Effects Of Modafinil Research Articles

A retrospective chart review of the effects of modafinil on depression as monotherapy and as adjunctive therapy

Major depression is often refractory to antidepressants, and it is important to explore alternative medication treatments. Among the symptoms common with depression are energy loss/fatigue and anxiety. Modafinil has a novel mechanism of action and may have antidepressant properties. In a single outpatient clinic, data were systematically collected on all patients including those who began modafinil treatment for major depression. This clinician (C.P.) had used modafinil to treat major depression in patients who failed one or more adequate antidepressant treatments. To monitor changes during treatment, charting had included four rating scales: the Beck Depression Inventory, the Zung Self-Rating Depression Scale, and the Hamilton Depression and Hamilton Anxiety Rating Scales. A follow-up chart review identified 45 patients whose major depression was treated with modafinil over a 9-month period. The mean dose of modafinil was 184.3+/-100.0 mg/day (range=50-450 mg/day). For these 45 patients, all four rating scales showed significant improvement following 2 weeks and following 3 months of modafinil treatment. Fifteen of these patients were on modafinil monotherapy, and the remaining 30 on modafinil as an augmenting agent. For both subgroups, all three depression rating scales showed a significant improvement following 2 weeks and 3 months of modafinil treatment. This chart review provides preliminary evidence that modafinil treatment may be beneficial to those with major depression, even when unresponsive to other treatments.

Effect of Modafinil on Acute Pain: A Randomized Double‐Blind Crossover Study

The Journal of Clinical PharmacologyVolume 44, Issue 12 p. 1425-1427 Effect of Modafinil on Acute Pain: A Randomized Double-Blind Crossover Study Indu Taneja MD, PhD, Corresponding Author Indu Taneja MD, PhD Autonomic Dysfunction Center, Division of Clinical Pharmacology, Departments of Medicine, Pharmacology, Neurology, and Anesthesiology, Vanderbilt University, Nashville, TennesseeAddress for reprints: Indu Taneja, MD, PhD, AA3228, Medical Center North, Vanderbilt University, 1161 21st Avenue South, Nashville, TN 37232-2195.Search for more papers by this authorStephen Bruehl PhD, Stephen Bruehl PhD Autonomic Dysfunction Center, Division of Clinical Pharmacology, Departments of Medicine, Pharmacology, Neurology, and Anesthesiology, Vanderbilt University, Nashville, TennesseeSearch for more papers by this authorDavid Robertson MD, David Robertson MD Autonomic Dysfunction Center, Division of Clinical Pharmacology, Departments of Medicine, Pharmacology, Neurology, and Anesthesiology, Vanderbilt University, Nashville, TennesseeSearch for more papers by this author Indu Taneja MD, PhD, Corresponding Author Indu Taneja MD, PhD Autonomic Dysfunction Center, Division of Clinical Pharmacology, Departments of Medicine, Pharmacology, Neurology, and Anesthesiology, Vanderbilt University, Nashville, TennesseeAddress for reprints: Indu Taneja, MD, PhD, AA3228, Medical Center North, Vanderbilt University, 1161 21st Avenue South, Nashville, TN 37232-2195.Search for more papers by this authorStephen Bruehl PhD, Stephen Bruehl PhD Autonomic Dysfunction Center, Division of Clinical Pharmacology, Departments of Medicine, Pharmacology, Neurology, and Anesthesiology, Vanderbilt University, Nashville, TennesseeSearch for more papers by this authorDavid Robertson MD, David Robertson MD Autonomic Dysfunction Center, Division of Clinical Pharmacology, Departments of Medicine, Pharmacology, Neurology, and Anesthesiology, Vanderbilt University, Nashville, TennesseeSearch for more papers by this author First published: 08 March 2013 https://doi.org/10.1177/0091270004270292Citations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume44, Issue12December 2004Pages 1425-1427 RelatedInformation

EEG-tomographic studies with LORETA on vigilance differences between narcolepsy patients and controls and subsequent double-blind, placebo-controlled studies with modafinil

