Dopamine D1 signaling involvement in the effects of the phosphodiesterase 10A inhibitor, PDM-042 on cognitive function and extrapyramidal side effect in rats

Inhibition of phosphodiesterase 10A (PDE10A) results in activation of a dopamine Di receptor-mediated direct pathway in addition to a dopamine D-2 receptor-mediated indirect pathway in the striatum. Therefore, PDE10A inhibitors could be novel therapeutics for schizophrenia, which differ from the currently available antipsychotics that directly block the dopamine D-2 receptor. Previously, we found that a novel PDE10A inhibitor, PDM-042, had antipsychotic-like activity similar to currently available antipsychotics and minimal cataleptic effects in rats. The purpose of the present study was to examine the pharmacological effects of PDM-042 on cognitive function and extrapyramidal side effect. In addition, we aimed to examine whether these effects were mediated by activation of dopamine Di signaling in rats. PDM-042 (1-3 mg/kg) resulted in better discrimination of a novel object from a familiar one 48 h after the acquisition trial, suggesting that PDM-042 increased object recognition memory. A dopamine Di receptor antagonist, SCH23390 (0.1 mg/kg), significantly blocked the enhancement of the object recognition memory induced by PDM-042 (3 mg/kg) without affecting the recognition index by itself. We also found that the cataleptic effect of PDM-042 (1 mg/1<g) was significantly enhanced by SCH23390 (0.01-0.03 mg/kg). These results indicate that PDM-042 has the potential to increase object recognition memory and that the cognitive enhancing and cataleptic effects of PDM-042 are mediated at least by activation of dopamine Di signaling. (C) 2016 Elsevier B.V. All rights reserved.