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Related Experiment Videos

Pharmacodynamic and receptor binding changes during chronic lorazepam administration.

J M Fahey1, G A Pritchard, J M Grassi

  • 1Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.

Pharmacology, Biochemistry, and Behavior
|June 23, 2001
PubMed
Summary

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Chronic lorazepam administration in mice led to behavioral tolerance, evidenced by normalized open-field activity after 14 days. This tolerance correlated with a decrease in benzodiazepine receptor binding in the cortex, but not necessarily receptor function.

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.

Related Experiment Videos

  • 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.