The aim of the present study was to identify brain regions associated with vigilance in untreated and modafinil-treated narcoleptic patients by means of low-resolution brain electromagnetic tomography (LORETA). 16 drug-free narcoleptics and 16 normal controls were included in the baseline investigation. Subsequently patients participated in a double-blind, placebo-controlled crossover study receiving a three-week fixed titration of modafinil (200, 300, 400 mg) and placebo. Measurements comprised LORETA, the Multiple Sleep Latency Test (MSLT) and the Epworth Sleepiness Scale (ESS) obtained before and after three weeks' therapy. Statistical overall analysis by means of the omnibus significance test demonstrated significant inter-group differences in the resting (R-EEG), but not in the vigilance-controlled recordings (V-EEG). Subsequent univariate analysis revealed a decrease in alpha-2 and beta 1-3 power in prefrontal, temporal and parietal cortices, with the right hemisphere slightly more involved in this vigilance decrement. Modafinil 400 mg/d as compared with placebo induced changes opposite to the aforementioned baseline differences (key-lock principle) with a preponderance in the left hemisphere. This increase in vigilance resulted in an improvement in the MSLT and the ESS. LORETA provided evidence of a functional deterioration of the fronto-temporo-parietal network of the right-hemispheric vigilance system in narcolepsy and a therapeutic effect of modafinil on the left hemisphere, which is less affected by the disease.

The effect of modafinil on counter-regulatory and cognitive responses to hypoglycaemia

Our hypothesis is that reducing release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) with modafinil will enhance symptomatic and hormonal responses to hypoglycaemia. Nine healthy men received, in random order, two 100-mg doses of modafinil or placebo, followed by an insulin clamp in which plasma glucose was either reduced stepwise to 2.4 mmol/l or was sustained at euglycaemia (four studies). Catecholamines, symptom scores and cognitive function were measured. Modafinil had no effect on the measured parameters during euglycaemia. During hypoglycaemia, autonomic symptom scores were significantly higher with modafinil (increase at lowest plasma glucose concentration 271.3+/-118.9 vs 211.2+/-80.4/40 min, p=0.019), and the heart rate response was increased (12,928+/-184 vs 6773+/-148 bpm/140 min, p=0.016). Deterioration in performance of two cognitive tasks was reduced: Stroop colour-word test (613+/-204 vs 2375+/-161/65 min, p=0.009) and accuracy of a simple reaction task (11.3+/-1.8 vs 9.4+/-3.7, p=0.039). We conclude that modafinil improves adrenergic sensitivity and some aspects of cognitive function at hypoglycaemia, possibly by reducing neuronal central GABA concentrations.

Effect of the Wake-Promoting Agent Modafinil on Sleep-Promoting Neurons from the Ventrolateral Preoptic Nucleus: an In Vitro Pharmacologic Study

The pharmacologic profile of modafinil, an increasingly popular wake-promoting drug for narcolepsy treatment, differs from those of classic psychostimulants such as amphetamine. However, its brain targets are still a matter of debate. We hypothesized that modafinil could increase waking by inhibiting the sleep-promoting neurons from the ventrolateral preoptic nucleus (VLPO). Such action could be direct or indirect via the potentiation of inhibition mediated by waking neurotransmitters. We thus studied the effect of modafinil on the membrane potential and firing rate of VLPO neurons recorded in rat-brain slices. We further determined whether pretreatment with modafinil modifies the effect of noradrenaline, carbachol, serotonin, histamine, dopamine, or clonidine. Pretreatment with modafinil specifically increased the inhibition of VLPO neurons induced by noradrenaline but had no effect when applied alone or in combination with other substances. Pretreatment with nisoxetine, a selective noradrenaline reuptake blocker, similarly increased the noradrenaline-induced inhibition of VLPO cells. Further, the potentiation by modafinil was minimized when modafinil and nisoxetine were applied together. These results suggest that modafinil blocks the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons from the VLPO. Such a mechanism could be at least partially responsible for the wake-promoting effect of modafinil.

Wake-promoting agents with different mechanisms of action: comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity

Despite efforts to achieve a desirable weight, two-thirds of the population has an elevated body weight. Medications are useful in supporting weight loss, but produce adverse effects. This study compared the effects of amphetamine and modafinil on food intake and cardiovascular activity in healthy men and women. Participants ( n=11) completed 11 sessions. In random order, participants received placebo on five separate sessions and single oral doses of modafinil (1.75, 3.5, or 7.0 mg/kg) and amphetamine (0.035, 0.07, 0.14 mg/kg). Free time between hourly performance testing intervals gave participants the opportunity to eat. Like amphetamine, modafinil reduced the amount of food consumed and decreased energy intake, without altering the proportion of macronutrients consumed. Although both medications significantly increase heart rate and blood pressure at higher doses, the dose of modafinil that was efficacious in decreasing food intake did not significantly increase heart rate. Modafinil may be well suited for the treatment of obesity, although further studies with repeated dosing in overweight populations are warranted. Modafinil may have less adverse health consequences than some anorectic agents and greater treatment efficacy.

Modafinil in the treatment of excessive daytime sleepiness in children

Background Modafinil is an alerting agent approved for the treatment of narcolepsy in adults. There are no studies examining the long-term effects and safety profile of modafinil in children with excessive daytime somnolence (EDS). Objectives To determine the effects of modafinil on clinical manifestations of narcolepsy and idiopathic hypersomnia. Methods A systematic chart review was conducted for 13 children (mean age 11.0±5.3 years , six males, 10 with narcolepsy and three with idiopathic hypersomnia) receiving modafinil. Results The mean modafinil dose was 346±119 mg/ day , with a mean treatment duration of 15.6±7.8 months . For approximately 90% of the children treated, parents reported a favorable response with the reduction in sudden sleep attacks, as documented by sleep–wake diaries. One child failed to improve on 400 mg/day modafinil and was switched to methylphenidate. Two other children showed only partial improvement and required additional stimulant medication to control EDS symptoms. Seven children underwent repeated nocturnal polysomnography and multiple sleep latency tests (MSLT). Compared to baseline MSLT measures (mean sleep latency: 6.6±3.7 min ), modafinil prolonged mean sleep latency ( 10.2±4.8 min , p=0.02) without significant alteration in nocturnal polysomnographic measures. However, a trend towards REM sleep reduction was noted ( 16.8±5.1 % TST vs. 11.8±6.2 % TST ). Exacerbation of seizures and psychotic symptoms was reported with modafinil therapy in two children with preexisting conditions. Hematological and hepatic functions assessed every 3 months remained unaltered. Conclusion Modafinil has a modest, yet significant effect on EDS in children and appears to be safe and well tolerated.

Effects of modafinil on sustained attention performance and quality of life in OSA patients with residual sleepiness while being treated with nCPAP

Background: Some patients with obstructive sleep apnea/hypopnea syndrome (OSA/HS) who are regular users of nasal continuous positive airway pressure (nCPAP) therapy continue to experience daytime sleepiness that impairs performance and quality of life. A randomized, double-blind, placebo-controlled, parallel-group study was conducted to determine the effect of modafinil on sustained attention performance and functional quality of life in OSA/HS patients with residual daytime sleepiness, who were regular users of nCPAP therapy. Methods: Seventy-seven patients received modafinil (200 mg/day, week 1; 400 mg/day, weeks 2–4) and 80 patients received matching placebo once daily for 4 weeks. Sustained attention performance on the psychomotor vigilance task (PVT) and functional status and quality of life using the Functional Outcomes of Sleep Questionnaire (FOSQ) were measured. Results: The frequency of lapses of attention during PVT performance was significantly decreased, and both the median and slowest reaction times were significantly improved in patients receiving nCPAP plus modafinil compared with those receiving nCPAP plus placebo ( P=0.010 for the number of lapses [transformed], P=0.023 for the median reaction time, and P=0.014 for the reciprocal of the 10% slowest reaction times). Treatment with nCPAP plus modafinil significantly improved the FOSQ total score (weeks 1 and 4), the vigilance subscale score (weeks 1 and 4), and the activity level subscale score (week 4) compared with treatment with nCPAP plus placebo (all P<0.05). Conclusions: Consistent with previous results for objective and subjective measures of sleepiness, modafinil used adjunctively improved performance on a test of behavioral alertness and reduced functional impairments in patients with OSA/HS who were regular users of nCPAP therapy but still experiencing sleepiness.

Modafinil maintains waking in the fruit fly drosophila melanogaster.

