Initial sensitivity and tolerance to ethanol in mice genetically selected for diazepam sensitivity

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Benzodiazepine (BZ) receptors modulate GABA-receptor chloride-ionophore complexes, mediating inhibitory neurotransmission.
• BZ effects like sedation and anticonvulsion are linked to this system, but mechanisms remain unclear.
• Ethanol and barbiturates also interact with this system, influencing their behavioral effects.

Purpose of the Study:

• To investigate if benzodiazepine sensitivity in selectively bred mice extends to ethanol.
• To compare ethanol sensitivity and tolerance development between diazepam-resistant (DR) and diazepam-sensitive (DS) mouse lines.

Main Methods:

• Utilized selectively bred DR and DS mouse lines previously developed based on diazepam response.
• Assessed ethanol-induced ataxia, recovery times, and tolerance development after repeated dosing.
• Determined high-dose ethanol toxicity by measuring brain ethanol concentrations at respiratory cessation.

Main Results:

• DS mice exhibited greater sensitivity to ethanol, showing ataxia at lower brain concentrations and slower recovery.
• DS mice developed minimal rapid tolerance to ethanol, while DR mice developed considerable tolerance.
• Sex differences were observed, with males showing greater sensitivity differences between lines.
• No significant differences in high-dose ethanol toxicity were found between lines or sexes.

Conclusions:

• Genetic factors influencing benzodiazepine receptor sensitivity also affect ethanol sensitivity.
• Selective breeding can create distinct lines for studying neurochemical bases of drug response.
• These findings offer insights into the neurobiological underpinnings of sedative-hypnotic drug effects and individual differences in sensitivity.