Abstract
Modafinil is a wake promoting drug approved for clinical use and also has cognitive enhancing properties. Its enantiomer R-Modafinil (R-MO) is not well studied in regard to cognitive enhancing properties. Hence we studied its effect in a spatial memory paradigm and its possible effects on dentate gyrus long-term potentiation (DG-LTP). Clinically relevant doses of R-MO, vehicle dimethyl sulfoxide (DMSO) or saline were administered for three days during the hole-board test and in in vivo DG-LTP. Synaptic levels of dopamine receptors D1R, D2R, dopamine transporter (DAT), and its phosphorylated form (ph-DAT) in DG tissue 4 h after LTP induction were quantified by western blot analysis. Monoamine reuptake and release assays were performed by using transfected HEK-293 cells. Possible neurotoxic side effects on general behaviour were also studied. R-MO at both doses significantly enhanced spatial reference memory during the last training session and during memory retrieval compared to DMSO vehicle but not when compared to saline treated rats. Similarly, R-MO rescues DG-LTP from impairing effects of DMSO. DMSO reduced memory performance and LTP magnitude when compared to saline treated groups. The synaptic DR1 levels in R-MO groups were significantly decreased compared to DMSO group but were comparable with saline treated animals. We found no effect of R-MO in neurotoxicity tests. Thus, our results support the notion that LTP-like synaptic plasticity processes could be one of the factors contributing to the cognitive enhancing effects of spatial memory traces. D1R may play an important regulatory role in these processes.
Highlights
Hippocampal LTP is widely considered as a cellular model of memory formation
Sprague Dawley male rats, aged between 12–14 weeks were used for the neurotoxicity (20 rats), hole-board (40 rats) and electrophysiological (32 rats) experiments. They were bred and Effect of R-Modafinil on spatial memory and synaptic plasticity maintained in standard Makrolon cages filled with autoclaved woodchips in the Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna
A reuptake inhibition assay was performed to determine the efficacy of R-MO to block the uptake of substrates [3H]DA, [3H]MPP+ and [3H]5-HT by their respective transporters dopamine transporter (DAT), noradrenaline transporter (NET) and serotonin transporter (SERT)
Summary
Hippocampal LTP is widely considered as a cellular model of memory formation. The role of specific kinases like mitogen activated protein kinase (MAPK) [1], Ca2 +/calmodulin-dependent protein kinase II (CAMkII) [2] or Protein kinase M zeta (PKM zeta) [3], and neuro-modulatory transmitters like dopamine [4] or noradrenaline [5] in the regulation of LTP and memory have mostly been targeted. Cognition enhancing drugs so far are less well studied. Animal model studies revealed that MO has the potential to improve memory and cognitive abilities including working memory [6], spatial memory [7], fear memory [7], avoidance learning [8], attention [9], impulsive behavior [10], speed of response and accuracy [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
