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PubMed1994

6-hydroxy-dopamine treatment counteracts the reduction of cortical GABA release produced by the vigilance promoting drug modafinil in the awake freely moving guinea-pig.

The effects of acute and repeated treatments with modafinil (30 mg/kg, s.c.) alone or after i.c.v. 6-hydroxy-dopamine injection were studied on cortical GABA release as well as on cortical/striatal catecholamine levels in awake freely moving guinea pig. The results show that repeated daily modafinil treatment produces a similar but short-lasting reduction of GABA outflow compared with acute administration. A significant reduction of cortical basal GABA outflow was observed in animals treated with 6-hydroxy-dopamine, which was maintained also after modafinil treatments. Furthermore, after the 6-hydroxy-dopamine treatment, modafinil fails to inhibit cortical GABA release. The depleting action of the toxin, 17% reduction of neostriatal dopamine levels and 35% of noradrenaline levels in the parietal cortex, was not influenced by repeated modafinil treatment. The catecholaminergic telencephalic networks therefore seem essential for the elicitation of the inhibitory effects of modafinil on GABA release.

Animals↗
PubMed2004

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.

Adult↗
PubMed2004

Modafinil prevents the MPTP-induced increase in GABAA receptor binding in the internal globus pallidus of MPTP-treated common marmosets.

The psychostimulant drug modafinil induces a reversal of motor deficits in MPTP treated primates and prevents MPTP toxicity to substantia nigra but its mechanism of action is not clear. In common marmosets acutely treated with MPTP in the presence or absence of modafinil, we have studied changes in GABA(A) receptor binding in the basal ganglia. MPTP treatment had no effect on [(3)H]-flunitrazepam (FNZ) binding density in the striatum or external globus pallidus (GPe) but increased [(3)H]-FNZ binding density in the internal globus pallidus (GPi). Administration of modafinil (10-100 mg/kg) with MPTP did not alter [(3)H]-FNZ binding density in the striatum or GPe. Low doses of modafinil (10 and 30 mg/kg) had no effect on the increased [(3)H]-FNZ binding density in the GPi but high dose modafinil (100 mg/kg) significantly decreased [(3)H]-FNZ binding density in GPi. These findings suggest that modafinil can selectively alter GABA binding density in the GPi either by preventing MPTP-induced toxicity or through an action on striatal output pathway related to its antiparkinsonian activity and its ability to inhibit MPTP toxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

Enhancement of learning processes following an acute modafinil injection in mice.

Modafinil is a wakeness-promoting drug, which is effective in the treatment of narcolepsy; its effects on learning processes are however little studied. Thus, the present study was aimed at determining the effects of an acute modafinil injection on a serial reversal discrimination task performed in a T-maze in mice. Independent groups of mice varying by the level of pretest training (either 1 or 4 days of training) were used. Mice were injected each day with a gum arabic solution before each session began. On the second or the fifth day of training, a single dose of modafinil was injected before testing. Modafinil at 64 mg/kg but not at 32 mg/kg dramatically improved performance as compared to controls in subjects being trained 4 days, but not in subjects being trained 1 day. This improvement of learning was due to the more rapid emergence of a win-stay strategy in modafinil-treated subjects as compare to controls. Thus, our data show that an acute modafinil injection enhances learning processes.

Animals↗
PubMed2004

Modafinil facilitates performance on a delayed nonmatching to position swim task in rats.

Modafinil is a wake-promoting drug approved by the FDA for the treatment of narcolepsy. Recent evidence suggests that modafinil may improve learning and memory processes. To further evaluate possible cognitive properties associated with modafinil, male Sprague-Dawley rats were tested in a delayed nonmatching to position (DNMTP) task. A modified water maze allowed animals to make one of two choices for the location of the escape platform. Each trial consisted of two swims. On the information swim (IS), only one choice was open to the animal for escape. One minute later, a choice swim (CS) presented the animal with two choices with the escape platform in the opposite position. There were 10 trials per day for 10 days. Rats received 0, 30, 55, or 100 mg/kg ip of modafinil 30 min prior to testing. Locomotor activity was also assessed. Animals that received 55 and 100 mg/kg made significantly more correct choices, indicating that higher doses of modafinil learned the task faster than did controls. While animals that received 100 mg/kg did exhibit an enhancement of locomotor activity, this effect did not result in more efficient goal-directed behavior. The evidence is consistent with previous research showing that modafinil facilitates cognitive processes.

Animals↗
PubMed1998

Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinil.

