title: Lurasidone and fluoxetine reduce novelty-induced hypophagia and NMDA receptor subunit and PSD-95 expression in mouse brain.
abstract: Lurasidone, a novel second-generation antipsychotic agent, exerts antidepressant actions in patients suffering from bipolar type I disorder. Lurasidone acts as a high affinity antagonist at multiple monoamine receptors, particularly 5-HT2A, 5-HT7, D2 and α2 receptors, and as a partial agonist at 5-HT1A receptors. Accumulating evidence indicates therapeutic actions by monoaminergic antidepressants are mediated via alterations of glutamate receptor-mediated neurotransmission. Here, we used mice and investigated the effects of chronic oral administration of vehicle, lurasidone (3 or 10mg/kg) or fluoxetine (20mg/kg) in the novelty induced hypophagia test, a behavioral test sensitive to chronic antidepressant treatment. We subsequently performed biochemical analyses on NMDA receptor subunits and associated proteins. Both lurasidone and fluoxetine reduced the latency to feed in the novelty-induced hypophagia test. Western blotting experiments showed that both lurasidone and fluoxetine decreased the total levels of NR1, NR2A and NR2B subunits of NMDA receptors and PSD-95 (PostSynaptic Density-95) in hippocampus and prefrontal cortex. Taken together, these data indicate that antidepressant/anxiolytic-like effects of lurasidone, as well as fluoxetine, could involve reduced NMDA receptor-mediated signal transduction, particularly in pathways regulated by PSD-95, in hippocampus and prefrontal cortex.
authors.affiliation: Section of Translational Neuropharmacology, Center of Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institute, 17176 Stockholm, Sweden.
authors.forename: Tiberiu Loredan
authors.initials: TL
authors.lastname: Stan
authors.affiliation: Section of Translational Neuropharmacology, Center of Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institute, 17176 Stockholm, Sweden.
authors.forename: Vasco Cabral
authors.initials: VC
authors.lastname: Sousa
authors.affiliation: Section of Translational Neuropharmacology, Center of Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institute, 17176 Stockholm, Sweden.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Sumitomo Dainippon Pharma, Osaka, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Ono
authors.affiliation: Section of Translational Neuropharmacology, Center of Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institute, 17176 Stockholm, Sweden. Electronic address: per.svenningsson@ki.se.
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D000928:Antidepressive Agents / Q000008:administration & dosage*; D014150:Antipsychotic Agents / Q000008:administration & dosage; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000008:administration & dosage*; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D000069056:Lurasidone Hydrochloride / Q000008:administration & dosage*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011897:Random Allocation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C121673:Gprin1 protein, mouse; D008565:Membrane Proteins; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D005473:Fluoxetine; D051528:Guanylate Kinases; D000069056:Lurasidone Hydrochloride
keywords: Depression; Glutamate; Hippocampus; PSD-95; Prefrontal cortex