Variables affecting prepulse inhibition of the startle reflex and the response to antipsychotics in DBA/2NCrl mice.
BACKGROUND
DBA/2 mice demonstrate poor prepulse inhibition (PPI) as is also observed in schizophrenic patients, and their PPI is improved by antipsychotics. Thus, the DBA/2 mouse is increasingly used for testing of novel antipsychotics in PPI; however, the strain has not been fully characterized for relevant variables affecting compound testing.


OBJECTIVE
The objectives of this study were to compare four DBA/2 substrains, evaluate light- and dark-phase testing on startle, PPI, and drug-induced improvement in PPI in DBA/2NCrl mice, test chamber lighting on startle and PPI in DBA/2NCrl mice and to evaluate vehicles on baseline PPI in DBA/2NCrl mice.


RESULTS
DBA/2NCrl and DBA/2J mice were acceptable for PPI testing, while DBA/2NHsd mice had diminished startle reflexes. Startle responses to the prepulses alone were observed in 46% of the DBA/2NTac mice. PPI and startle did not show diurnal variations or variations due to chamber lighting. Olanzapine and aripiprazole showed better drug-induced improvements in PPI during the light phase. The vehicle 25% (2-hydroxypropyl)-beta-cyclodextrin variably improved PPI, an effect not observed with other vehicles.


CONCLUSIONS
DBA/2NHsd and DBA/2NTac mice were unacceptable for PPI experiments. The finding of responses to the prepulses alone by DBA/2NTac mice further indicates the advisability of routinely monitoring responses to prepulses alone. Unlike rats, DBA/2NCrl mice did not have greater startle amplitudes during the dark phase. Compound efficacy was better during the light phase because of poorer PPI in the vehicle group. Some vehicles may have unacceptable effects on PPI in DBA/2NCrl mice and may not be appropriate for studies evaluating novel compounds.
CNS Biology, Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. dflood@cephalon.com
Dorothy G
DG
Flood
Maciej
M
Gasior
Michael J
MJ
Marino
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000161:Acoustic Stimulation; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001569:Benzodiazepines / Q000494:pharmacology*; D002940:Circadian Rhythm; D005079:Excipients / Q000494:pharmacology; D008029:Lighting; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D000077152:Olanzapine; D010879:Piperazines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D013216:Reflex, Startle / Q000187:drug effects*; D013045:Species Specificity; D047392:beta-Cyclodextrins / Q000494:pharmacology
D014150:Antipsychotic Agents; D005079:Excipients; D010879:Piperazines; D015363:Quinolones; D047392:beta-Cyclodextrins; D001569:Benzodiazepines; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000068180:Aripiprazole; D000077152:Olanzapine