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

Abstract

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.Antipsychotic medications were introduced more than 50 years ago for the treatment of hallucinations, delusions, thought disorganization, and behavioral disorders. Although initially targeted for the treatment of schizophrenia, these medications act on psychotic symptoms irrespective of cause. Currently approved antipsychotic medications produce their beneficial effects through antagonism of the dopamine D2 receptor. Their potency is proportional to their affinity for this target (Kapur and Mamo, 2003). Blockade of D2 receptors causes an increase in intracellular cAMP, a ubiquitous second messenger. Inhibition of phosphodiesterase (PDE) activity, a family of enzymes with the ability to degrade cyclic nucleotides, causes the same effect. The conceptual linkage between the dopamine D2 receptor and PDE activity via cAMP suggests a possible therapeutic potential for PDE inhibitors in schizophrenia (Fig. 1).No single antipsychotic substance has emerged as the gold standard for a first-line treatment in clinical trials or expert consensus guidelines, and with the notable exception of clozapine, all approved antipsychotics are of comparable efficacy. Antipsychotics vary in side effects including risk of extrapyramidal symptoms, weight gain, metabolic ...

Novel Environment and GABA Agonists Alter Event-Related Potentials in N-Methyl-d-aspartate NR1 Hypomorphic and Wild-Type Mice

“…No significant differences were found on S2 for either component. This is consistent with previous studies demonstrating that deficits in gating are primarily a function of changes in the first stimulus response of mice Halene and Siegel, 2008).…”

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

“…Recording sessions were preceded by a 15-min acclimation phase. Auditory ERPs were recorded as described earlier (77,78). Stimuli were generated by Micro 1401 hardware with Spike 5 software (Cambridge Electronic Design) and delivered through speakers attached to the cage top.…”

Ketamine Modulates Theta and Gamma Oscillations

“…Previous studies from our group and others demonstrate a high degree of similarity between human and mouse EEG and ERPs for morphology, as well as physiological and pharmacological response properties using this configuration (Ehrlichman, Maxwell, Majumdar, & Siegel, 2008;Halene & Siegel, 2008;Rabin et al, 2008;Metzger, Maxwell, Liang, & Siegel, 2007;Phillips, Ehrlichman, & Siegel, 2007;Maxwell, Ehrlichman, Liang, Gettes, et al, 2006;Maxwell, Ehrlichman, Liang, Trief, et al, 2006;Siegel et al, 2003Siegel et al, , 2005Connolly et al, 2003Connolly et al, , 2004Maxwell, Kanes, Abel, & Siegel, 2004;Maxwell, Liang, et al, 2004;Umbricht et al, 2004;Umbricht, Latanov, Vissotksi, Nitsch, & Lipp, 2002;Stevens, Kem, & Freedman, 1999;Stevens, Kem, Mahnir, & Freedman, 1998;Stevens & Wear, 1997;Stevens et al, 1996;Stevens, Meltzer, & Rose, 1995). In animals, acute injection of ketamine similarly affects this ratio, as well as the magnitude and latency of the ERP components Maxwell, Ehrlichman, Liang, Trief, et al, 2006;Connolly et al, 2003Connolly et al, , 2004.…”

“…Although the ketamine doses used in this study represent 5% and 20% of the minimum anesthetic dose, we assessed their effects on locomotor activity to control for possible motor effects on EEG. Mice (n = 6/group, total = 18) were tested in the same home cage environment for the same duration as recording of ERPs according to previously published methods (Halene & Siegel, 2008). Animals were transferred from their housing facility to the locomotor activity testing room in their home cages for a habituation period of 15 min prior to testing.…”