title: Lack of dopamine D4 receptor affinity contributes to the procognitive effect of lurasidone.
abstract: We previously demonstrated among several antipsychotics exhibiting potent dopamine D2 receptor antagonism that only lurasidone, (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1] heptanedicarboximide hydrochloride, improved performance in the object retrieval detour (ORD) task by marmosets. The mechanisms by which only lurasidone causes enhancements in cognitive function have not yet been established; however, most antipsychotics, except for lurasidone, have been shown to exhibit potent antagonistic activity against the dopamine D4 receptor. The objectives of this study were to evaluate the role of the dopamine D4 receptor on executive function with the selective agonist, Ro10-5824 and antagonist, L-745,870, and elucidate a possible mechanism for the procognitive effect of lurasidone. The effects of these drugs were evaluated in naïve marmosets using the ORD task. Changes in the success rate during the difficult trial in the task were used to assess the cognitive effect of the drugs. Ro10-5824 (0.3-3 mg/kg) increased the success rate in the difficult trial, potentiated the effect of lurasidone, and reversed the cognitive impairment induced by clozapine. Interestingly, the co-administration of L-745,870 with lurasidone decreased the success rate in the difficult trial, whereas the single administration of L-745,870 had no effect. These results suggest that activation of the dopamine D4 receptor may improve executive function, whereas concomitant blockade of dopamine D4 and D2 receptors may have the opposite effect. In addition to the other unique binding profiles of other monoamine receptors, the lack of affinity for the dopamine D4 receptor by lurasidone could also contribute, at least partly, to its cognitive-enhancing effect.
authors.affiliation: Ikeda Lab., Drug Development Research Laboratories, Dainippon Sumitomo Pharma, Co., Ltd., Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Murai
authors.affiliation: Ikeda Lab., Drug Development Research Laboratories, Dainippon Sumitomo Pharma, Co., Ltd., Osaka, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Nakako
authors.affiliation: Ikeda Lab., Drug Development Research Laboratories, Dainippon Sumitomo Pharma, Co., Ltd., Osaka, Japan. Electronic address: kazuhito-ikeda@ds-pharma.co.jp.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Ikeda Lab., Drug Development Research Laboratories, Dainippon Sumitomo Pharma, Co., Ltd., Osaka, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ikejiri
authors.affiliation: Innovative Drug Discovery Laboratories, Dainippon Sumitomo Pharma, Co., Ltd., Osaka, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Ishiyama
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma, Co., Ltd., Osaka, Japan.
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Taiji
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002144:Callithrix; D003071:Cognition / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D054833:Isoindoles / Q000494:pharmacology*; D000069056:Lurasidone Hydrochloride; D008297:Male; D011939:Mental Recall / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D014150:Antipsychotic Agents; D015259:Dopamine Agents; D054833:Isoindoles; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; C475158:RO 10-5824; D013844:Thiazoles; D050638:Receptors, Dopamine D4; D000069056:Lurasidone Hydrochloride
keywords: Cognition; Common marmoset; Dopamine D(4) receptor; Lurasidone; Object retrieval detour; Schizophrenia