Pharmacodynamic and receptor binding changes during chronic lorazepam administration

Area of Science:

• Neuroscience
• Pharmacology

Background:

• Benzodiazepines are widely prescribed for anxiety and insomnia.
• Tolerance to benzodiazepines can develop with chronic use, necessitating higher doses.
• The neurochemical mechanisms underlying benzodiazepine tolerance are not fully understood.

Purpose of the Study:

• To investigate the pharmacodynamic and neurochemical changes associated with the development of lorazepam tolerance.
• To examine the relationship between behavioral tolerance and alterations in benzodiazepine receptor binding and function.

Main Methods:

• Chronic administration of lorazepam (2 mg/kg/day) or vehicle to mice via osmotic pumps.
• Assessment of open-field behavior at 1 and 14 days.
• In vitro benzodiazepine receptor binding assays using [125I]diazepam.
• Measurement of muscimol-stimulated chloride uptake in cortical synaptoneurosomes.

Main Results:

• Lorazepam treatment initially depressed open-field activity, which returned to baseline levels by Day 14, indicating behavioral tolerance.
• A significant decrease in benzodiazepine receptor binding was observed in the cortex on Day 14, but not in the hippocampus.
• Cortical receptor binding changes were attributed to decreased receptor number, not altered ligand affinity.
• Muscimol-stimulated chloride uptake remained unchanged in lorazepam-treated animals compared to controls.

Conclusions:

• Down-regulation of benzodiazepine receptor binding in the cortex is closely associated with the development of behavioral tolerance to lorazepam.
• These binding changes may not necessarily correlate with significant alterations in overall receptor function.