Elsevier

Neuropharmacology

Volume 59, Issues 1–2, July–August 2010, Pages 9-19
Neuropharmacology

The psychostimulant modafinil facilitates water maze performance and augments synaptic potentiation in dentate gyrus

https://doi.org/10.1016/j.neuropharm.2010.03.010Get rights and content

Abstract

Modafinil is a psychostimulant drug used widely for the treatment of narcolepsy, which also has additional positive effects on cognition. Here, we investigate the effects of modafinil on behavioural performance and synaptic plasticity in rats. Improved acquisition in the water maze task was observed in animals that underwent chronic treatment with modafinil. We found that the distance traveled and escape latency were reduced after the first day in chronically-treated rats, compared to controls. Importantly, swim velocity was similar for both groups, excluding pharmacological effects on motor skills. We also found that modafinil increases synaptic plasticity in the dentate gyrus of urethane-anaesthetized rats; modafinil induced a robust augmentation of the population spike, evident after application of 2 bursts of 200 Hz high-frequency stimulation. Furthermore, the modafinil-dependent enhancement of postsynaptic potentials correlated selectively with theta rhythm augmentation. We propose that modafinil may facilitate hippocampal-associated spatial representation via increased theta-related hippocampal plasticity.

Introduction

Modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide] is a psychostimulant used for the treatment of excessive sleepiness associated with narcolepsy (Moldofsky et al., 2000, Mignot et al., 2002, Mignot and Nishino, 2005), Parkinson’s disease (Ferraro et al., 1998, Nieves and Lang, 2002) and multiple sclerosis (Kraft and Bowen, 2005). In contrast to traditional psychostimulants, modafinil has relatively few side-effects and a lower risk of adverse effects on organ systems such as the cardiovascular system (Scammell and Matheson, 1998, Jasinski and Kovacevic-Ristanovic, 2000, Cox and Pappagallo, 2001, Deroche-Gamonet et al., 2002, Minzenberg and Carter, 2007). Modafinil appears to bind directly to and inhibit the dopamine and noradrenaline transporters (Madras et al., 2006, Korotkova et al., 2007).

Modafinil promotes enhanced alertness and sustaining wakefulness and also is effective in sustaining and restoring executive functions in sleep-deprived subjects (Schwartz et al., 2004, Wesensten, 2006). Furthermore, in non sleep-deprived healthy subjects, modafinil has a positive effect on visual pattern recognition memory, spatial planning and stop-signal reaction time (Turner et al., 2003). Preclinical studies have also revealed positive effects on neurocognitive performance. Modafinil treatment in normal mice induced a significant improvement in learning and memory, compared to vehicle-treated controls, using spontaneous alternation and serial spatial discrimination T-maze tasks (Beracochea et al., 2001, Beracochea et al., 2003), although it appears to be without effect on the five-choice serial reaction time in rats (Waters et al., 2005). Finally, modafinil treatment in mice and rats is not associated with an increase in anxiety, stereotyped behavior (Duteil et al., 1990, Simon et al., 1994) or visual discrimination (Morgan et al., 2007).

In order to evaluate the influence of modafinil on rats’ spatial performance, we have explored in this study the performance of modafinil-treated rats in the water maze (Morris, 1984). The hippocampal region is believed to play a key role in the formation of episodic memories (in particular spatial memory), and long-term synaptic plasticity is generally accepted as the mechanism underlying experience-dependent alterations in hippocampus. Thus, the second objective of the present work was to examine the treatment effect of modafinil on hippocampal synaptic plasticity, using extracellular recording from the dentate gyrus. Synaptic plasticity and the formation of memory traces have been linked to particular states of the hippocampal network, determined by theta rhythm (Buzsáki, 2002, Buzsáki and Draguhn, 2004). Therefore, we have also explored how oscillatory activity changes in response to modafinil application.

Section snippets

Animals

Experiments were conducted in accordance with European Community directive, 86/609/EC, and the Cruelty to Animals Act, 1876, and followed Bioresources Ethics Committee, Trinity College, Dublin, Ireland, and international guidelines of good practice. Male (15 week-old) Wistar rats (Harlan, UK) were triple housed and maintained on 12:12 h light:dark cycles with food and water provided ad libitum.

Morris water maze training

The Morris water maze procedure (Morris, 1984), designed to test spatial reference memory, utilized a

Chronic treatment with modafinil improves water maze performance

We observed a significant main effect due to treatment group on the distance traveled measure (ANOVA, F(2, 702) = 3.572, p < 0.05, n = 8); path lengths in the modafinil-treated groups were shorter compared to controls (Fig. 1A). The effect of modafinil group by day interaction was also significant (ANOVA, F(12, 702) = 4.102, p < 0.001, n = 8). Additional analysis (Tukey’s test following One-Way ANOVA) revealed that these differences were statistically significant on day 2 (Tukey’s, p < 0.05 for 10 mg/kg

Discussion

Our data demonstrate that the behavioural and plasticity effects of modafinil are expressed by facilitated performance in the water maze and increased hippocampal long-lasting potentiation, respectively. Furthermore, modafinil is able to augment both postsynaptic responsiveness and theta rhythm in dentate gyrus after a single application.

Conclusions

The present study describes hippocampal-dependent behavioural and electrophysiological effects of modafinil. Our investigation focused on the long-lasting changes in neuronal activity resulting from modafinil application that might alter behavioural performance. It is important to note that the improved performance is not necessarily directly linked to improved learning of the task, as it is possible that modafinil has effects on performance that are independent of effects on learning. Further

Acknowledgements

This work was supported in part by a Health Research Board of Ireland grant to Shane M. O’Mara. We thank Dr Cathal Walsh of the School of Statistics and Computer Science, Trinity College, Dublin, for assistance with statistical analyses.

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