Differential effects of wake promoting drug modafinil in aversive learning paradigms

Shanmugasundaram, Bharanidharan; Korz, Volker; Fendt, Markus; Braun, Katharina; Lubec, Gert

doi:10.3389/fnbeh.2015.00220

Cited by 7 publications

(5 citation statements)

References 42 publications

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“…Modafinil (MO) 2-[(diphenylmethyl) sulfinyl] acetamide is a wake-promoting drug approved by the FDA in the year 1998 for treating excessive daytime sleepiness in narcolepsy. Animal model studies revealed that MO has also 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 ].…”

Section: Introductionmentioning

confidence: 99%

R-Modafinil exerts weak effects on spatial memory acquisition and dentate gyrus synaptic plasticity

et al. 2017

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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.

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Section: Introductionmentioning

confidence: 99%

R-Modafinil exerts weak effects on spatial memory acquisition and dentate gyrus synaptic plasticity

et al. 2017

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“…Modafinil (Sigma, UK) was injected at 5 mg/kg (10 mg/ml in 50% DMSO in saline, i.p.) 60 min prior to reactivation (Shanmugasundaram et al 2015). All i.p.…”

Section: Methodsmentioning

confidence: 99%

Dopaminergic D1 receptor signalling is necessary, but not sufficient for cued fear memory destabilisation

Flavell

2019

Psychopharmacology

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RationalePharmacological targeting of memory reconsolidation is a promising therapeutic strategy for the treatment of fear memory-related disorders. However, the success of reconsolidation-based approaches depends upon the effective destabilisation of the fear memory by memory reactivation.ObjectivesHere, we aimed to determine the functional involvement of dopamine D1 receptors in cued fear memory destabilisation, using systemic drug administration.ResultsWe observed that direct D1 receptor agonism was not sufficient to stimulate tone fear memory destabilisation to facilitate reconsolidation disruption by the glucocorticoid receptor antagonist mifepristone. Instead, administration of the nootropic nefiracetam did facilitate mifepristone-induced amnesia, in a manner that was dependent upon dopamine D1 receptor activation. Finally, while the combined treatment with nefiracetam and mifepristone did not confer fear-reducing effects under conditions of extinction learning, there was some evidence that mifepristone reduces fear expression irrespective of memory reactivation parameters.ConclusionsThe use of combination pharmacological treatment to stimulate memory destabilisation and impair reconsolidation has potential therapeutic benefits, without risking a maladaptive increase of fear.

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“…In doses less than 0.05 mg/kg in rats, amphetamine enhanced the freezing reaction in a cued fear conditioning paradigm whereas at the same dose it had no effect on a contextual fear conditioning test. In contrast, modafinil had opposite actions in fear conditioning tests, increasing contextual memory whereas cued related memory remains unaffected ( Shuman et al, 2009 ; Shanmugasundaram et al, 2015a ). Thus, these drugs can produce different effects in learning and memory tasks based on the nature of cognitive tasks, the dosage, MAT blocking profile and activation of drug specific various other cellular targets.…”

Section: Introductionmentioning

confidence: 92%

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

Aher

Subramaniyan

Shanmugasundaram

et al. 2016

Front. Behav. Neurosci.

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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.

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Differential effects of wake promoting drug modafinil in aversive learning paradigms

Cited by 7 publications

References 42 publications

R-Modafinil exerts weak effects on spatial memory acquisition and dentate gyrus synaptic plasticity

R-Modafinil exerts weak effects on spatial memory acquisition and dentate gyrus synaptic plasticity

Dopaminergic D1 receptor signalling is necessary, but not sufficient for cued fear memory destabilisation

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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