Enhancement of learning processes following an acute modafinil injection in mice
Introduction
Modafinil (diphenyl-methyl)sulphinil-2-acetamide) is a wakeness-promoting drug that is effective in the treatment of narcolepsy and idiopathic hypersomnia (Bastuji and Jouvet, 1988). Several studies have shown that modafinil has an agonist action on α-1-adrenergic postsynaptic receptors (Lin et al., 1992) and an antagonist action on glutamatergic receptors (Lagarde et al., 1996). Modafinil also reduces the release of extracellular GABA, which decreases GABAergic transmission (Piérard et al., 1997). Modafinil therefore modifies both glutamatergic and GABAergic activities and their interaction Piérard et al., 1995, Ferraro et al., 1997, Perez de la Mora et al., 1999.
The effects of modafinil on memory processes have not yet been extensively studied, either in humans or animals. To date, only three studies have reported an improvement of short-term memory functions in humans following modafinil intake, but in subjects suffering from severe sleep apnea syndrome (Arnulf et al., 1997) or chronic alcoholism (Saletu et al., 1993). In animals, one study showed that modafinil increases performance in operant conditioning tasks but this improvement was due to a facilitation of sensorimotor processes (Bizot, 1998). 2-DG autoradiography (Engberg et al., 1998), EEG power spectral analysis (Seban et al., 1999), and functional magnetic resonance imaging (Ellis et al., 1999) studies have shown that modafinil substantially modifies the activity of brain areas, such as the hippocampus and the prefrontal cortex. Given the involvement of these two brain areas in learning processes and memory functions Thomas, 1984, Winocur, 1992, we studied in previous experiments the effects of acute modafinil administration on an “episodic working” memory task involving spatial information (Beracochea et al., 2000). We showed in this study that modafinil slowed down the forgetting rates as compared to control mice, without modifying exploratory activity or anxiogenic reactivity in a hole-board apparatus.
Our previous results have also shown that chronic modafinil administration enhances the rate of learning of a cognitive set rule in a serial spatial discrimination reversal (SSDR) task carried out in a T-maze (Beracochea et al., 2002). This task allows the study of the rate of acquisition of a cognitive learning set rule. Indeed, we previously showed that normal mice exhibited, in the SSDR task, a substantial and progressive improvement of performance insofar as the number of trials required to master the criterion decreased progressively over successive days of training. This phenomenon would be the result of an incremental learning process, based on the detection of invariance over successive discrimination sessions Krazem et al., 1995, Borde and Béracochéa, 1999. We showed that daily injection of modafinil over five reversal sessions accelerated the rate of learning the SSDR task and that this anterograde and progressive cognitive enhancement was based on a more rapid development of a win–stay rule, as compared to controls (Beracochea et al., 2002).
The aims of the present study were to investigate the effects of an acute modafinil injection on learning processes. For that purpose, in a first experiment using independent groups, modafinil injections were given following two different learning stages of the SSDR task, either following a single day of training or following four consecutive days of training. Therefore, the aim of this first experiment was to determine if modafinil administered before testing at the fifth day of training would facilitate performance, as compared to controls. In so far as mice are obliged to repeat daily the same choice in the SSDR task, we have decided to evaluate the effects of modafinil on a series of contingently reinforced alternations run in the T-maze already used in the SSDR task. This second experiment allowed us to ensure that the ability to shift response functions normally in modafinil-treated animals and that eventual improvement of performance in modafinil-treated subjects in the SSDR task would not be due to indirect effects of modafinil on behavioral inhibition processes.
Section snippets
Animals
The study was conducted using male mice of the C57 Bl/6 Jico strain obtained at 6 weeks of age from Iffa-Credo (Lyon, France). On arrival, mice were housed in groups in colony cages (40 cm long×25 cm high × 20 cm wide; n=20 per cage), matched for weight, and placed in an animal room (ambient temperature: 22 °C; automatic light cycle, the light periods being between 08:00 and 20:00 h) with free access to food and water. They remained in collective cages for at least 16 weeks. In all cases, at
Acquisition (Day 1)
On Day 1 of testing (first discrimination), all five groups (controls, M32A, M32B, M64A, and M64B) received a gum arabic injection before testing. The number of trials required to reach the criterion was not significantly different among the five groups [groups: F(4,44)=1.2, P=.31]. In addition, choices of the left or right arm at the first trial were evenly distributed among all groups.
Performance savings over days of testing (from Days 1 to 4)
This analysis was performed using mice of the control, M32B, and M64B groups. During the first four days of
Discussion
As compared to controls, modafinil administration at 64 mg/kg but not at 32 mg/kg induced behavioral changes in the SSDR task. More specifically, modafinil-treated subjects required fewer trials than controls to master the criterion on the fifth day days of testing whereas the same dose did not modify performance when administered on the second day of testing. The M64 mice also exhibited normal alternation behavior in a contingently reinforced procedure.
As shown during the first four days of
Acknowledgements
The authors are indebted to Drs. Martine Kerguelen and Didier Lagarde for their assistance in this project. This study was supported by the CNRS and by a grant from DGA (Paris, France).
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