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.
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.
Kelly
Michele P
MP
Department of Neuroscience, Discovery Research, Wyeth, Princeton, NJ 08852, USA. kellym22@wyeth.com
Logue
Sheree F
SF
Dwyer
Jason M
JM
Beyer
Chad E
CE
Majchrowski
Heather
H
Cai
Zhang
Z
Liu
Zhi
Z
Adedoyin
Adedayo
A
Rosenzweig-Lipson
Sharon
S
Comery
Thomas A
TA
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
D018692:Antimanic Agents; D014635:Valproic Acid; D002707:Chlordiazepoxide; D000661:Amphetamine