Effects Of Modafinil Research Articles

Effects of amphetamine and modafinil on the sleep/wake cycle during experimental hypersomnia induced by sleep deprivation in the cat.

Modafinil is a newly discovered waking substance now being used in the treatment of hypersomnia and narcolepsy. We have shown previously in the cat that, unlike amphetamine, modafinil induces long-lasting wakefulness (W) without behavioral excitation and subsequent sleep rebound, and that its waking effect does not depend on endogenous catecholamines. To further characterize the awakening properties of modafinil and current psychostimulants in experimental models of hypersomnia, we examined the effect of oral administration of placebo, modafinil (5 mg kg-1) or amphetamine (1 mg kg-1) on the sleep/wake cycle and power spectral density (PSD) in cats after an 18-h water-tank sleep deprivation period. We found that the placebo had no effect on the dynamics of sleep recovery, while both modafinil and amphetamine induced suppression of cortical slow activity and a waking state lasting 6-8 h. After the amphetamine-induced waking period, both deep slow wave sleep (SWS2) and paradoxical sleep (PS) occurred in greater amounts than after placebo and the PSD during SWS was also increased. Thus, the cumulative time spent in W during a 48-h period was similar to that with placebo, indicating enhanced sleep rebound. In contrast, after the modafinil-induced W, the occurrence and evolution of SWS2 or PS, as well as the PSD during SWS, were similar to those seen with placebo during the same period, so that the total time spent in W in a 48-h period remained significantly higher than the control level, indicating no additional sleep rebound. These results indicate that modafinil is effective against somnolence and hypersomnia and does not produce a subsequent increase in sleep and suggest that the pharmacological profile of modafinil is different from that of amphetamine.

Effect of Modafinil on Fatigue Associated with Neurological Illnesses

Fatigue is a common symptom of a variety of neurological illnesses, such as Alzheimer's disease, chronic fatigue syndrome, multiple sclerosis, Parkinson's disease, and stroke. Fatigue severely impairs productivity, performance, social functioning, and quality of life. Modafinil (PROVIGIL(r)) has been shown to significantly improve fatigue associated with multiple sclerosis and depression. Here, a retrospective review of the medical charts of 25 patients treated with modafinil for fatigue associated with various neurological illnesses was conducted. Modafinil was effective for the treatment of fatigue in 21 of 25 patients (84%), and was well tolerated. Therefore, modafinil appears to be a potentially attractive candidate for the treatment of fatigue associated with neurological disorders.

Health-Related Quality of Life Effects of Modafinil for Treatment of Narcolepsy

To evaluate the burden of illness of narcolepsy and assess the health-related quality-of-life (HQL) effects of oral modafinil, a wake-promoting therapy for excessive daytime sleepiness associated with narcolepsy. Subjects with narcolepsy enrolled in a nine-week, placebo-controlled, double-blind study and were randomized to placebo, modafinil 200 mg, or modafinil 400 mg. After the study, consenting subjects received modafinil in a 40-week open-label extension. A self-administered HQL questionnaire consisting of the 36-Item Short Form Health Survey (SF-36) and supplemental narcolepsy-specific scales was given to subjects at baseline, study endpoint, and several open-label timepoints. 481 subjects completed a baseline and double-blind endpoint HQL assessment. Compared to population norms, baseline HQL scores reflected substantial burden in vitality, social functioning, and performing usual activities. At study endpoint, subjects in the 400 mg modafinil group had significantly higher scores than placebo for 10 of the 17 HQL scales. The 400 mg modafinil group had more energy, fewer difficulties performing usual activities, fewer interferences with social activities, improved psychological well-being and higher productivity, attention and self-esteem compared to placebo subjects (p<.05). The positive treatment effects were sustained over the open-label extension. Modafinil significantly improves health-related quality of life in narcolepsy.

The Vigilance Promoting Drug Modafinil Increases Extracellular Glutamate Levels in the Medial Preoptic Area and the Posterior Hypothalamus of the Conscious Rat: Prevention by Local GABAA Receptor Blockade

The effects of modafinil on glutamatergic and GABAergic transmission in the rat medial preoptic area (MPA) and posterior hypothalamus (PH), are analysed. Modafinil (30–300 mg/kg) increased glutamate and decreased GABA levels in the MPA and PH. Local perfusion with the GABAA agonist muscimol (10 μM), reduced, while the GABAA antagonist bicuculline (1 μM and 10 μM) increased glutamate levels. The modafinil (100 mg/kg)-induced increase of glutamate levels was antagonized by local perfusion with bicuculline (1 μM). When glutamate levels were increased by the local perfusion with the glutamate uptake inhibitor L-trans-PDC (0.5 mM), modafinil produced an additional enhancement of glutamate levels. Modafinil (1–33 μM) failed to affect [3H]glutamate uptake in hypothalamic synaptosomes and slices. These findings show that modafinil increases glutamate and decreases GABA levels in MPA and PH. The evidence that bicuculline counteracts the modafinil-induced increase of glutamate levels strengthens the evidence for an inhibitory GABA/glutamate interaction in the above regions controlling the sleep-wakefulness cycle.

Effects of the vigilance promoting drug modafinil on the synthesis of GABA and glutamate in slices of rat hypothalamus

The effects of the vigilance promoting drug modafil were studied ex vivo (100 mg/kg; i.p.) and in vitro (10–1000 μM modafinil) on the synthesis of [ 3H] γ-aminobutyric acid ([ 3H]GABA) and [ 3H]glutamate from [ 3H]glutamine within the rat hypothalamus. No effects of modafinil were observed on the overall synthesis of these neurotransmitters nor, in vitro (1–33 μM modafinil) on other parameters related to the compartmentalization of their synthesis (glutamate decarboxylase and phosphate-activated glutaminase activities, and [ 3H]glutamine uptake). It is suggested on these grounds, that the modafinil-induced reductions and increases in regional GABA and glutamate extracellular levels respectively using in vivo microdialysis may be a consequence of an indirect effect of modafinil on these neurons.

Effects of modafinil on attentional processes during 60 hours of sleep deprivation

The present study investigates the eAects of modafinil (300 mg/24 h) versus a placebo on the performance of a visual search task during 60 h of sleep deprivation. Modafinil was administrated in doses of 100 mg three times per day during sleep deprivation. Six healthy volunteers participated in a double-blind experiment including two experimental sessions of 7 days each. The experiment used the visual search paradigm for an ‘O’ target among ‘Q’ distractors and the reverse. The speed and accuracy in detecting the target were measured by RTs slopes (i.e. search rates) and the number of errors (i.e. error rates), respectively. Many authors attribute rapid search rates obtained for ‘Q’ targets (low RTs slopes) to parallel/automatic processes and slow search rates obtained for ‘O’ targets (high RTs slope) to serial/attentional processes. The results revealed an asymmetrical search pattern for the detection of ‘Q’ versus ‘O’ targets across the sleep deprivation period (i.e. parallel versus serial search, respectively). Rapid search rates for ‘Q’ targets remained unchanged between placebo and modafinil conditions during sleep deprivation. However, slow search rates for ‘O’ targets increased linearly in placebo condition, but remained at the same level as the control-test in modafinil condition. Error rates and search rates also increased. For ‘O’ and ‘Q’ targets, the number of errors increased in the placebo condition, but remained stable in the modafinil condition. In summary, we can conclude that the administration of modafinil (300 mg/24 h) during sleep deprivation prevents the slowing of serial processes (attentional shifts) and the increasing of errors. #1998 John Wiley & Sons, Ltd.

Effects of modafinil on attentional processes during 60 hours of sleep deprivation

The present study investigates the effects of modafinil (300 mg/ 24 h) versus a placebo on the performance of a visual search task during 60 h of sleep deprivation. Modafinil was administrated in doses of 100 mg three times per day during sleep deprivation. Six healthy volunteers participated in a double-blind experiment including two experimental sessions of 7 days each. The experiment used the visual search paradigm for an ‘O’ target among ‘Q’ distractors and the reverse. The speed and accuracy in detecting the target were measured by RTs slopes (i.e. search rates) and the number of errors (i.e. error rates), respectively. Many authors attribute rapid search rates obtained for ‘Q’ targets (low RTs slopes) to parallel/ automatic processes and slow search rates obtained for ‘O’ targets (high RTs slope) to serial/ attentional processes. The results revealed an asymmetrical search pattern for the detection of ‘Q’ versus ‘O’ targets across the sleep deprivation period (i.e. parallel versus serial search, respectively). Rapid search rates for ‘Q’ targets remained unchanged between placebo and modafinil conditions during sleep deprivation. However, slow search rates for ‘O’ targets increased linearly in placebo condition, but remained at the same level as the control-test in modafinil condition. Error rates and search rates also increased. For ‘O’ and ‘Q’ targets, the number of errors increased in the placebo condition, but remained stable in the modafinil condition. In summary, we can conclude that the administration of modafinil (300 mg/ 24 h) during sleep deprivation prevents the slowing of serial processes (attentional shifts) and the increasing of errors. © 1998 John Wiley & Sons, Ltd.

The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission

The effects of the anti-narcoleptic drug modafinil (30–300 mg/kg i.p.) on GABA and glutamate release were evaluated in the basal ganglia of the conscious rat, by using the microdialysis technique. Modafinil (100 mg/kg) inhibited striatal (85±4% of basal values) and pallidal (85±2%) GABA release without influencing local glutamate release. At the highest dose (300 mg/kg), modafinil induced a further reduction of pallidal (75±2%) but not striatal (82±7%) GABA release and increased striatal (134±11%) but not pallidal glutamate release. On the contrary, in the substantia nigra modafinil reduced GABA release only at the 300 mg/kg dose (59±5%) without affecting glutamate release. The preferential reduction in striato-pallidal GABA release at the 100 mg/kg dose of modafinil suggests that modafinil may be useful in the treatment of Parkinsonian diseases.

Brain regional substrates for the actions of the novel wake-promoting agent modafinil in the rat: comparison with amphetamine

Modafinil is a novel wake-promoting compound for which the mechanism and sites of action are unknown. We examined the neural substrates in the brain for the actions of modafinil using 2-deoxyglucose autoradiography and compared the findings to those obtained with amphetamine. Modafinil showed a relatively restricted pattern of changes in brain regional metabolic activity, while amphetamine altered glucose utilization in a wide variety of brain regions. Both modafinil and amphetamine increased glucose utilization in all subregions of the hippocampus (subiculum, CA1–CA3 and dentate gyrus) and in the centrolateral nucleus of the thalamus. Modafinil also increased glucose utilization in the central nucleus of the amygdala, but amphetamine had no effect in this region. Brain structures in which amphetamine increased metabolic rate but modafinil had no effect included regions of the basal ganglia, other nuclei of the thalamus, the frontal cortex, the nucleus accumbens, the ventral tegmental area and the pontine reticular fields. These findings suggest that, while both modafinil and amphetamine promote wakefulness, they act via distinctly different mechanisms. Modafinil appears to act on a specific subset of brain pathways which regulate sleep and wakefulness, whereas amphetamine affects a greater number of cerebral structures involved in the regulation of these behavioral states. Modafinil also lacks the pronounced effects on the extrapyramidal motor system which are characteristic of amphetamine and other psychomotor stimulants, implying that the effects of modafinil are not mediated by the dopamine system and that modafinil may selectively increase wakefulness with fewer side effects.

Modafinil : A Review of its Pharmacology and Clinical Efficacy in the Management of Narcolepsy.

Modafinil promotes wakefulness through an as yet unknown mechanism of action. It significantly increases daytime sleep latency and reduces excessive daytime sleepiness (EDS) compared with placebo in patients with narcolepsy. However, the drug does not suppress cataplexy. Although direct comparative data are lacking, modafinil offers advantages over amphetamines and methylphenidate in patients with narcolepsy because of its lack of rebound phenomena after treatment withdrawal and its low abuse potential. Clinical trials have shown modafinil to be well tolerated in patients with narcolepsy. Except for headache, which was reported with a significantly greater frequency in modafinil recipients, the tolerability profile of modafinil 200 to 400 mg/day was similar to that of placebo in patients treated for 9 weeks. Preliminary data suggest that the tolerability of modafinil is maintained long term (40 weeks). Thus, modafinil is effective in the treatment of EDS in patients with narcolepsy, although it is not effective against cataplexy. Preliminary findings indicate that, unlike other psychostimulants, the drug is unlikely to be abused and is not associated with withdrawal phenomena. Therefore, modafinil is likely to be an effective therapeutic option for the treatment of EDS in patients with narcolepsy. The mechanism of action of modafinil has not been clearly established. However, it may indirectly increase wakefulness, at least in part, through inhibition of cortical γ-aminobutyric acid (GABA) release via serotonergic mechanisms. Modafinil induces wakefulness and increases locomotor activity in a variety of animal species without causing stereotyped behaviour. In rhesus monkeys, the effects of oral modafinil were not associated with changes in blood pressure or heart rate. In contrast to dexamphetamine 20mg, single night-time doses of modafinil 100 or 200mg had no significant effects on objective sleep variables or sleep structure in young or elderly healthy volunteers. Modafinil reduced the impairment of cognitive performance induced by sleep deprivation in volunteers, suppressed microsleeps and reduced the length of recovery sleep required. However, volunteers treated with modafinil reported recovery sleep patterns which were similar to those of placebo recipients. Studies in volunteers indicate that modafinil has less abuse potential than dexamphetamine or methylphenidate. Peak plasma concentrations of modafinil (mean 4.82 mg/L) were reached 2.3 hours after a single 200mg oral dose in healthy volunteers. Over the dose range 200 to 600mg, the pharmacokinetics of modafinil were linear and dose dependent. Orally administered modafinil is extensively biotransformed in the liver to the inactive metabolites modafinil acid and modafinil sulphone, before being eliminated primarily in the urine (elimination half-life 9 to 14 hours). The pharmacokinetics of modafinil are not affected to a clinically significant extent by volunteer age or food intake, but both the maximum plasma concentration and the elimination half-life of the drug are increased in patients with hepatic or renal impairment. The efficacy of modafinil 200 or 400 mg/day was rated as good or excellent (using a 4-point scale) in 84 of 131 evaluable patients (64%) with excessive daytime sleepiness treated for 1 to 114 months in a noncomparative study. 53 patients withdrew from the study (43 because of loss of efficacy). In another study, 1 or 2 months' treatment with modafinil reduced or eliminated symptoms of excessive daytime sleepiness in 17 of 24 patients with narcolepsy. Modafinil 200 or 400 mg/day for 9 weeks significantly increased daytime sleep latency and reduced daytime sleepiness compared with placebo in patients with narcolepsy, but did not suppress cataplexy. It tended to improve psychomotor performance, although this effect was variable. Importantly, modafinil did not affect patients' nocturnal sleep parameters, ability to nap when necessary or feelings on awakening. There was no evidence of a withdrawal phenomenon (e.g. fatigue, vivid or unpleasant dreams, insomnia or hypersomnia) after treatment cessation. Clinical data comparing the efficacy of modafinil with that of other stimulants in patients with narcolepsy are limited. Although tolerability data for modafinil are limited, the drug appears to be well tolerated in patients with narcolepsy. A study in 283 evaluable patients showed that 9 weeks' treatment with modafinil 200 or 400 mg/day was as well tolerated as placebo, with only headache reported with significantly greater frequency (52 and 51 vs 36% of patients; p < 0.05). Nausea and nervousness also tended to occur more frequently in modafinil than in placebo recipients, but this difference did not reach statistical significance. The incidence or severity of adverse events associated with the use of modafinil did not appear to be dose related. Preliminary data showed that open-label modafinil was well tolerated for up to 40 weeks. The recommended dosage of modafinil is 200 or 400 mg/day, given once or twice daily (morning and midday) to patients with narcolepsy. Modafinil is contraindicated in patients with moderate to severe hypertension and may reduce the efficacy of low dose oral contraceptives via enzymatic induction.