We examined the neuronal targets in the rat brain for the novel wakefulness-promoting agent modafinil and for amphetamine using c-Fos immunohistochemistry. Both modafinil and amphetamine induced neuronal expression of c-Fos-like immunoreactivity in the paraventricular nucleus of the hypothalamus, anterior hypothalamus and central nucleus of the amygdala. Modafinil also increased c-Fos-like immunoreactivity in the suprachiasmatic nucleus, while amphetamine had no effect. Brain regions in which amphetamine increased c-Fos-like immunoreactivity, but modafinil had no effect, included frontal cortex, striatum, lateral habenula, supraoptic nucleus and basolateral nucleus of the amygdala. These findings suggest that the mechanism of action of modafinil is different from that of amphetamine and that the neuronal targets for modafinil in the brain include nuclei of the hypothalamus and amygdala.

Amphetamine↗
PubMed1998

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.

Animals↗
PubMed1999

A stereological study on the neuroprotective actions of acute modafinil treatment on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigral lesions of the male black mouse.

The effect of an acute administration of the vigilance-promoting drug modafinil ((+/-)(diphenyl-methyl)-sulfinyl-2 acetamide; Modiodal) on the nigrostriatal dopamine system was studied after damage induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) by means of immunohistochemistry for tyrosine hydroxylase (TH) and a stereological method. MPTP (40 mg/kg) reduced from 24,380 +/- 902 to 13,501 +/- 522 and from 37,868 +/- 3300 to 20,568 +/- 1270, respectively, the number of TH immunoreactive (IR) and non-TH IR nigral neurons. Co-administration of Modafinil restored to normal the number of these neuronal populations. MPTP treatment induced also a reduction in the volume of TH IR neurons, which was counteracted by Modafinil administration. The data provide morphological evidence, based on unbiased stereological analysis, for a potential neuroprotective role of Modafinil, not only in dopaminergic neurons, but also with a similar magnitude in the non-DA nerve cell population of the substantia nigra after MPTP lesion. These results suggest that Modafinil has a neuroprotective role in the substantia nigra via a still undefined mechanism in which a crucial role of DA uptake blockade should be excluded. Modafinil may therefore have a therapeutic potential in neurodegenerative processes such as those occurring in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia.

Modafinil, a novel cognitive enhancer, selectively improves neuropsychological task performance in healthy volunteers and adult patients with attention deficit hyperactivity disorder (ADHD). It has been argued that persistent cognitive deficits in patients with schizophrenia are responsible for the failure of many patients to rehabilitate socially even when psychotic symptoms are in remission. The present study examined the potential of modafinil as a cognitive enhancer in schizophrenia. Twenty chronic patients with a diagnosis of schizophrenia were entered into a double-blind, randomized, placebo-controlled crossover study using a 200 mg dose of modafinil. Modafinil had some cognitive enhancing properties in schizophrenia similar to those observed in healthy adults and adult patients with ADHD. Improvement was seen on short-term verbal memory span, with trends towards improved visual memory and spatial planning. This was accompanied by slowed response latency on the spatial planning task. No effect on stop-signal performance was seen. Importantly, significant improvement in attentional set shifting was seen, despite no effect of modafinil on this task being seen in healthy volunteers or ADHD patients. Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia, particularly because of its beneficial effects on attentional set shifting.

Adult↗
PubMed2006

Cognitive performance during sustained wakefulness: A low dose of caffeine is equally effective as modafinil in alleviating the nocturnal decline.

Cognitive performance at night exhibits a substantial drop, typically before dawn. One of the means of dealing with this phenomenon, as well as with the accompanying sleepiness during sustained wakefulness, is the administration of stimulants. The most widely used and well-documented stimulants are caffeine, amphetamines, and modafinil. Of these, amphetamines are the least recommended, as they may severely affect behavior. Caffeine and modafinil seem to produce relatively milder side effects and usually only at high doses. Previous comparison studies have revealed equal efficacy of both the stimulants in maintaining alertness and performance during sustained wakefulness. However, these studies used relatively high, and thus not completely safe, doses of these drugs (600 mg caffeine and 400 mg modafinil). Therefore, the aim of the present study was to assess the efficacy of a low and medically safe dose of caffeine (200 mg) and modafinil (200 mg) in maintaining cognitive performance during sustained wakefulness. A flight simulation task was chosen for the assessment of the stimulants in a counter-balanced, within-subject design under four different conditions: baseline (no drugs), placebo, caffeine (200 mg), and modafinil (200 mg). The equal effectiveness of both drugs in abolishing the nocturnal drop in cognitive performance, as well as of oral temperature and blood pressure, supported the use of low doses of caffeine and modafinil for the maintenance of alertness in healthy subjects during sustained wakefulness.

Adult↗
PubMedDate not supplied

Modafinil as adjunctive therapy in depressed outpatients.

