NeuropharmacologyRolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity
Section snippets
Mice
Eight to 10 week old male C57BL/6J mice were purchased from Jackson Laboratory (Bar Harbor, ME, USA). Mice were housed in an Association for Assessment of Accreditation of Laboratory Animal Care–approved animal facility at the University of Pennsylvania. Mice were maintained on a 12-h light/dark cycle and housed in a light- and temperature-controlled facility with food and water available ad libitum. Behavioral testing was performed during the light phase. Mice were acclimated to the housing
Rolipram increases PPI in a dose-dependent manner
We tested directly the hypothesis that increasing cAMP levels would increase PPI (based on “Protocol 2,” Gould et al 2004, Kelly et al 2006). Using C57BL6/J mice, we examined the effect of vehicle vs. four doses of rolipram (0.1, 0.66, 1 and 10 mg/kg), a PDE4 inhibitor known to increase cAMP levels (n=18 per group; Fig. 1). Rolipram increased PPI at select prepulse intensities. In trials where the prepulse was played 8 dB above bg, rolipram significantly increased PPI in a dose-dependent manner
Discussion
By measuring PPI in C57BL6/J mice we have examined the potential antipsychotic activity of rolipram. Rolipram is a drug that increases cAMP levels by inhibiting PDE4, an enzyme that degrades cAMP. Our results show that rolipram increases baseline PPI in a dose-dependent manner and blocks the disruption of PPI caused by amphetamine. These effects of rolipram on PPI are elicited at marginally sub-cataleptic doses. These data support previous studies in endophenotypic mouse models of
Acknowledgments
This work was supported by NIMH P50-MH064045 (S.J.K., S.J.S., J.T. and T.A.), NIMH K08-MH067091 (S.J.K.) and NIMH T32 MH019112 (M.P.K.) as well as a grant from the Tourettes Syndrome Association (M.P.K.). The authors would like to thank Dr. Mark Geyer for his help with experimental design.
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