title: Dopamine D1signaling involvement in the effects of the phosphodiesterase 10A inhibitor, PDM-042 on cognitive function and extrapyramidal side effect in rats.
abstract: Inhibition of phosphodiesterase 10A (PDE10A) results in activation of a dopamine D1receptor-mediated direct pathway in addition to a dopamine D2receptor-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 D2receptor. 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 D1signaling in rats. PDM-042 (1-3mg/kg) resulted in better discrimination of a novel object from a familiar one 48h after the acquisition trial, suggesting that PDM-042 increased object recognition memory. A dopamine D1receptor antagonist, SCH23390 (0.1mg/kg), significantly blocked the enhancement of the object recognition memory induced by PDM-042 (3mg/kg) without affecting the recognition index by itself. We also found that the cataleptic effect of PDM-042 (1mg/kg) was significantly enhanced by SCH23390 (0.01-0.03mg/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 D1signaling.
authors.affiliation: Biology Laboratory, Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Arakawa
authors.affiliation: Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Biology Laboratory, Discovery Research, Mochida Pharmaceutical Co., Ltd., 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan. Electronic address: shunsuke.maehara@mochida.co.jp.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Maehara
mesh_terms: D000818:Animals; D001480:Basal Ganglia Diseases / Q000139:chemically induced*; D001552:Benzazepines / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced; D003071:Cognition / Q000187:drug effects*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D015259:Dopamine Agents; C000625207:PDM-042; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D014230:Triazoles
keywords: Catalepsy; Dopamine; Novel object recognition; Phosphodiesterase 10A (PDE10A); Schizophrenia