Fruit flies exhibit a sleep-like rest state that shares behavioral characteristics with mammalian sleep, including a homeostatic increase in rest after deprivation by mechanical methods. We tested the effect of modafinil, a novel wake-promoting agent, to discover whether its effect is conserved. Flies fed various concentrations of modafinil were compared to groups of control flies fed diluent only. Flies were also tested for a homeostatic response to the modafinil-related rest deprivation by examining rest and activity during recovery after 48H modafinil administration, compared to rest deprivation alone and to both treatments combined. The duration and consolidation of rest, and the duration, intensity, and circadian rhythms of activity were measured. Modafinil significantly and dose-dependently decreased rest when fed at concentrations from 2.5 mg/ml to 0.3125 mg/ml. Activity intensity was not increased, and circadian timing was unchanged, although the 2.5 mg/ml dose blunted the amplitude of overt circadian locomotor rhythms. Compared to controls, the duration of rest bouts was decreased in flies fed 2.5 mg/ml, and waking was frequently interrupted by 5-min periods of immobility. A rest rebound (significant increase in rest) followed withdrawal of either 2.5mg/ml or 0.625mg/ml modafinil after 48H. When directly compared to 6H total rest deprivation, the increase after withdrawal was briefer, reminiscent of the attenuated rest rebound seen in mammals, including humans, after modafinil. However, modafinil withdrawal combined with 6H total rest deprivation significantly enhanced the rebound, suggesting that a rest debt is accumulating during modafinil. We conclude that modafinil affects states of arousal in Drosophila in the same direction as it does in mammals. This discovery provides a tool for searching for conserved molecular mechanisms by which modafinil regulates rest and waking.

Modafinil increases histamine release in the anterior hypothalamus of rats

Modafinil, ( RS)-2-(Diphenylmethylsulfinyl)acetamide, is a well known wake promoting drug used for the treatment of narcolepsy. We investigated the effect of modafinil on the hypothalamic histamine release in the anesthetized rat using in vivo microdialysis. Modafinil (150 mg/kg, i.p.) increased histamine release by 150% of the basal release. The intracerebroventricular (i.c.v.) injection of modafinil (1 nmol) also increased histamine release, however, when modafinil (1 nmol) was injected directly into the tuberomammillary nucleus, a limited region where cell bodies of the histaminergic neurons are located, histamine release was not altered. These observations suggest that modafinil may promote waking via the activation of the histaminergic system, although it does not appear to be a direct pharmacological target of modafinil.

Comparison of the effects of modafinil and sleep deprivation on sleep and cortical EEG spectra in mice

Modafinil is a wakefulness-promoting substance whose profile differs from that of the classical psychostimulants. It is still unknown whether waking induced by modafinil and wakefulness induced by sleep deprivation differ in terms of their effect on subsequent sleep. To investigate this problem sleep was recorded in two groups of OF1 mice. One group received modafinil (200 mg/kg, i.p.) at light onset which induced a period of wakefulness of approx. 5 h, while animals of the subsequent control group were injected with vehicle and kept awake for an equivalent duration. The effect of the two treatments on sleep was similar. REM sleep was initially reduced and slow-wave activity (SWA; EEG power in the 0.75–4.0 Hz range) in nonREM sleep was enhanced for several hours. The SWA increase was more prominent over the frontal cortex than over the occipital cortex after both treatments. A minor difference was seen at the occipital site where the initial rise of power in the low-frequency range was larger after vehicle combined with enforced waking than after modafinil. The study shows that the homeostatic sleep response following the modafinil-induced wakefulness corresponds largely to the response following a non-pharmacologically induced extended waking episode.

Discriminative-stimulus effects of modafinil in cocaine-trained humans

Modafinil is a novel stimulant that is effective in the treatment of narcolepsy and excessive daytime sleepiness. In vitro and in vivo neuropharmacological data suggest that the mechanism of action of modafinil is distinct from that of prototypical abused stimulants like cocaine and d-amphetamine. In the present experiment, six human volunteers with recent histories of cocaine use learned to discriminate 150 mg oral cocaine HCL. After acquiring the discrimination (i.e. ≥80% correct responding on 4 consecutive days), a range of doses of oral cocaine (50, 100, and 150 mg), modafinil (200, 400, and 600 mg), and placebo were tested to determine if they shared discriminative-stimulus and self-reported effects with 150 mg cocaine. Methylphenidate (60 mg) and triazolam (0.5 mg) were included as positive and negative controls, respectively. Cocaine and methylphenidate, but neither modafinil nor triazolam, produced cocaine-like discriminative-stimulus, subject-rated, and cardiovascular effects. The results of the present experiment suggest that cocaine discrimination in humans is pharmacologically specific within and across drug classes.

