Journal article
Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity
Neuroscience, Vol.144(1), pp.239-246
2007
DOI: 10.1016/j.neuroscience.2006.09.026
PMCID: PMC3313447
PMID: 17081698
Abstract
Currently available antipsychotic medications work primarily by antagonizing D
2 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 (PDE
4) 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 PDE
4 represents an important novel target for further antipsychotic drug development.
Details
- Title: Subtitle
- Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity
- Creators
- S.J Kanes - Department of Psychiatry and Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA 19104, USAJ Tokarczyk - Department of Psychiatry and Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA 19104, USAS.J Siegel - Department of Psychiatry and Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA 19104, USAW Bilker - Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA 19104, USAT Abel - Department of Biology, University of Pennsylvania, 422 Lynch Labs, 433 South University Avenue, Philadelphia, PA 19104, USAM.P Kelly - Department of Psychiatry and Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA 19104, USA
- Resource Type
- Journal article
- Publication Details
- Neuroscience, Vol.144(1), pp.239-246
- Publisher
- Elsevier Ltd
- DOI
- 10.1016/j.neuroscience.2006.09.026
- PMID
- 17081698
- PMCID
- PMC3313447
- ISSN
- 0306-4522
- eISSN
- 1873-7544
- Language
- English
- Date published
- 2007
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984065737702771
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