TY - JOUR T1 - 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 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 230 LP - 239 DO - 10.1124/jpet.108.138586 VL - 326 IS - 1 AU - T. B. Halene AU - S. J. Siegel Y1 - 2008/07/01 UR - http://jpet.aspetjournals.org/content/326/1/230.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -