Effects Of Modafinil Research Articles

Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice

Previously established dose-response curves indicated that modafinil 20–40 mg/kg i.p. elicited in mice an obvious stimulation of locomotor activity roughly similar to that induced by (+) amphetamine 2–4 mg/kg. The effects of various agents modifying dopamine transmission were compared on the locomotor response to both drugs. The preferential D2 dopamine receptor antagonist haloperidol 37.5–150 μg/kg i.p. suppressed the stimulant effect of (+) amphetamine in a dose dependent manner, but not that of modafinil. The D1 dopamine receptor antagonist SCH 23390 (7.5–30 μg/kg s.c.) reversed the (+) amphetamine but not the modafinil induced hyperactivity. The tyrosine hydroxylase inhibitor α-methyl-para-tyrosine (200 mg/kg) suppressed the hyperactivity induced by 4 mg/kg dexamphetamine but not that induced by 20 mg/kg modafinil. Associating L-DOPA 150 mg/kg and benserazide 37.5 mg/kg with (+) amphetamine 2 mg/kg resulted in stereotyped climbing behavior, that was not observed with modafinil 10–80 mg/kg. The profound akinesia induced by reserpine (4 mg/kg s.c.; 5 h before testing) was reversed by (+) amphetamine 2 mg/kg but not by modafinil 40 mg/kg. Finally, on synaptosomes prepared from mouse striata preloaded with [ 3H]dopamine, modafinil 10 −5 M did not increase the spontaneous [ 3H]dopamine release whereas (+) amphetamine, at the same concentration, doubled it. From all these differences between the two drugs, it is concluded that the mechanism underlying the modafinil induced stimulant locomotor effect differs completely from that of (+) amphetamine.

Effects of a vigilance-enhancing drug, modafinil, on rat brain metabolism: 2D COSY 1H-NMR study

The effects of modafinil, a vigilance-enhancing drug, on brain metabolism were investigated directly in situ by the 2D COSY 1H-NMR spectroscopy in anesthetized rats. Modafinil (600 mg/kg, i.p.) induced significant increases in both aspartate (72% ± 15%) and glutamate-glutamine pool (28% ± 8%) simultaneously with increases in inositol (51% ± 19%) and creatine-phosphocreatine pool (47% ± 14%) in comparison with control values ( P < 0.05; n = 5). These results suggest that the awakening properties of modafinil could be mediated by metabolic activation.

Awakening properties of modafinil without paradoxical sleep rebound: comparative study with amphetamine in the rat

We have studied the effect of modafinil and amphetamine, two waking drugs, on the sleep-wake cycle of the Sprague-Dawley rat. Both modafinil (64 or 128 mg/kg) and amphetamine (2.5 or 5 mg/kg) cause a dose dependent increase in wakefulness. However, amphetamine wakefulness is followed by a paradoxical sleep rebound on the injection day, whereas modafinil does not produce this effect. In modafinil-treated rats, the sleep pattern on the post-injection day is similar to that of controls, while that of amphetamine-treated rats is modified.

Modafinil and cortical γ-aminobutyric acid outflow. Modulation by 5-hydroxytryptamine neurotoxins

The acute or chronic administration of modafinil, (diphenyl-methyl-sulfinyl-2-acetamide, 30 mg/kg s.c.) decreased γ-aminobutyric acid (GABA) outflow from the cerebral cortex of freely moving guinea pigs and rats. In 5,7-dihydroxytryptamine intracerebroventricularly pretreated guinea pigs, the effect of modafinil on GABA outflow was reversed and the noradrenaline cortical levels increased. Prazosin (35,8 ng/kg i.p.) blocked the drug-induced increase in GABA efflux. In vitro experiments, performed in rat cortical slices, showed that modafinil failed to affect [ 3H]GABA release and uptake as well as glutamic acid decarboxylase activity. In conclusion, our results suggest that the balance between central noradrenaline and 5-hydroxytryptamine transmission is important for the regulation by modafinil of the GABAergic release in the cerebral cortex.

Modafinil in Diurnal Sleepiness. A Study of 123 Patients

The efficacy of modafinil, a psychostimulant drug acting on postsynaptic alpha-1 adrenergic receptors, as a treatment for excessive daytime sleepiness was studied in 123 patients. Subjects included 94 narcoleptic patients (76 with cataplexy), 23 hypersomnia patients and 6 patients with disrupted nocturnal sleep (DNS) and excessive daytime sleepiness (EDS). Clinical efficacy of the treatment on each symptom (EDS, cataplexy and DNS) was evaluated on a four-point scale from excellent to absent. The effectiveness of modafinil as a treatment for EDS was excellent in 17% of all patients, good in 63%, fair in 17% and absent in 3%. The incidence of side effects was rather low (14 of 123 patients) and most of them disappeared (11 patients) when doses were reduced.

Lack of pre-synaptic dopaminergic involvement in modafinil activity in anaesthetized mice: In vivo voltammetry studies

Modafinil was compared to the indirect dopaminergic drugs, dexamphetamine and methylphenidate, using in vivo differential normal pulse voltammetry with carbon fibre electrodes located in the caudate nucleus to study extracellular catechol level in anaesthetized mice. Modafinil (16–256 mg kg −1) failed to modify the catechol oxidation peak height (peak 2). Dexamphetamine at low doses (2 and 4 mg kg −1) decreased, while at a higher dose (8 mg kg −1) did not modify peak 2 height. A low dose of methylphenidate (16mg kg −1) did not display any effect, while higher doses (32 and 64mgkg −1) increased peak 2 height. Pargyline-induced monoamine oxidase inhibition elicited a rapid and dramatic decrease in peak 2 height (related to the decrease of catechol levels). In these conditions modafinil (64 and 256 mg kg −1) did not modify, while dexamphetamine (2, 4 and 8mg kg −1) and methylphenidate (16, 32 and 64mgkg −1) increased peak 2 height in relation to synaptic dopamine level increase. This study, in mice, demonstrated the lack of effects of modafinil on nigro-striatal function, at the pre-synaptic level, as opposed to dexamphetamine and methylphenidate.

The stimulant effect of modafinil on wakefulness is not associated with an increase in anxiety in mice

Modafinil is a new drug used in the treatment of narcolepsy. Its administration in mice induced a dose-dependent increase in locomotor activity. The effects of modafinil were compared with those of dexamphetamine on three tests that assessed the anxiety level (drugs were used at doses which induced a roughly similar stimulation of locomotor activity). Dexamphetamine increased the latency of exploration of a white compartment, increased thigmotaxis in an open-field and decreased the time spent in the open arms of an elevated plus-maze. None of these responses was significantly modified by modafinil. We conclude that modafinil does not share the anxiogenic effects of dexamphetamine.

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 doapmine 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.

Subjective effects of modafinil, a new central adrenergic stimulant in healthy volunteers: a comparison with amphetamine, caffeine and placebo

SummaryThe subjective, behavioral and physiological effects of modafinil (300 mg PO) a new central adrenergic stimulant, were compared with those of dextroamphetamine (15 mg PO), caffeine (300 mg PO) and placebo in a randomized double-blind cross-over study. Sixteen healthy volunteers participated in the study y: 8 males and 8 females with no history of drug abuse and moderate use of caffeine. Subjective and behavioral effects were studied using the Addiction Research Center Inventory (ARCI), Profile of Mood States (POMS) and Visual Analog Scales before and 1, 2, 4 and 8 h post single oral dosing. Results showed that subjective effects of modafinil (300 mg) differed markedly from those of dextroamphetamine (15 mg). They were close to those produced by caffeine (300 mg). These results indicate that modafinil (300 mg) does not possess amphetamine-like subjective effects in a healthy population. If subjective feelings are related to drug abuse liability, it could be assumed that modafinil, at the dose used in therapeutics, does not possess any abuse liability comparable to amphetamine.

Effets du modafinil (300 mg) sur le sommeil, la somnolence et la vigilance du narcoleptique

CNS stimulants are the most widely used drugs to treat narcolepsy which is characterized by the excessive daytime sleepiness and typically associated with cataplexy. However, a number of side effects may often arise with this therapeutic approach. Thus, investigating new drugs which are efficient but well tolerated is of utmost importance in the treatment of narcolepsy. Although modafinil, an alpha-1 adreno-receptor agonist, has been reported to bring substantial awakening properties in animals, the studies performed in man, particularly in narcoleptic subjects, are few. In the present study, we evaluated the effects of a 300 mg daily dose of modafinil on sleepiness and psychomotor performance of 16 narcoleptic subjects. The major effect of modafinil in narcoleptic subjects was a decrease of daytime sleepiness and corresponding improvement of performances involving attentive functions. However, the learning effect in psychomotor tests may mask the drug effect.

Inhibitory effects of the psychoactive drug modafinil on gamma-aminobutyric acid outflow from the cerebral cortex of the awake freely moving guinea-pig. Possible involvement of 5-hydroxytryptamine mechanisms.

The effects of modafinil on acetylcholine and GABA outflow from the cerebral cortex of awake freely moving guinea pigs provided with an epidural cup were studied. In the dose range of 3-30 mg/kg s.c. modafinil produced a dose dependent significant inhibition of GABA outflow without influencing cortical acetylcholine release. Methysergide (2 mg/kg, i.p.) and ketanserin (0.5 mg/kg, i.p.) but not prazosin (0.14 mg/kg, i.p.) counteracted the inhibitory action of modafinil on cortical GABA outflow. Modafinil both acutely and chronically in the same dose range increased striatal 5-HIAA levels and 5-HT utilization in the rat (acute) and mouse (chronic). The action on cortical GABA release may be dependent on activity at 5-HT2 receptors, since the action of modafinil in this respect is blocked by the non-selective 5-HT antagonist methysergide and the 5-HT2 antagonist ketanserin. The involvement of 5-HT mechanisms in the inhibitory action of modafinil on cortical GABA release is also suggested by the findings that 5-HT metabolism may become increased by modafinil at least in the striatum. The reduction of cortical GABA outflow via 5-HT2 receptors by modafinil is probably related to some of its actions on the central nervous system including behavioural effects.

