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

Yogesh D Aher,Bharanidharan Shanmugasundaram,Ajinkya Sase,Johann J Leban,Tetyana Beryozkina,Gert Lubec,Marion Holy,Saraswathi Subramaniyan,Harald H Sitte,Harald Höger,Sivaprakasam R Saroja

doi:10.3389/fnbeh.2016.00020

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.

Highlights

Psychostimulants are a class of psychoactive compounds that have diverse behavioral effects such as increasing arousal, alertness and motivation, altering mood, facilitating working, and long term memories
From various electrophysiological recordings (Chafee and Goldman-Rakic, 1998), lesioning (Granon et al, 1994; van Asselen et al, 2006), and functional neuroimaging (D’Esposito et al, 2000; Fletcher and Henson, 2001) studies it is evident that the prefrontal cortex (PFC) is involved in the processing of WM mechanisms
A study revealed that direct infusion of methylphenidate (0.5 μg/500 nl) into the dorsal anterior cingulate/dorsal prelimbic subfields of the medial PFC of rats improves spatial WM performance, comparable to that seen with systemic administration (Spencer et al, 2012)

Summary

Introduction

Psychostimulants are a class of psychoactive compounds that have diverse behavioral effects such as increasing arousal, alertness and motivation, altering mood, facilitating working, and long term memories. Basic research and clinical trials show that these compounds improve performance in cognitive challenging tasks in healthy subjects (Husain and Mehta, 2011) The majority of these compounds inhibit monoamine neurotransmitter transporters (MATs) which reuptake the released neurotransmitters back into the presynaptic nerve terminal (Kristensen et al, 2011), induce an increase of extracellular monoamine neurotransmitter (MNT) levels and related subsequent signaling (Berridge and Devilbiss, 2011). This class of drug targets MAT of prefrontal cortex (PFC) regions, which are largely implicated in mediating complex executive cognitive functions (Spencer et al, 2012). Other mechanism includes activation of MNT receptors or candidate targets of the downstream signaling pathway, increasing the oxygen and glucose supply to the nerve cells (Froestl et al, 2012, 2014a,b)

Methods

Results

Conclusion