Dual 5-HT(3) and 5-HT(6) Receptor Antagonist FPPQ Normalizes Phencyclidine-Induced Disruption of Brain Oscillatory Activity in Rats

Schizophrenia is a severe mental disorder featuring psychotic, depressive, and cognitive alterations. Current antipsychotic drugs preferentially target dopamine D(2)-R and/or serotonergic 5-HT(2A/1A)-R. They partly alleviate psychotic symptoms but fail to treat negative symptoms and cognitive deficits. Here we report on the putative antipsychotic activity of (1-[(3-fluorophenyl)sulfonyl]-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline dihydrochloride) (FPPQ), a dual serotonin 5-HT(3)-R/5-HT(6)-R antagonist endowed with pro-cognitive properties. FPPQ fully reversed phencyclidine-induced decrease of low-frequency oscillations in the medial prefrontal cortex of anaesthetized rats, a fingerprint of antipsychotic activity. This effect was mimicked by the combined administration of the 5-HT(3)-R and 5-HT(6)-R antagonists ondansetron and SB-399 885, respectively, but not by either drug alone. In freely moving rats, FPPQ countered phencyclidine-induced hyperlocomotion and augmentation of gamma and high-frequency oscillations in medial prefrontal cortex, dorsal hippocampus, and nucleus accumbens. Overall, this supports that simultaneous blockade of 5-HT(3)R and 5-HT(6)-R-like that induced by FPPQ-can be a new target in antipsychotic drug development.