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

• The novel PDE10A inhibitor, PDM-042, enhanced object recognition memory in rats.
• A dopamine D1 antagonist, SCH23390, blocked the pro-cognitive effect of PDM-042.
• SCH23390 potentiated the cataleptic effect of PDM-042.
• Dopamine D1 signaling may be involved in the pharmacological effects of PDM-042.

Inhibition of phosphodiesterase 10A (PDE10A) results in activation of a dopamine D1 receptor-mediated direct pathway in addition to a dopamine D2 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 D2 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 D1 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 D1 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/kg) 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 D1 signaling.