In Search of a Mechanisms of Action

As soon as the original profile of adrafinil was described, a number of research teams, among them some with existing collaborations with Laboratoire L. Lafon, used different approaches in attempts to elucidate the mechanism(s) of action of adrafinil and modafinil, in order to differentiate them from amphetamine and methylphenidate. Using classical pharmacological probes known to interact preferentially (but probably not specifically) with neurotransmitter systems and receptors, it was found that centrally but not peripherally acting ^-adrenoceptor antagonists reduced the stimulant and wake-promoting effects of both adrafinil and modafinil: locomotor activity in mice,5'6'24 nocturnal activity in monkeys,12,13 electroencephalogram sleep-wake in cats,10 and convulsions in quaking mice.25,26 Moreover, while the motor stimulant and wake-promoting effects of amphetamine and methylphenidate were blocked by the dopamine receptor antagonists, haloperidol or sulpiride, and by a-methyl tyrosine blockade of catecholamine synthesis, these agents did not affect modafinil activity.27 Moreover, while modafinil was unable to modify the firing pattern of central dopaminergic and noradrenergic neurons in the rat, amphetamine consistently inhibited their activity, leading to the conclusion that, in contrast to amphetamine, the waking effect of modafinil was not mediated by catecholaminergic systems.28 Similarly, using in vivo voltammetry in mouse caudate nucleus, modafinil was ineffective in modulating presynaptic nigrostriatal function, in contrast to dexamphetamine and methylphenidate.29 A c-fos immunocytochem-istry study in cat produced an additional demonstration that the neuronal targets through which modafinil induced wakefulness were different from those of amphetamine and methylphenidate.30 Additional studies in the rat supported these results and concluded that the brain neuronal targets for modafinil included nuclei of the hypothalamus and amygdala.31 The wake-promoting effects of modafinil were associated with activation of the tuberomammillary nucleus and orexin neurons, two regions implicated in the promotion of normal wakefulness.32

While amphetamine altered glucose utilization in a wide variety of brain regions, modafinil had a relatively restricted pattern of changes (hippocampus, centrolateral nucleus of the thalamus, central nucleus of the amygdala), suggesting that modafinil was acting on a specific subset of brain pathways that regulated sleep and wakefulness, whereas amphetamine activated a greater number of cerebral structures where modafinil had no effect (basal ganglia, nuclei of the thalamus, frontal cortex, nucleus accumbens, ventral tegmental area, and pontine reticular formation), involved in the regulation of sleep and wakefulness.33

Despite these findings, controversy exists regarding an indirect involvement of central dopaminergic systems in the wake-promoting effects of modafinil. In a variety of studies, modafinil has shown minimal interactions with a wide variety of receptors, including adrenergic, histaminergic, dopaminergic, P1, and orexin-1 and 2. Modafinil did however bind with low affinity (Ki^ - 3-4 mmol L-1) to dopamine transporter-binding sites (DAT).

In addition, in vitro [3H]-modafinil (specific activity 20 Ci mmol-1) was, in our hands, unable to bind specifically to many brain tissues from various animal species (mouse: total brain, cortex, hippocampus, thalamus, hypothalamus, pons medulla; rat: total brain; rabbit: cortex, hippocampus; dog: total brain, cortex) and autoradiography studies in the rat did not display any affinity of the labeled compound for any brain area (unpublished results).

The involvement of dopamine in the wake-promoting effects of modafinil and other CNS stimulants was supported by studies in control and narcoleptic canines.35 Like amphetamine, modafinil increased caudate extracellular dopamine at least in narcoleptic dogs, via a mechanism independent of the hypocretin receptor.36 Additionally, in DAT knockout mice, modafinil-like methamphetamine and the selective DAT blocker, GBR 12909, lacked wake-promoting effects.36 Increases in dopamine release in the rat nucleus accumbens were observed following modafinil administration but this was secondary to a reduction in GABAergic transmission that led to a reduction of GABAA receptor signaling in dopamine terminals.37 Modafinil dose-dependently reduced g-amino-butyric acid (GABA) outflow from the cortex of awake guinea-pig,38 and from the striatum, pallidum, and substantia nigra,39 and, more importantly, from the medial preoptic area and posterior hypothalamus of the awake rat.40 The latter are hypothalamic fields where functional inhibition of GABA release by modafinil may be relevant for its vigilance-promoting effects. Modafinil also increased glutamate release in the ventrolateral and ventromedial thalamic areas, hippocampus,41 medial preoptic area, and posterior hypothalamus, where its effects were dependent on decreased GABA efflux.42 The decrease in GABA outflow and the concomitant increase in glutamate release appear to be indirect effects on GABAergic and glutamatergic neurons.43 Additionally, the decrease in cortical GABA outflow appeared to be regulated by a balance between noradrenergic and serotonergic neurotransmission.44'45

Modafinil has complex interactions in the central nucleus of amygdala46 and increases histamine release in the anterior hypothalamus, suggesting that modafinil may promote waking via the activation of histaminergic systems, despite the lack of direct interactions of modafinil with any of the four subtypes of histamine receptor family.47 Modafinil potentiated the effects of norepinephrine on sleep-promoting neurons in the ventrolateral preoptic (VLPO) nucleus, as did nisoxetine, leading to the suggestion48 that the wake-promoting effects of modafinil may involve inhibition of the norepinephrine transporter (NET) in VLPO neurons, even though the compound had no effect on NETat concentrations up to 100 mmol L-1. In both orexin-null and wild-type mice, modafinil produced similar patterns of neuronal activation, as indicated by Fos immunohistochemistry. Interestingly, modafinil was more effective in increasing wake time in orexin-null than in the wild-type mice, suggesting that orexin was not mandatory for the wake-promoting effects of modafinil, but might be involved in some aspect of the alerting actions of the compound.49

Many of these studies, while providing intriguing evidence for a potential mechanism of action of modafinil, have, in toto, provided little in the way of testable hypotheses that are unequivocal in their focus on the mechanism of action of modafinil. One intriguing question is whether the effects of modafinil are, per se, wake-promoting, or rather are due to a possible inhibition of sleep-inducing systems.

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