title: The amphetamine-chlordiazepoxide mixture, a pharmacological screen for mood stabilizers, does not enhance amphetamine-induced disruption of prepulse inhibition.
abstract: In rodents, administration of a mixture of the psychostimulant d-amphetamine and the benzodiazepine chlordiazepoxide results in supra-additive hyperlocomotion, a phenomenon used to identify mood stabilizers. In an attempt to determine whether the d-amphetamine/chlordiazepoxide assay could extend to other behaviors that are affected in mania, we evaluated the effects of the mixture on prepulse inhibition. In addition, we combined chlordiazepoxide with the selective dopamine reuptake inhibitor GBR 12909 or the noradrenergic stimulant (-) ephedrine, and tested these alternative mixtures in locomotor activity and prepulse inhibition tests. Chlordiazepoxide (3mg/kg) robustly potentiated amphetamine-induced hyperactivity, but did not change the amphetamine-induced disruption of prepulse inhibition. This indicates that the d-amphetamine-chlordiazepoxide-induced hyperlocomotion does not extend to other dopamine-driven behaviors. GBR 12909 (16mg/kg) and (-) ephedrine (50mg/kg) both enhanced locomotor activity and disrupted PPI, but combined treatment of either of these compounds with chlordiazepoxide had no significant additive effect on locomotor activity or prepulse inhibition. These findings suggest that the effect of the d-amphetamine/chlordiazepoxide mixture cannot be accounted for by the dopamine enhancing properties of amphetamine alone. Last, valproic acid (120-240mg/kg) did not reduce the GBR-induced hyperactivity. Therefore, further pharmacological evaluation of GBR 12909-induced hyperactivity is warranted to determine its pharmacological potential to model mania-like behavior. Based on the current results, it is concluded that the utility of the pharmacological d-amphetamine/chlordiazepoxide assay as a tool to study brain mechanisms relevant to mania is limited.
authors.affiliation: Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences and Rudolf Magnus Institute of Neuroscience, Utrecht University, Universiteitsweg 99, Utrecht, Netherlands. t.n.douma@uu.nl
authors.forename: Tessa N
authors.initials: TN
authors.lastname: Douma
authors.forename: Adam
authors.initials: A
authors.lastname: Kolarz
authors.forename: Ynte
authors.initials: Y
authors.lastname: Postma
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.forename: Lucianne
authors.initials: L
authors.lastname: Groenink
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000339:Affect / Q000187:drug effects*; D000661:Amphetamine / Q000008:administration & dosage* / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D018692:Antimanic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002707:Chlordiazepoxide / Q000008:administration & dosage* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D007266:Inhibition, Psychological; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000633:toxicity; D013216:Reflex, Startle / Q000187:drug effects*; D014635:Valproic Acid / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D018692:Antimanic Agents; D010879:Piperazines; D014635:Valproic Acid; D002707:Chlordiazepoxide; C043425:vanoxerine; D000661:Amphetamine