The drug modafinil is a highly effective treatment for many neuropsychiatric disorders and is also widely used off-label for fatigue, obstructive sleep apnea, and postanesthesia sedation. However, its effects on cognition are less well understood than its neurochemical actions.
Modafinil Online Australia dose-dependently improves performance in a serial reversal learning task in mice, an effect mediated by the anterior cingulate cortex and the mediodorsal nucleus of the thalamus. It does not affect the basal or evoked release, or uptake of glutamate.
Dopamine Receptors
Dopamine (DA) is a potent and important wakefulness-promoting neurotransmitter that is also important for normal cognition. Modafinil is known to increase DA activity by inhibiting its reuptake and increasing its synthesis. This increase in DA signaling is mediated by the D1 and D2 dopamine receptors, both of which are upregulated by modafinil.
Modafinil enhances working memory (WM) in a spatial task and does so in a dose-dependent manner. WM performance is improved in rats trained for 10 days on the radial arm maze and this improvement was related to modafinil dosage.
The cognitive-enhancing effects of modafinil were observed even in animals that had lesioned mesencephalic dopamine neurons, as shown by behavioral sensitization. This is consistent with previous results showing that VTA dopamine neurons play an essential role in spontaneous sleep-wake cycles and arousal, as well as modulation of behavioral responses to motivationally relevant stimuli (Eban-Rothschild et al, 2016).
Dopamine agonists are known to reduce WM errors by directly blocking the actions of acetylcholine (Ach) on medial prefrontal cortex pyramidal cells. The dopamine agonists methylphenidate, guanfacine, and amphetamine all have similar effects on reducing WM errors in the rat.
Modafinil has no such effect on Ach-mediated WM errors. However, DA does affect glutamate excitability in the medial PFC pyramidal cell dendrites by inhibiting the reuptake of glutamate and enhancing the release of glutamate onto these neurons. Moreover, the DA autoreceptor agonist quinpirole has a similar effect on WM error reduction in a rat WM paradigm.
GABA Receptors
Modafinil (Provigil 200 Australia) has a wide range of central neurochemical actions on cognitive systems and demonstrates initial promise as a medication for psychiatric disorders including treatment-resistant depression, attention-deficit/hyperactivity disorder, and schizophrenia. However, little is known about the neural basis of modafinil’s effects on cognition. Modafinil affects several central neurotransmitter systems, notably DA and NE.
In the LC, it does not affect the activity of NE single units and appears to potentiate NE-induced inhibition of sleep-promoting neurons in the ventrolateral preoptic nucleus (VLPO) of anesthetized rats (de Saint Hilaire et al, 2001). Similarly, modafinil elevates extracellular levels of glutamate in the PFC and rostromedial hypothalamus. These effects appear to be mediated by the DAT and are abolished by the DAT inhibitors 6-hydroxy-DA and prazosin (Ferraro et al, 1999).
The vigilance-promoting drug enhances the increase in cortical serotonin levels induced by the antidepressant drugs fluoxetine and imipramine (Ferraro et al, 2000). Serotonin also inhibits GABA release, but this action is mediated by adrenergic mechanisms that are not affected by modafinil.
Moreover, the stimulant enhances the increase in VLPO GABA-mediated inhibition of adrenergic motor activation during a stop signal reaction time task, but this effect is not counteracted by the adrenergic antagonist cis-flupenthixol (Edgar DM, Tufft MR, Goodchild HL, Robbins TW, 1997). This suggests that the cognition-enhancing actions of modafinil are partly mediated by an enhancement of cortical HA effects on adrenergic mechanisms.
Adenosine Receptors
Modafinil increases the concentrations of extracellular glutamate and GABA in the medial preoptic area and the posterior hypothalamus. However, the increases in these areas are not mediated by the direct actions of modafinil on glutamate or GABA receptors (Ferraro et al, 1999).
Administration of the glutamate uptake blocker bicuculline prevents a modafinil-induced increase in extracellular glutamate in both of these regions but does not inhibit the effect of modafinil on the HA neurons that project to the hypothalamus and control their inhibition of the TMN during sleep. Modafinil also does not alter acetylcholine levels in the hypothalamus and does not reverse scopolamine-induced omission errors in a 5-choice serial reaction time test in the presence of physostigmine.
The effect of modafinil on adenosine is complex, with some evidence that it acts via dopamine and others that it acts via a noradrenergic mechanism. Modafinil decreases the accumulation of cytochrome P450 metabolites and has an effect on adenosine deaminase (DAD), which is important for reducing the availability of the adenosine A1B receptor agonist adenosine.
Several studies have found that modafinil has stimulant and wake-promoting effects, primarily by acting on the catecholamine system but also via a noradrenergic mechanism. These studies have also tended to show that the effects of modafinil on waking and activity are not mediated by changes in monoamine availability or release but rather by an increase in the creatine kinase pool of the brain. This is a mechanism whereby the drug can disrupt the positive feedback loop of free radical production and reduced ATP.
Norepinephrine Receptors
The wake-promoting effects of modafinil are mediated to some degree by its effect on the dopamine and norepinephrine transporters (see below). In vitro, modafinil occupies both dopamine and norepinephrine
and modulates their transporters and trace amine activity. In vivo, it reduces excessive somnolence in patients with myotonic dystrophy and enhances learning processes in chronically stressed mice.
Modafinil also exerts modest, but nonspecific effects on central adrenergic systems. In cortical slices, it increases electrically evoked (5HT) efflux in a concentration-dependent manner and inhibits spontaneous (5HT) efflux in a similar fashion. This activity is not related to the presence of adenosine or histamine, as modafinil has no agonistic activity at these receptors and has no effect on adenosine or histamine synthesis, vesicular storage, or release.
Studies using low-resolution brain electromagnetic tomography (LORETA) have identified specific regions of the prefrontal cortex that are active during vigilance enhancement by modafinil in narcolepsy patients and healthy volunteers following nocturnal sleep deprivation. These arousal-enhancing actions of modafinil are similar to those of the dopamine D1 agonist pramipexole and may be mediated in part by dopamine D1 receptors. However, other mechanisms may also contribute to the wake-enhancing activities of modafinil.
Several studies have reported that the wake-promoting effect of modafinil is accompanied by a dose-dependent decrease in GABA in the cortex (Tanganelli et al, 1994; 1992; 1995), medial preoptic area, and posterior hypothalamus, striatum, and globus pallidus, as well as in the hippocampus and nucleus accumbens (Ferraro et al, 2000b). Thus, it appears that, in addition to its effect on DA and dopamine systems, modafinil may directly modulate GABAergic neurotransmission.