Effect of modafinil on pancreatic exocrine secretion in the rat. A comparison with methadone

Modafinil is a recently developed drug which increases wakefulness in several animal species and in man, an effect involving, at least in part, central adrenoceptors. In the present experiments, the effect of modafinil was studied on a model of neurally stimulated secretion, pancreatic secretion induced by 2-deoxyglucose (2DG) in the rat, and compared with that of the μ-opiate methadone. Modafinil induced a dose-related inhibition of 2DG-stimulated pancreatic secretion, reaching more than 80% after 250 mg/kg i.p. The modafinil effect was suppressed by idazoxan or by large doses of prazosin but not by naloxone. In addition modafinil (250 mg/kg i.p.) did not change the pancreatic response to electrical vagal stimulation. Methadone also potently suppressed 2DG-stimulated pancreatic secretion, but in contrast to modafinil, the methadone effect was blocked by naloxone, but not by the adrenoceptor antagonists idazoxan, prazosin and propranolol. It is concluded that modafinil decreases centrally 2DG-stimulated pancreatic secretion through a pathway involving α 1- and α 2-adrenoceptors, without an interaction with opiate receptors.

Effect of modafinil and amphetamine on the rat catecholaminergic neuron activity

We have studied the effect of modafinil and amphetamine, two waking drugs, on the electrical activity of central dopaminergic and noradrenergic neurons in the rat. Modafinil (128 mg/kg, i.p.) was unable to modify the firing pattern of these neurons, while amphetamine (2 or 5 mg/kg, i.p.) consistently inhibited their activity. A pretreatment with modafinil did not change thereafter the effect of amphetamine. Contrary to amphetamine, the waking effect of modafinil does not seem to be mediated by the catecholaminergic neuron activity per se.

Comparative study of stimulant effects of d-Araphetamine Sulfate and Modafinil, an original psychostimulant

Comparative study of stimulant effects of d-Araphetamine Sulfate and Modafinil, an original psychostimulant

Central α1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals

Single administration of the new drug modafinil was followed by an increase in locomotor activity in mice and in nocturnal activity in monkeys. Stereotyped behaviour in mice and rats, and potentiation of amphetamine-induced stereotyped behaviour were not observed; however, at the highest dose used, a slight potentiation of apomorphine-induced stereotyped behaviour was observed in rats. The modafinil-induced increase in locomotor activity in mice was prevented by the centrally acting α 1-adrenoceptor antagonists, prazosin and phenoxybenzamine, and by reserpine but not by the mixed dopamine D-1/D-2 antagonist, haloperidol, the dopamine D-2 antagonist, sulpiride, the peripherally acting α 1-adrenoceptor antagonist, phentolamine, the α 2-adrenoceptor antagonist, yohimbine, the β-adrenoceptor antagonist, propranolol, or by the catecholamine synthesis inhibitor, α-methyl-p-tyrosine. Likewise, the modafinil-induced increase in nocturnal activity in monkeys was prevented by prazosin. Interestingly, modafinil did not produce obvious peripheral sympathetic effects in mice and rats (no salivation, no contraction of the pilomotor muscles, slight mydriasis only at high doses). Therefore, modafinil appears to produce a strong stimulating effect in rodents and in primates. These effects could be linked to modulation (stimulation) of central α 1-adrenoceptors unaccompanied by peripheral sympathetic effects, which is unexpected.

On the treatment of the alcoholic organic brain syndrome with an alpha-adrenergic agonist modafinil: double-blind, placebo-controlled clinical, psychometric and neurophysiological studies

1. In a double-blind study forty abstinent hospitalized male patients with an alcoholic organic brain syndrome (OBS) were treated for 6 weeks with either 200 mg modafinil or placebo. 2. Modafinil (CRL 40476) is a putative central alpha-1 adrenergic agonist. It's pharmacological profile is quite different from that of amphetamine, which can be seen by the lack of peripheral sympathomimetic effects. The vigilance promoting effect of modafinil has been shown previously in pharmaco-EEG and psychometric studies as well as in clinical studies involving treatment of daytime sleepiness in idiopathic hypersomniacs and narcoleptics. 3. The present clinical investigations demonstrated that the spontaneous restitution of the alcoholic OBS was significantly augmented and accelerated by modafinil. 4. Psychometric tests did not show significant intergroup differences. Modafinil- and placebo-treated patients improved continously over the 6-week period. 5. Psychophysiological and autonomous nervous system parameters were affected neither by placebo nor by modafinil. 6. Neurophysiological investigations by means of quantitative pharmacoEEG showed partly inconsistent findings. However, superimposed dosages of modafinil (on the top of 6 weeks chronic administration) induced a decrease of slow activity and an increase of alpha activity suggesting an improvement of vigilance after the daily drug intake. 7. Considering the beneficial effects of modafinil in abstinent chronic alcoholic patients, it may be said that activation and improvement of adaptive behaviour by an alpha-adrenergic agonist could be regarded as a therapeutic principle in the treatment of the OBS, eventually due to noradrenergic deficits.