title: A Novel Heterocyclic Compound CE-104 Enhances Spatial Working Memory in the Radial Arm Maze in Rats and Modulates the Dopaminergic System.
abstract: Various psychostimulants targeting monoamine neurotransmitter transporters (MATs) have been shown to rescue cognition in patients with neurological disorders and improve cognitive abilities in healthy subjects at low doses. Here, we examined the effects upon cognition of a chemically synthesized novel MAT inhibiting compound 2-(benzhydrylsulfinylmethyl)-4-methylthiazole (named as CE-104). The efficacy of CE-104 in blocking MAT [dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter] was determined using in vitro neurotransmitter uptake assay. The effect of the drug at low doses (1 and 10 mg/kg) on spatial memory was studied in male rats in the radial arm maze (RAM). Furthermore, the dopamine receptor and transporter complex levels of frontal cortex (FC) tissue of trained and untrained animals treated either with the drug or vehicle were quantified on blue native PAGE (BN-PAGE). The drug inhibited dopamine (IC50: 27.88 μM) and norepinephrine uptake (IC50: 160.40 μM), but had a negligible effect on SERT. In the RAM, both drug-dose groups improved spatial working memory during the performance phase of RAM as compared to vehicle. BN-PAGE Western blot quantification of dopamine receptor and transporter complexes revealed that D1, D2, D3, and DAT complexes were modulated due to training and by drug effects. The drug's ability to block DAT and its influence on DAT and receptor complex levels in the FC is proposed as a possible mechanism for the observed learning and memory enhancement in the RAM.
authors.affiliation: Department of Pediatrics, Medical University of Vienna Vienna, Austria.
authors.forename: Yogesh D
authors.initials: YD
authors.lastname: Aher
authors.affiliation: Department of Pediatrics, Medical University of Vienna Vienna, Austria.
authors.forename: Saraswathi
authors.initials: S
authors.lastname: Subramaniyan
authors.affiliation: Department of Pediatrics, Medical University of Vienna Vienna, Austria.
authors.forename: Bharanidharan
authors.initials: B
authors.lastname: Shanmugasundaram
authors.affiliation: Department of Pediatrics, Medical University of Vienna Vienna, Austria.
authors.forename: Ajinkya
authors.initials: A
authors.lastname: Sase
authors.affiliation: Department of Pediatrics, Medical University of Vienna Vienna, Austria.
authors.forename: Sivaprakasam R
authors.initials: SR
authors.lastname: Saroja
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna Vienna, Austria.
authors.forename: Marion
authors.initials: M
authors.lastname: Holy
authors.affiliation: Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna Himberg, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Höger
authors.affiliation: Ural Federal University Yekaterinburg, Russia.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Beryozkina
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna Vienna, Austria.
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
authors.affiliation: Department of Pediatrics, Medical University of Vienna Vienna, Austria.
authors.forename: Johann J
authors.initials: JJ
authors.lastname: Leban
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna Vienna, Austria.
authors.forename: Gert
authors.initials: G
authors.lastname: Lubec
keywords: CE-104; cognitive enhancement; dopamine receptor complexes; dopamine transporter complexes; dopamine uptake inhibitor; monoamine neurotransmitter uptake inhibitor; radial arm maze