The central nucleus of the amygdala and the wake-promoting effects of modafinil

Modafinil, a novel non-amphetamine stimulant recently approved for the treatment of narcolepsy, has been shown to increase waking in both animals and humans. However, its mechanism of action is currently unknown. Earlier research into the brain structures responsible for the wake-producing actions of modafinil implicated the central nucleus of the amygdala (ACe) as a possible site of action [Neuroscience 87 (1998) 905–911; Neurosci. Lett. 241 (1998) 95–98]. The present experiments were designed to test the hypothesis that the ACe is, at least in part, involved in the wake-producing actions of modafinil. In the first experiment, rats with lesions of the ACe were injected systemically with varying doses of modafinil and sleep was recorded. At the highest dose, modafinil significantly increased waking and decreased sleep. However, there was no interaction between the lesion and the effect of the drug. In the second experiment, varying doses of modafinil were injected directly into the ACe and sleep was recorded. Injection of modafinil into the ACe did not affect sleep architecture. Thus, ACe does not play a simple role in modafinil’s wake-promoting action. We suggest that more complex testing will be required to elucidate its role.

Effects of Modafinil on Cognitive Performance During 40 Hr of Sleep Deprivation in a Warm Environment

This study examined the effect of the psychostimulant modafinil on cognitive performance during 40 hr of sleep deprivation in a warm environment. Five men were randomly assigned to a modafinil (3 × 100 mg/24 hr) and a placebo trial on consecutive weeks, with a 5-day intervening “wash-out” period. Each trial involved a thermoneutral control day (outside of the climatic chamber) followed by a 40-hr sleep deprivation period in a climatic chamber at 30°C with 50% relative humidity. Ten cognitive testing sessions were conducted on each trial; each session lasted approximately 45 min, and they occurred at 6-hr intervals. The task battery included subjective assessments of mood, fatigue, and motivation and cognitive assessments of serial reaction time, logical reasoning (logical reasoning task [LRT]), visual comparison (CMP), mental addition (ADD), vigilance (detection of repeated numbers [DRN]), and multitasking. In addition, for 4 of the cognitive tasks that permitted a quantitative index of response accuracy (i.e., LRT, CMP, DRN, and ADD), participants provided estimates of their performance before and after each session to permit an evaluation of the extent to which they could accurately self-monitor their own cognitive abilities. The findings revealed that (a) despite significant increases in core body temperature, cognitive performance was largely unaffected by the warm environment per se; (b) sleep loss induced a general reduction in cognitive performance that was largely but not completely eliminated by modafinil; and (c) participants were able to accurately self-monitor their own cognitive capabilities during both the placebo and modafinil trials. In this article, we discuss the potential utility of modafinil in sustained military operations and the general implications of these findings for Hancock's (1986) theory of sustained attention under thermal stress.

Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats

The role of brain amines in mediating the effects of the wake-promoting agent modafinil, used in the treatment of sleepiness associated with narcolepsy is still uncertain. Therefore we studied the effects of modafinil on extracellular serotonin (5-HT), dopamine (DA) and noradrenaline (NA), in rat prefrontal cortex and in the medial hypothalamus area. Modafinil (128 mg/kg i.p.) significantly increased waking in the first 4 h of EEG sleep recording. This cortical and behavioral activation was associated with an initial increase in extracellular 5-HT, DA and NA during the first 60 min following modafinil administration. In the prefrontal cortex, 5-HT release remained high for 3 h after modafinil administration. In contrast, in the hypothalamus, only NA release was enhanced while DA and 5-HT levels remained low. In a first step, modafinil may generate waking partly via cortical monoamine release, particularly DA and 5-HT, and also hypothalamic NA. In a second step, maintenance of waking might depend on hypothalamic NA.

Modafinil in Fibromyalgia Treatment

Modafinil in Fibromyalgia Treatment

Efficacy of stimulants for fatigue management: the effects of Provigil® and Dexedrine® on sleep-deprived aviators

Abstract The present report details the results of a quasi-experimental comparison between the alerting effects of modafinil (Provigil ® ) and those of dextroamphetamine (Dexedrine ® ) in sleep-deprived pilots. Data from two separate placebo-controlled studies (one on Dexedrine ® and one on Provigil ® ) were merged and analyzed to determine whether one compound produced greater effects than the other relative to placebo. The results indicated there were differences between the two stimulants on only two of the 14 dependent measures. In one case (a flight performance measure), modafinil was more effective than dextroamphetamine, and in the other case (subjective fatigue ratings), dextroamphetamine was better than modafinil. The remaining measures indicated no statistically-significant differences between the two stimulants. However, in the majority of cases, it was clear that performance, subjective mood ratings, and physiological indices of alertness were substantially better under both drugs than under placebo. Thus, with the exception that modafinil produced more spontaneous reports of side effects than dextroamphetamine, the overall results indicated equivalent efficacy with the two compounds. Limitations of this study were that the two compounds were tested on different samples at different points in time, and there was no systematic measurement of side effects (instead, spontaneous reports were recorded). Future work should validate the present results in a controlled side-by-side comparison of dextroamphetamine and modafinil under conditions similar to the ones reported here.