The wake-promoting agent modafinil (PROVIGIL) may prove useful as an adjunctive treatment in patients with suboptimal responses to antidepressant regimens. This retrospective chart review describes the use of modafinil as an adjunct to antidepressant therapy in 78 outpatients in a general psychiatric practice and discusses in detail treatment outcomes for 3 patients. Statistically significant improvements in mean Carroll Depression Rating Scale scores (p < 0.01), Visual Analog Scale scores for overall feeling (p < 0.003), and Clinical Global Impression of Severity ratings (p < 0.001) were demonstrated following treatment with modafinil. Treatment with modafinil rapidly improved wakefulness, fatigue, and everyday functioning in individual cases. Modafinil was well tolerated in combination with antidepressants and other medications. These findings suggest that adjunctive modafinil may improve treatment outcomes when used with antidepressant therapy in depressed patients, particularly in those with problematic sleepiness or fatigue.

Adolescent↗
PubMed2001

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.

Animals↗
PubMed2006

Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects.

The vigilance-enhancing agent modafinil has neuroprotective properties: it prevents striatal ischemic injury, nigrostriatal pathway deterioration after partial transsection and intoxication with 1-methyl-1,2,3,6-tetrahydropyridine. The present study determines the protective effects of modafinil in the marmoset 1-methyl-1,2,3,6-tetrahydropyridine Parkinson model on behavior and on monoamine levels. Twelve marmoset monkeys were treated with a total dose of 6 mg/kg 1-methyl-1,2,3,6-tetrahydropyridine. Simultaneously, six animals received a daily oral dose of modafinil (100 mg/kg) and six animals received vehicle for 27 days. Behavior was observed daily and the locomotor activity, hand-eye coordination, small fast movements, anxiety-related behavior and startle response of the animals were tested twice a week for 3 weeks. Modafinil largely prevented the 1-methyl-1,2,3,6-tetrahydropyridine-induced change in observed behavior, locomotor activity, hand-eye coordination and small fast movements, whereas the vehicle could not prevent the devastating effects of 1-methyl-1,2,3,6-tetrahydropyridine. Dopamine levels in the striatum of the vehicle+1-methyl-1,2,3,6-tetrahydropyridine-treated animals were reduced to 5% of control levels, whereas the dopamine levels of the modafinil+1-methyl-1,2,3,6-tetrahydropyridine-treated animals were reduced to 41% of control levels. The present data suggest that modafinil prevents decrease of movement-related behavior and dopamine levels after 1-methyl-1,2,3,6-tetrahydropyridine intoxication and can be an efficaceous pharmacological intervention in the treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived?

In a double-blind, parallel groups study, 60 healthy student volunteers (29 men and 31 women, aged 19-22 years) were randomly allocated to receive placebo, 100 or 200 mg modafinil. Two hours later, in the early evening, they completed an extensive cognitive battery. The 3 groups did not differ in self-ratings of sleepiness or tiredness before the testing session, and there were no treatment-associated changes in these or in mood ratings during the tests. Modafinil was without effect in several tests of reaction time and attention, but the 200-mg group was faster at simple color naming of dots and performed better than placebo in the Rapid Visual Information Processing test of sustained attention. Modafinil was without effect on spatial working memory, but the 100-mg group performed better in the backward part of the digit span test. Modafinil was without effect on verbal short-term memory (story recall), but 100 mg improved digit span forward, and both doses improved pattern recognition, although this was accompanied by a slowing of response latency in the 200-mg group. There were no significant effects of modafinil compared with placebo in tests of long-term memory, executive function, visuospatial and constructional ability, or category fluency. These results suggest that the benefits of modafinil are not clearly dose-related, and those from 100 mg are limited to the span of immediate verbal recall and short-term visual recognition memory, which is insufficient for it to be considered as a cognitive enhancer in non-sleep-deprived individuals.

Adult↗
PubMed2007

A randomized, double-blind, crossover trial of modafinil on mood.

Modafinil, a medication for the excessive sleepiness associated with narcolepsy, has been hypothesized to improve not just alertness but mood as well. The purpose of this study was to determine how treatment with modafinil affects mood in healthy volunteers. Normal healthy volunteers (n = 12, 10 men and 2 women; 30-44 years) underwent a 3-day, counterbalanced, randomized, crossover, inpatient trial of modafinil (400 mg daily) versus placebo with 4-day washout period between 2 treatments. Mood was assessed daily using both the Positive and Negative Affect Schedule and a general mood scale, which consisted of 10 bipolar adjective ratings based on a severity scale ranging from 1 to 10. Modafinil increased general mood and Negative Affect scales relative to placebo and had a significant effect on Positive Affect scales. These results suggest that modafinil may have general mood-elevating effects accompanied by increased negative affect (anxiety). The findings may have implications for clinical practice, in particular for the adjunctive use of modafinil in treatment-resistant depression.

Administration, Oral↗
PubMed2006

Modafinil [2-[(diphenylmethyl)sulfinyl]acetamide] and circadian rhythms in syrian hamsters: assessment of the chronobiotic potential of a novel alerting compound.

