The supra-additive hyperactivity caused by an amphetamine-chlordiazepoxide mixture exhibits an inverted-U dose response: Negative implications for the use of a model in screening for mood stabilizers |
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Authors: | Michele P Kelly Sheree F Logue Chad E Beyer Zhang Cai Adedayo Adedoyin Thomas A Comery |
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Institution: | a Department of Neuroscience, Discovery Research, Wyeth, Princeton, NJ 08852, USA b Department of Drug Safety and Metabolism, Discovery Research, Wyeth, Princeton, NJ 08852, USA |
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Abstract: | One of the few preclinical models used to identify mood stabilizers is an assay in which amphetamine-induced hyperactivity (AMPH) is potentiated by the benzodiazepine chlordiazepoxide (CDP), an effect purportedly blocked by mood stabilizers. Our data here challenge this standard interpretation of the AMPH-CDP model. We show that the potentiating effects of AMPH-CDP are not explained by a pharmacokinetic interaction as both drugs have similar brain and plasma exposures whether administered alone or in combination. Of concern, however, we find that combining CDP (1-12 mg/kg) with AMPH (3 mg/kg) results in an inverted-U dose response in outbred CD-1 as well as inbred C57Bl/6N and 129S6 mice (peak hyperactivity at 3 mg/kg CDP + 3 mg/kg AMPH). Such an inverted-U dose response complicates interpreting whether a reduction in hyperactivity produced by a mood stabilizer reflects a “blockade” or a “potentiation” of the mixture. In fact, we show that the prototypical mood stabilizer valproic acid augments the effects of CDP on hypolocomotion and anxiolytic-like behavior (increases punished crossings by Swiss-Webster mice in the four-plate test). We argue that these data, in addition to other practical and theoretical concerns surrounding the model, limit the utility of the AMPH-CDP mixture model in drug discovery. |
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Keywords: | AMPH d-amphetamine" target="_blank">d-amphetamine CDP Chlordiazepoxide LMA Locomotor activity MDD Major depressive disorder |
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