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.

Highlights

  • Reduced cognitive flexibility is a major symptom in the decline of cognitive ability induced by aging or mental diseases

  • dopamine transporter (DAT) inhibition blocks the reuptake of dopamine from extracellular space into the synapse, increasing the amount of available dopamine which enhances the probability of dopamine receptor activation

  • Since the improving effects of Modafinil upon attentional set shifting is already known (Goetghebeur and Dias, 2009) we focused here on the novel compound

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Summary

Introduction

Reduced cognitive flexibility is a major symptom in the decline of cognitive ability induced by aging or mental diseases. Besides other neurotransmitters, regulated by dopamine and especially through dopamine receptor type 1 (D1R) activity, as assessed by the attentional set-shifting task (ASST), a widely used test for cognitive flexibility The specificity for DAT of most of the DAT inhibitors is limited as they significantly bind to noradrenaline and serotonine transporters and these substances can cause adverse side effects in healthy subjects (Kumar, 2008; Dolder et al, 2017), including increased impulsivity (Waters et al, 2005), there is evidence that other neurotransmitters such as noradrenaline regulate set-shifting (Tait et al, 2007). We synthetized a novel compound CE-123, targeting the DAT with high specificity, and tested the effects on cognitive flexibility by using an ASST. Since the improving effects of Modafinil upon attentional set shifting is already known (Goetghebeur and Dias, 2009) we focused here on the novel compound

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