Modafinil: a novel stimulant for the treatment of narcolepsy

Excessive daytime sleepiness (EDS) is a common and debilitating symptom of narcolepsy and other sleep disorders. Modafinil is a novel stimulant which effectively treats EDS, yet lacks many of the undesirable side-effects commonly encountered with currently available compounds. The specific mode of action of modafinil is not well understood, but it may promote sleep by indirectly influencing adrenergic or GABAergic neurotransmission. Modafinil-induced wakefulness is not associated with rebound hypersomnolence or the potential for abuse as is often encountered with other stimulants such as amphetamines. At typical therapeutic doses, modafinil may produce dry mouth but generally has a low incidence of minor side-effects. Many preclinical and clinical studies have demonstrated the effectiveness of modafinil in promoting wakefulness and vigilance in normal subjects and in those with EDS. Modafinil significantly improves the EDS of narcolepsy and also may improve the EDS of idiopathic hypersomnia and obstructive sleep apnoea. Modafinil’s low prevalence of side-effects, minimal potential for abuse, and lack of rebound hypersomnia indicate that it has potential to become a widely prescribed drug for the treatment of narcolepsy.

The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus.

The antinarcoleptic drug modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide; Modiodal] dose-dependently inhibits the activity of GABA neurons in the cerebral cortex and in the nucleus accumbens, as well as in sleep-related brain areas such as the medial preoptic area and the posterior hypothalamus. This study examined the effects of modafinil (30-300 mg/kg, i.p.) on dialysate glutamate and GABA levels in the ventromedial (VMT) and ventrolateral (VLT) thalamus and hippocampal formation (Hip) of the awake rat. The results show a maximal increase in glutamate release in these brain regions at the 100 mg/kg dose, associated with a lack of effect on GABA release. Thus modafinil may increase excitatory glutamatergic transmission in these regions, altering the balance between glutamate and GABA transmission.

Self‐monitoring cognitive performance during sleep deprivation: effects of modafinil, d‐amphetamine and placebo

Self-monitoring refers to the ability to assess accurately one's own performance in a specific environment. The present study investigated the effects of the stimulating drugs modafinil (300 mg) and d-amphetamine (20 mg) on the ability to self-monitor cognitive performance during 64 h of sleep deprivation (SD) and sustained mental work. Two cognitive tasks were investigated: a visual (perceptual) judgement task and a complex mental addition task. Subjects in the placebo condition displayed marked circadian and SD effects on cognitive task performance but their self-monitoring was substantively undisturbed by SD. Subjects performing under the influence of d-amphetamine likewise displayed highly proficient self-monitoring throughout the SD period. In contrast, modafinil had a disruptive effect on self-monitoring, inducing a reliable 'overconfidence' effect (i.e. an overestimation of actual cognitive performance), which was particularly marked 2-4 h post-dose. Although modafinil has proven to be a safe and effective countermeasure to the effects of extensive SD on cognitive task performance, we encourage a more comprehensive understanding of the relation between its subjective and performance enhancing effects before the drug is recommended as a viable fatigue countermeasure.

