Kelly MP, Logue SF, Dwyer JM, Beyer CE, Majchrowski H, Cai Z, Liu Z, Adedoyin A, Rosenzweig-Lipson S, Comery TA
The supra-additive hyperactivity caused by an amphetamine-chlordiazepoxide mixture exhibits an inverted-U dose response: Negative implications for use of model in screening for mood stabilizers. [JOURNAL ARTICLE]
Pharmacol Biochem Behav 2009 Mar 17.
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 challenges 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 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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