First evidence of a delay-dependent working memory-enhancing effect of modafinil in mice.

This study investigated the effects of pretest injection of modafinil on delayed spontaneous alternation rates (SA) used to evaluate working memory in C57 Bl/6 mice. In a first experiment, systemic modafinil at 64 mg/kg, but not at 8 mg/kg or 32 mg/kg doses produced a significant increase of alternation scores (intertrial interval (ITI) 60s) when compared with controls. In a second experiment, modafinil (64 mg/kg) enhanced the alternation rates mainly at long (60 s and 180 s) but not at short (5 s) ITIs. Exploratory latencies and activity in a four hole-board apparatus were not modified by modafinil administration. These experiments are the first to demonstrate a delay-dependent working memory-enhancing effect of modafinil.

Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil

The present in vitro and in vivo studies examined the effects of modafinil on serotonergic transmission in the rat frontal cortex. In the in vitro study modafinil (0.3–30 μM) increased electrically-evoked, but not spontaneous, serotonin ([ 3H]5-HT) efflux from cortical slices in a concentration-dependent manner while the indirect serotonin agonist dl-fenfluramine (1–15 μM) enhanced both spontaneous and evoked [ 3H]5-HT efflux. The effects of modafinil were more pronounced when the 5-HT reuptake was blocked by paroxetine. Contrary to paroxetine (0.3–3 μM) and dl-fenfluramine (1–5 μM), modafinil failed to influence the [ 3H]5-HT uptake. In the in vivo study modafinil (3–100 mg/kg i.p.) increased 5-HT dialysate levels, the maximal effect being already reached at the 30 mg/kg dose. dl-fenfluramine (5 mg/kg) induced an increase in 5-HT levels which was significantly higher than that displayed by modafinil at 30 mg/kg. In the presence of paroxetine (3 μM), the effect of modafinil at 30 mg/kg was higher than that observed in the absence of 5-HT reuptake inhibition. Finally, in the presence of the selective 5-HT 1A receptor agonist 8-OH-DPAT, modafinil at 100 mg/kg failed to affect 5-HT dialysate levels. These results demonstrate that modafinil regulates cortical serotonergic transmission and suggest that the drug preferentially acts by amplifying the electro-neurosecretory coupling mechanisms and via mechanisms which do not involve the reuptake process.

Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset.

The psychostimulant drug, modafinil, protects rodents against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, striatal ischemia and partial transection of the nigro-striatal pathway. We now report on the ability of modafinil to reverse motor disability in MPTP-treated common marmosets and to prevent MPTP-induced nigral cell death in this species. In the initial experiments, adult common marmosets were treated with MPTP to produce stable motor deficits. The subsequent administration of modafinil (10, 30 or 100 mg/kg/day, p.o.) produced a dose-dependent reversal of motor disability. In a subsequent experiment, normal common marmosets were concurrently treated with 10, 30 or 100 mg/kg of modafinil once daily by gavage during acute MPTP administration (daily for 5 days), continuing for 2 weeks after the last dose of MPTP. Modafinil dose-dependently prevented the decline in motor activity normally produced by MPTP treatment. MPTP treatment caused a 76% loss of nigral tyrosine-hydroxylase-immunoreactive cells in placebo-treated animals, and this was dose-dependently prevented by modafinil. At the highest dose (100 mg/kg/day) of modafinil, there was no significant loss of tyrosine-hydroxylase-immunoreactive cells in the substantia nigra compared with normal animals. MPTP treatment also reduced striatal dopamine uptake sites by 95%, as measured by specific [3H]-mazindol binding, compared with normal controls. Modafinil treatment dose-dependently reduced the loss of specific [3H]-mazindol binding. Behavioural and morphological evidence in the present study indicate a potential antiparkinsonian and neuroprotective role for modafinil, which may form a new pharmacological approach to the treatment of Parkinson's disease.