Ethanol and barbiturate withdrawal convulsions are extensively codetermined in mice

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Selective breeding is a powerful tool for studying genetic influences on complex behaviors.
• Ethanol and phenobarbital are widely used central nervous system depressants with abuse potential.
• Physical dependence is a key factor in substance use disorders.

Purpose of the Study:

• To investigate the genetic basis of ethanol physical dependence using selective breeding.
• To compare the development of physical dependence to ethanol and phenobarbital.
• To identify common mechanisms underlying physical dependence induced by different drugs.

Main Methods:

• Selective breeding of mice for high (WSP) and low (WSR) handling-induced convulsions (HIC) during ethanol withdrawal.
• Administration of ethanol and phenobarbital to induce physical dependence.
• Measurement of HIC scores as an index of physical dependence severity.
• Assessment of brain drug concentrations and functional tolerance.

Main Results:

• Five generations of selective breeding resulted in WSP mice with 3-fold greater HIC scores than WSR mice.
• Similar differences in HIC severity were observed when phenobarbital was used as the dependence-inducing drug.
• WSP and WSR mice exhibited equivalent brain phenobarbital concentrations and functional tolerance.

Conclusions:

• Selective breeding effectively isolated genetic factors influencing ethanol physical dependence.
• The determinants of handling-induced convulsions during withdrawal show significant commonality between ethanol and phenobarbital.
• These findings suggest shared neurobiological pathways for physical dependence on different sedative-hypnotic drugs.