Elsevier

Neuroscience

Volume 144, Issue 1, 5 January 2007, Pages 239-246
Neuroscience

Neuropharmacology
Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity

https://doi.org/10.1016/j.neuroscience.2006.09.026Get rights and content

Abstract

Currently available antipsychotic medications work primarily by antagonizing D2 dopamine receptors, thus raising intracellular cAMP levels. We hypothesized that intracellular stimulation of cAMP levels in the CNS would have similar effects to treatment with antipsychotic medication. To test this hypothesis, we studied the effect of an acute treatment of rolipram, an inhibitor of type 4 phosphodiesterases that degrade cAMP, on acoustic startle and prepulse inhibition (PPI) of the acoustic startle response in C57BL/6J mice known to exhibit poor PPI. PPI is disrupted in schizophrenia patients, and the ability of a drug to increase PPI in mice is predictive of antipsychotic efficacy. We show here that acute treatment with rolipram significantly increases PPI at doses that do not alter the acoustic startle response (lowest effective dose 0.66 mg/kg). In addition, rolipram (0.66 mg/kg) blocks the disruptive effects of amphetamine (10 mg/kg) on PPI. At a slightly higher dose (1.0 mg/kg), rolipram also induces catalepsy. Thus, phosphodiesterase-4 (PDE4) inhibition has many of the same behavioral effects as traditional antipsychotic medications. In contrast to traditional antipsychotics, these effects are achieved through alteration of an intracellular second messenger system rather than antagonism of neurotransmitter receptors. Given previous reports showing rolipram improves cognition, we conclude that PDE4 represents an important novel target for further antipsychotic drug development.

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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