Antipsychotic-like properties of phosphodiesterase 4 inhibitors: evaluation of 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO-20-1724) with auditory event-related potentials and prepulse inhibition of startle.
Antipsychotic medications function through antagonism of D2 dopamine receptors. Blockade of D2 receptors causes an increase in intracellular cAMP, a ubiquitous second messenger. Inhibition of phosphodiesterase (PDE) activity, a family of enzymes that degrade cyclic nucleotides, causes the same effect. The conceptual linkage between dopamine D2 receptors and PDE activity via cAMP suggests a possible therapeutic potential for PDE inhibitors in schizophrenia. The limited number of studies in support of this hypothesis used rolipram, a specific inhibitor of the PDE4 family. In this study, we investigated the impact of 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO-20-1724), another PDE4-specific inhibitor, on auditory event-related potentials (ERPs), prepulse inhibition (PPI) of the startle reflex, and locomotor activity in mice. The ability to reverse amphetamine-induced alterations in ERPs and PPI was used as a model for psychosis. ERPs after RO-20-1724 revealed increased amplitude for the P20 and N40 ERP components. RO-20-1724 reversed the disruptive effect of amphetamines on ERPs and restored gating at a dose that did not impair locomotor activity. However, RO-20-1724 failed to reverse a amphetamine-induced decrease of PPI. Inconsistent results between these two psychosis models suggest that pure sensory processing, as measured with auditory ERPs, may be more sensitive to the effects of intracellular cAMP than sensorimotor effects as assessed with PPI. It remains unclear whether antipsychotic-like properties are a common feature of PDE4 inhibition, or if they are restricted to the pharmacological profile of rolipram. Future studies should examine how PDE4 subtype specificity might contribute to differences between rolipram and RO-20-1724 in sensorimotor gating.
Halene
T B
TB
International Research Training Group 1328 Schizophrenia and Autism, Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany.
Siegel
S J
SJ
D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology*; D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000502:physiology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005072:Evoked Potentials, Auditory / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology
D014150:Antipsychotic Agents; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4