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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 ?M) and norepinephrine uptake (IC50: 160.40 ?M), 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.

SUBMITTER: Aher YD

PROVIDER: S-EPMC4761905 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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A Novel Heterocyclic Compound CE-104 Enhances Spatial Working Memory in the Radial Arm Maze in Rats and Modulates the Dopaminergic System.

Aher Yogesh D YD Subramaniyan Saraswathi S Shanmugasundaram Bharanidharan B Sase Ajinkya A Saroja Sivaprakasam R SR Holy Marion M Höger Harald H Beryozkina Tetyana T Sitte Harald H HH Leban Johann J JJ Lubec Gert G

Frontiers in behavioral neuroscience 20160222

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 norepi ...[more]

PMID: 26941626

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Project description:BackgroundComparisons between animal and human neurotoxicology studies are a foundation of risk assessment, but are hindered by differences in measured behaviors. The radial arm maze (RAM), a rodent visuospatial learning and memory task, has a computerized version for use in children, which may help improve comparisons between animal and human studies.ObjectiveTo describe the characteristics and correlates of the virtual radial arm maze (VRAM) in 255 children age 10-15 years from Italy.MethodsWe administered the VRAM using a laptop computer and measured children's performance using the latency, distance, and working/reference memory errors during eight trials. Using generalized linear mixed models, we described VRAM performance in relation to demographic factors, child activities, and several standard neuropsychologic tests (Italian translations), including the Conners Parent Rating Scales-Short Version (CPRS), California Verbal Learning Test (CVLT), Wechsler Intelligence Scales for Children, finger tapping speed, reaction time, and motor skills.ResultsChildren's VRAM performance tended to improve between trials 1 and 6 and then plateaued between trials 6 and 8. Males finished the task 14 s faster (95% confidence interval [CI]: -20, -9) than females. Children who played 2+h of video games per day finished 16 s faster (CI: -26, -6) and with 34% (CI: 5, 54%) fewer working memory errors than children who reported not playing video games. Higher IQ and better CVLT scores were associated with better VRAM performance. Higher cognitive/inattention CPRS scores were associated with more working (11%; CI: 1, 22) and reference memory errors (7%; CI: 1, 12).ConclusionsConsistent with animal studies, VRAM performance improved over the course of test trials and males performed better than females. Better VRAM performance was related to higher IQ, fewer inattentive behaviors, and better verbal memory. The VRAM may help to improve the integration and comparison between animal and epidemiological studies of environmental neurotoxicants.

Dataset Information

A Novel Heterocyclic Compound CE-104 Enhances Spatial Working Memory in the Radial Arm Maze in Rats and Modulates the Dopaminergic System.

Publications

A Novel Heterocyclic Compound CE-104 Enhances Spatial Working Memory in the Radial Arm Maze in Rats and Modulates the Dopaminergic System.

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