title: 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.
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.
authors.affiliation: Department of Neuroscience, Discovery Research, Wyeth, Princeton, NJ 08852, USA. kellym22@wyeth.com
authors.forename: Michele P
authors.initials: MP
authors.lastname: Kelly
authors.forename: Sheree F
authors.initials: SF
authors.lastname: Logue
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dwyer
authors.forename: Chad E
authors.initials: CE
authors.lastname: Beyer
authors.forename: Heather
authors.initials: H
authors.lastname: Majchrowski
authors.forename: Zhang
authors.initials: Z
authors.lastname: Cai
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Adedayo
authors.initials: A
authors.lastname: Adedoyin
authors.forename: Sharon
authors.initials: S
authors.lastname: Rosenzweig-Lipson
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Comery
mesh_terms: D000339:Affect / Q000187:drug effects*; D000661:Amphetamine / Q000008:administration & dosage*; D000818:Animals; D018692:Antimanic Agents / Q000008:administration & dosage; D001007:Anxiety / Q000188:drug therapy; D001714:Bipolar Disorder / Q000188:drug therapy; D002707:Chlordiazepoxide / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004357:Drug Synergism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009043:Motor Activity / Q000187:drug effects; D014635:Valproic Acid / Q000008:administration & dosage
chemical_list: D018692:Antimanic Agents; D014635:Valproic Acid; D002707:Chlordiazepoxide; D000661:Amphetamine