In Syrian hamsters, behavioral procedures for inducing arousal (e.g., running in a novel wheel or gentle handling) can shift circadian rhythms when applied during the usual sleep period ("subjective day") and can attenuate phase shifts to light during the active period ("subjective night"). This raises the possibility that drugs that affect behavioral state may have "chronobiotic" potential. We characterized the effects of modafinil (2-[(diphenylmethyl)sulfinyl]acetamide), an atypical alerting compound, on circadian rhythms in male Syrian hamsters. Electroencephalogram recordings and video observations confirmed that modafinil dose dependently increases wakefulness at the expense of slow-wave and paradoxical sleep with no increase in locomotor activity per unit of time awake. Despite inducing arousal, modafinil at these doses (150 or 300 mg/kg), administered in the subjective day or early or late in the subjective night, did not perturb circadian phase. Modafinil (300 mg/kg) also had no effect on phase shifts to light exposure either early or late in the night and did not alter the size of phase shifts induced by running in a novel wheel for 3 h during the mid-day. Modafinil (300 mg/kg) did, however, decrease by approximately 50% the amount of novel wheel-stimulated running, moving leftward the dose-response relation between wheel revolutions and shift magnitude. These results indicate that, in Syrian hamsters, modafinil alone has no significant chronobiotic efficacy. Nevertheless, this agent may increase the sensitivity of the circadian pacemaker to nonphotic stimuli and may thus have some potential as a tool for promoting clock resetting in combination with behavioral strategies.

Animals↗
PubMed2005

Modafinil for daytime somnolence in Parkinson's disease: double blind, placebo controlled parallel trial.

BACKGROUND: Excessive daytime somnolence (EDS) commonly complicates Parkinson's disease (PD). The aetiology of EDS is probably multifactorial but is probably exacerbated by dopaminergic medications. Modafinil is a wake-promoting agent approved for use in narcolepsy, but it is often used to treat a variety of somnolent conditions. METHOD: A double blind, placebo controlled parallel design trial was conducted to assess the efficacy of modafinil (200-400 mg/day) for the treatment of EDS in PD. The primary efficacy measure was the Epworth Sleepiness (ES) scale score. Secondary efficacy points included the Unified Parkinson's Disease Rating Scale (UPDRS), the Fatigue Severity Scale, the Hamilton Depression Scale, and the multiple sleep latency test (MSLT). RESULTS: Of a total of 40 subjects (29 men, mean (SD) age 64.8 (11.3) years), randomised to modafinil or placebo, 37 completed the study. Modafinil failed to significantly improve ES scores compared with placebo (2.7 v 1.5 points improvement, respectively, p = 0.28). MSLT failed to improve with modafinil relative to placebo (-0.16 v -0.70, respectively, p = 0.14). UPDRS, global impressions, Fatigue Severity Scale, and Hamilton Depression Scale scores were unchanged. Adverse events were minimal. CONCLUSION: Modafinil failed to significantly improve EDS in PD compared with placebo. The drug did not alter motor symptoms in PD and was well tolerated.

Aged↗
PubMed2006

Comparison of diphenhydramine and modafinil on arousal and autonomic functions in healthy volunteers.

Arousal is regulated by the interplay between wakefulness- and sleep-promoting nuclei. Major wakefulness-promoting nuclei are the histaminergic tuberomamillary nucleus (TMN) of the hypothalamus and the noradrenergic locus coeruleus (LC) of the pons, which also play a role in autonomic regulation. First generation antihistamines, such as diphenhydramine, are likely to cause sedation by blocking excitatory H1 histamine receptors in the cerebral cortex, and the anti-narcolepsy drug modafinil may promote wakefulness by activating the locus coeruleus. We compared the effects of single doses of diphenhydramine (75 mg) and modafinil (200 mg) on arousal and autonomic functions in 16 healthy male volunteers, using a placebo-controlled, balanced, double-blind design. Arousal was assessed by critical flicker fusion frequency (CFFF), visual analogue scales (VAS) and pupillary fatigue waves (Pupillographic Sleepiness Test (PST)). Autonomic functions measured included resting pupil diameter, light and darkness reflex responses, blood pressure, heart rate and salivation. Data were analysed with ANOVA, with multiple comparisons. Diphenhydramine had sedative effects as shown by reductions in CFFF, VAS alertness ratings and increases of the indices of pupillary fatigue. Modafinil had alerting effects as indicated by reductions in the measures of pupillary fatigue. Comparison of pre-post medication changes in pupil diameter showed a decrease after diphenhydramine and an increase after modafinil. Diphenhydramine reduced salivation, and modafinil increased systolic blood pressure. In conclusion, diphenhydramine and modafinil evoked opposite effects on arousal and sympathetic functions, which are likely to reflect their interaction with the central histaminergic and noradrenergic systems. Hyposalivation by diphenhydramine is likely to be due to its additional anticholinergic property.

Administration, Oral↗