A Novel Dopamine Transporter Inhibitor CE-123 Improves Cognitive Flexibility and Maintains Impulsivity in Healthy Male Rats

Abstract

Reduced cognitive abilities are often characterized by an impairment of flexibility, i.e., the ability to switch from learned rules or categories that were important in certain contexts to different new modalities that rule the task. Drugs targeting the dopamine transporter (DAT) are widely used for their potential to enhance cognitive abilities. However, commercially available drugs are of limited specificity for DAT, blocking also noradrenaline and serotonine transporters, that can lead to unwanted side effects in healthy subjects. Therefore, we tested a newly synthetized compound (CE-123) with higher specificity for DAT in male rats in an attentional set-shifting task (ASST), that proves for cognitive flexibility and a 5-choice serial-reaction time task (5-CSRTT) assessing visuospatial attention and impulsivity. Treated rats at a dose of 0.3 and 1.0 but not 0.1 mg/kg bodyweight showed reduced extra-dimensional shifts in the ASST compared to controls indicating increased cognitive flexibility. Rats treated with R-Modafinil, a commercially available DAT inhibitor at a dose of 10 mg/kg bodyweight showed increased premature responses, an indicator of increased impulsivity, during a 10 s but not a 2.5, 5, or 7.5 s intertrial interval when compared to vehicle-treated rats in the 5-CSRTT. This was not found in rats treated with CE-123 at the same dose as for R-Modafinil. Visuospatial attention, except premature responses, did not differ between R-Modafinil and CE-123-treated rats and their respective controls. Thus, CE-123 increased cognitive flexibility with diminished impulsivity.

Differential Effects of Novel Dopamine Reuptake Inhibitors on Interference With Long-Term Social Memory in Mice

“…The following drugs were used in the present study: rac -CE-123 = 5-((benzhydrylsulfinyl)methyl)-thiazole (Kristofova et al, 2018) and S -CE-123 = S-5-((benzhydrylsulfinyl)methyl)thiazole (Nikiforuk et al, 2017). The dosage of the drugs and the time point of administration were selected according to previous studies in which it was shown that 10 mg of the drugs per kg body weight administered 30 min before testing produces significant learning and memory effects without causing detectable undesired side effects in rats (Nikiforuk et al, 2017; Kristofova et al, 2018). The drugs were dissolved in 1% DMSO and 3.3% Tween 80 diluted in 0.9% NaCl.…”

“…Modafinil is a wake-promoting drug which is used to treat sleep apnea, narcolepsy and shift work sleep disorders (Battleday and Brem, 2015; Kristofova et al, 2018). Recently, the synthesis and test in different behavioral paradigms of modafinil analogue 5-((benzhydrylsulfinyl)methyl)-thiazole (CE-123; Kalaba et al, 2017; Nikiforuk et al, 2017) was reported. CE-123 was structurally modified by substituting the carboxyl-amide moiety of modafinil with a heterocycle thiazole group attached to position five which may provide a high metabolic stability of CE-123.…”

“…It improved working memory in the radial arm maze and seems to modulate also the DA receptor in vivo (Kristofova et al, 2018). Further, S -CE-123 has also proven to enhance the cognitive flexibility without triggering unnecessary impulsive responding (Nikiforuk et al, 2017).…”

Neurophysiological and Neurochemical Effects of the Putative Cognitive Enhancer (S)-CE-123 on Mesocorticolimbic Dopamine System

“…(S)-CE-123 ((S)-5-((benzhydrylsulfinyl)methyl)thiazole) was synthesized from the Lubec laboratory (University of Vienna, Austria) as reported previously [23]. In short, diphenylmethanol and thiourea were reacted to yield [(diphenylmethyl)sulfanyl]methanimideamide hydrobromide.…”

The Novel Atypical Dopamine Uptake Inhibitor (S)-CE-123 Partially Reverses the Effort-Related Effects of the Dopamine Depleting Agent Tetrabenazine and Increases Progressive Ratio Responding

“…A recently synthesized and chromatographically separated analog of modafinil, ( S ) -CE-123 ( Figure 1 ), is a highly selective atypical inhibitor of DAT that has been shown to enhance cognitive flexibility and reduce impulsivity in rats (Nikiforuk et al, 2017). The present paper describes the enantioselective synthesis and initial characterization of ( S ) -CE-123.…”