohol dependence and withdrawal: a genetic animal model

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Selective breeding can generate animal models for studying complex genetic traits.
• Ethanol dependence and withdrawal are significant public health concerns with complex genetic underpinnings.

Purpose of the Study:

• To characterize mouse lines selectively bred for differential severity of ethanol withdrawal-induced seizures.
• To investigate whether genes influencing ethanol withdrawal severity also affect other withdrawal signs and responses to other drugs.

Main Methods:

• Selective breeding of mice to create Withdrawal Seizure Prone (WSP) and Withdrawal Seizure Resistant (WSR) lines.
• Assessment of withdrawal signs, including handling-induced convulsions, tremor, and responses to various drugs (ethanol, diazepam, phenobarbital, nitrous oxide).
• Measurement of ethanol metabolism and receptor binding (MK 801) in the hippocampus.

Main Results:

• WSP mice exhibit significantly more severe ethanol withdrawal seizures and tremors than WSR mice.
• Both lines show similar ethanol metabolism, sensitivity to acute ethanol effects, and tolerance development.
• WSP mice display more severe withdrawal from other depressants and increased MK 801 binding sites in the hippocampus.

Conclusions:

• Ethanol withdrawal severity is genetically controlled and distinct from acute sensitivity and tolerance.
• Genes influencing ethanol withdrawal may broadly predispose to withdrawal from various depressant drugs.
• Differences in NMDA receptor antagonist binding sites may contribute to withdrawal severity.