The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT 3 receptor

The effect of modafinil on endogenous γ-aminobutyric acid (GABA) release in the medial preoptic area (MPA) and posterior hypothalamus (PH) and the role of local 5-HT 3 receptors in this effect was investigated in the awake rat using in vivo microdialysis. Modafinil (30–100 mg/kg i.p.) dose-dependently decreased GABA release from the MPA, while only the 100 mg/kg dose markedly reduced GABA release in the PH. The modafinil (100 mg/kg) induced inhibition of GABA release in the MPA and the PH was partially counteracted by the 5-HT 3 receptor antagonist MDL72222 (1 μM) when perfused locally alone or together with the non-selective 5-HT receptor antagonist methysergide (1 μM). Thus, the reduction of GABA transmission induced by modafinil in the MPA and in the PH, at least in part, involves local 5-HT 3 receptors. The GABA release inhibition by modafinil in the above areas may be relevant for its vigilance promoting action.

Modafinil decreases hypersomnolence in the English bulldog, a natural animal model of sleep-disordered breathing.

The English bulldog is a natural model of sleep-disordered breathing (SDB). This condition is marked by 1) hypersomnolence and 2) disordered breathing episodes that are most frequent and severe during rapid eye movement (REM) sleep. Modafinil has been found to increase arousal levels in animals and decrease excessive daytime sleepiness in humans. Therefore, in this study we focused mainly on the effects of the drug on total sleep time and sleep latency and secondarily assessed its effect on REM SDB. Five English bulldogs were implanted with subcutaneous electroencephalographic/electrooculographic (EEG/EOG) electrodes and instrumented with respiratory oscillation belts to measure abdominal and rib cage movements and an ear oximeter to measure saturation. The dogs were studied for approximately 8 hours each subsequent day on two consecutive days. On the first day, they received the vehicle dimethyl sulfoxide (DMSO) i.v. as a control. On the following day they received 10 mg/kg body weight of modafinil i.v. dissolved in the DMSO vehicle. Our findings indicate that modafinil significantly alleviates hypersomnolence (p < 0.05) in the bulldog, as evidenced by dramatically decreased mean total sleep time (from a control value of 50.5% to 8.3% with the drug) and increased mean sleep latency (from a control value of 71.0 minutes to a value of 346.6 minutes with the drug). We obtained limited data on the effect of modafinil on SDB because the drug either greatly diminished or entirely eradicated REM sleep in all five dogs.

Analysis of stimulant locomotor effects of modafinil in various strains of mice and rats.

Locomotor effects of modafinil were analysed and compared in various strains of mice and rats. A stimulation of locomotor activity was evidenced in all tested strains of mice: Swiss CD1, BALB/c, DBA2, C3H, B6CBAF1/JICO, Nude CD1 and in all tested strains of rats: Long Evans, Sprague Dawley, Wistar. In mice, from 10 mg/kg intraperitoneal, a precocious stimulant effect was observed. The drug seems to operate in its native form on the mouse brain since its intracerebroventricular administration (from 15 micrograms/mouse) elicited a stimulation of locomotion. In rats, the effective doses were higher (from 40 mg/kg ip); the effects of modafinil mainly oppose to the decrease in locomotion (habituation) which normally occurs in control animals. In addition, it was observed that administration of modafinil in rats habituated to their environment induced a recovery of locomotor activity.

Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil.

Modafinil [(diphenyl-methyl)sulphinyl-2-acetamide] is a novel psychostimulant drug which is effective in the treatment of narcolepsy and idiopathic hypersomnia. It also has neuroprotective effects in animal models of striatal neuropathology. Although the cellular mechanisms of action of modafinil are poorly understood, it has been shown to have a profile of pharmacological effects that differs considerably from that of amphetamine-like stimulants. There is some evidence that modafinil has central alpha 1-adrenergic agonist effects. In the present study modafinil was evaluated for cocaine-like discriminative stimulus effects in rats and for reinforcing effects in rhesus monkeys maintained on intravenous cocaine self-administration. Modafinil, l-ephedrine and d-amphetamine all produced dose dependent increases in cocaine-lever responding, with maximal levels of 67%, 82% and 100%, respectively. Modafinil produced full substitution in four out of the six rats tested while the highest levels of substitution were associated with substantial response rate decreasing effects. Little evidence was obtained that the discriminative stimulus effects of modafinil were produced by alpha 1-adrenergic activation, based upon results of tests performed in combination with prazosin. In the self-administration procedure, modafinil and l-ephedrine functioned as reinforcers in rhesus monkeys. The reinforcing and discriminative stimulus effects of modafinil-required very high doses: modafinil was over 200 times less potent than d-amphetamine and was also less potent than l-ephedrine. These results show that modafinil has some cocaine-like discriminative stimulus effects and, like other abused stimulants, can serve as a reinforcer at high doses.

