Rolipram: A specific phosphodiesterase 4 inhibitor with potential antipsychotic activity
| Autor: | Jan Tokarczyk, Warren B. Bilker, Michy P. Kelly, Ted Abel, Steven J. Siegel, Stephen J. Kanes |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Dyskinesia Drug-Induced Reflex Startle Startle response Dextroamphetamine Phosphodiesterase Inhibitors medicine.medical_treatment Pharmacology Article Mice Memory medicine Animals Phosphodiesterase inhibitor Amphetamine Antipsychotic Rolipram Prepulse inhibition Catalepsy Behavior Animal Dose-Response Relationship Drug medicine.diagnostic_test General Neuroscience Phosphodiesterase Effective dose (pharmacology) Cyclic Nucleotide Phosphodiesterases Type 4 Mice Inbred C57BL Acoustic Stimulation 3' 5'-Cyclic-AMP Phosphodiesterases Haloperidol Central Nervous System Stimulants Psychology Antipsychotic Agents medicine.drug |
| Zdroj: | Neuroscience. 144:239-246 |
| ISSN: | 0306-4522 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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