Effects of Modafinil on Behavioral Learning and Hippocampal Synaptic Transmission in Rats

Abstract

Purpose:Modafinil is a wake-promoting agent that has been proposed to improve cognitive performance at the preclinical and clinical levels. Since there is insufficient evidence for modafinil to be regarded as a cognitive enhancer, the aim of this study was to investigate the effects of chronic modafinil administration on behavioral learning in healthy adult rats.Methods:Y-maze training was used to assess learning performance, and the whole-cell patch clamp technique was used to assess synaptic transmission in pyramidal neurons of the hippocampal CA1 region of rats.Results:Intraperitoneal administration of modafinil at 200 mg/kg or 300 mg/kg significantly improved learning performance. Furthermore, perfusion with 1mM modafinil enhanced the frequency and amplitude of spontaneous postsynaptic currents and spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons in hippocampal slices. However, the frequency and amplitude of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons were inhibited by treatment with 1mM modafinil.Conclusions:These results indicate that modafinil improves learning and memory in rats possibly by enhancing glutamatergic excitatory synaptic transmission and inhibiting GABAergic (gamma-aminobutyric acid-ergic) inhibitory synaptic transmission.

An Overview of the Clinical Uses, Pharmacology, and Safety of Modafinil

“…Memory is the neurobiological function whereby critical information is retained and recalled at a later time . Cognitive improvements have been reported in experimental animals receiving MOD (200–300mg/kg), and such changes have also been demonstrated in humans. In line with this, potential uses of MOD for improving memory in disorders such as neurodegenerative diseases or psychiatric conditions have been suggested.…”

“…Despite the efficacy of MOD for managing excessive daytime sleepiness and fatigue, and apparently improving cognitive functions, − ,,− ,,− ,,,− critical studies are required to fully understand the likely risk of addiction to this drug (Table ). In recent years, special attention has been given to a limited but growing body of evidence suggesting that MOD has a potentially addictive profile, since this drug promotes reward as described in cocaine-dependent animals .…”

Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?

“…Importantly, MOD heightens attention independently of its effects on wakefulness/arousal ( Cope et al, 2017 ). MOD administration elicits changes in activation of brain regions associated with cognition, including the hippocampus ( Ferraro et al, 1997b ; Shuman et al, 2009 ; Brandt et al, 2014 ; Yan et al, 2015 ) and the PFC ( Müller et al, 2004 ; González et al, 2014 , 2018 ). Thus, improvements in cognitive functions associated with MOD’s actions on the dopaminergic system may underlie those specific changes in DA transmission (reviewed in Minzenberg and Carter, 2008 ; Mereu et al, 2013 ), for example in the PFC, that have been recognized for their role in working memory ( Sawaguchi and Goldman-Rakic, 1991 , 1994 ).…”

Chronic modafinil therapy ameliorates depressive-like behavior, spatial memory and hippocampal plasticity impairments, and sleep-wake changes in a surgical mouse model of menopause

“…Compared to traditional stimulants, such as amphetamine, MOD is well-tolerated, shows fewer or no adverse effects, and has a comparatively low potential for abuse 12 . Moreover, MOD has been proposed to improve cognitive performance in normal rats 13 – 15 or mice with sleep deprivation 16 , healthy human volunteers 17 , and patients with schizophrenia or depression 18 , 19 . Furthermore, an effective augmentation strategy for ameliorating depressive episodes in patients with depression has been revealed, indicated by significant improvements in overall depression scores and remission rates when MOD is administered combined with an antidepressant 20 .…”

“…Furthermore, an effective augmentation strategy for ameliorating depressive episodes in patients with depression has been revealed, indicated by significant improvements in overall depression scores and remission rates when MOD is administered combined with an antidepressant 20 . On the cellular level, MOD administration affects the synaptic transmission, increases precursor cell proliferation, and suppresses excessive autophagy and apoptosis in the hippocampus 15 , 16 , 21 .…”