An assessment of anxiolytic drug screening tests: Hormetic dose responses predominate

This article provides a comprehensive assessment of dose response relationships for anxiolytic (i.e., anxiety-reducing) agents within a broad representation of the animal model screening tests. These screening tests include the elevated plus maze test, light-dark test, hole board test, open field test, four plates test, social interaction test, Vogel's conflict test, staircase test, freeze behavior test, forced swimming test, tail suspension test, communication box test, and immobilization/cold stress test. The analysis revealed that hormetic-like biphasic dose responses were commonly observed across all screening tests, independent of the animal model, the conditions of the test, modifications of tests by investigators, and the chemical class of agents tested. The quantitative features of the dose response, as measured by the magnitude and width of the stimulation at low doses, were similar across all screening tests and experimental conditions, regardless of the mechanism and receptor activation pathway identified. These findings, which add more support to the perspective that the hormetic dose response represents the most fundamental and common dose-response model in the biomedical and toxicological sciences, have important implications for the process of drug discovery/development, clinical evaluation, and quantitative expectation of drug treatment effects.