The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism

The present in vivo microdialysis study demonstrated that the subcutaneous injection of modafinil (diphenyl-methyl-sulfinyl-2-acetamide) in doses of 30–300 mg/kg dose dependently increased dopamine release from the intermediate level of the nucleus accumbens along the rostro-caudal axis of the halothane anaesthetized rat. The effect of modafinil in a dose of 100 mg/kg was counteracted by the local perfusion in the nucleus accumbens with the GABA B receptor antagonist phaclofen (β- p-chlorophenyl-γ-aminopropyl-phosphonic acid) (50 μM), the GABA A agonist muscimol (3-hydroxy-5-aminomethyl-isoxazolol) (10 μM) and the neuronal GABA reuptake inhibitor SKF89976A (4,4-diphenyl-3-butenyl-nipecotic acid) (0.1 μM), whereas it was increased by the GABA B receptor agonist (−)-baclofen [β-( p-chlorophenyl-γ-aminobutyric acid)] (10 μM). In addition, the modafinil-induced increase of dopamine release was associated with a significant reduction of accumbens GABA release. These results suggest that the dopamine releasing action of modafinil in the rat nucleus accumbens is secondary to its ability to reduce local GABAergic transmission, which leads to a reduction of GABA A receptor signaling on the dopamine terminals.

Use of modafinil in the treatment of narcolepsy: A long term follow-up study

One hundred and forty patients (104 male and 36 female) aged 42.26 +/- 19.19 (range = 8 to 79.5 years) with narcolepsy-cataplexy were given modafinil (200 to 400 mg) at the Montpellier sleep disorders center from 1984 onwards. The follow-up focused on the reduction of excessive daytime somnolence (EDS), side effects and duration of treatment. In order to determine if any clinical aspect of narcolepsy could be involved in modafinil discontinuation, patients were divided into two groups according to continued or interrupted treatment. When modafinil effect on EDS was evaluated according to a scale varying from 0 (no effect) to 3 (excellent effect), 64.1% of the subjects, scored good or excellent. The mean duration of treatment was 22.05 months +/- 24.9, ranging from 1 to 114 months. Dependency signs were never observed.

Comparative Effects of Modafinil and Amphetamine on Daytime Sleepiness and Cataplexy of Narcoleptic Dogs

The effects of modafinil and amphetamine on daytime sleep (polysomnographic recordings) and cataplexy (the food-elicited cataplexy test) were compared using the narcoleptic canine model. Results indicate that both modafinil (5 and 10 mg/kg body weight i.v.) and amphetamine (100 and 200 micrograms/kg i.v.) increase wakefulness and reduce slow-wave sleep in control and narcoleptic dogs. In contrast, the results of cataplexy testing demonstrate that amphetamine (2.5-160 micrograms/kg i.v.), but not modafinil (0.125-8.0 mg/kg i.v.) significantly suppresses canine cataplexy. These results suggest that the pharmacological property of modafinil is distinct from amphetamine. Results of polysomnographic recordings also demonstrate that narcoleptic dogs slept significantly more during the daytime than control dogs and required very high doses (10 mg/kg i.v. modafinil; 200 micrograms/kg i.v. amphetamine) of stimulants to reduce their level of sleepiness to that of control dogs. This finding is consistent with the data collected in human narcolepsy and validates the use of this canine model for the screening of stimulant compounds.