Modafinil Tablet Australia is a wakefulness-promoting agent that has been shown to be effective in large randomized controlled trials for narcolepsy and idiopathic hypersomnolence. It has several clinical advantages over other CNS stimulants, including fewer adverse effects and no rebound sleepiness.
Interestingly, pre-treatment with the low dose of the a2 antagonist yohimbine potentiates Modafinil-induced wakefulness and activity increases, whereas higher doses inhibit NE-sensitive post-synaptic adrenergic receptors, attenuating these effects.
Dopaminergic Receptors
Modafinil, like other wakefulness promoting agents (such as methylphenidate and amphetamine), is known to enhance extracellular levels of dopamine in the nucleus accumbens. However, the exact mechanism through which Modafinil increases dopamine levels is unclear.
Dopamine D1 and D2 receptors are both thought to be involved in how sleep-wake patterns are controlled, but the roles of these two DA receptors in the wake-promoting effects of Modafinil are currently unknown. Unlike many CNS stimulants, Modafinil does not bind to most of the possible targets of sleep/wake regulation such as norepinephrine, serotonin, GABA, histamine-3, and melatonin.
To determine the role of D1R and D2R in modafinil’s arousal effects, mice with either D1R or D2R deficient were pretreated with an antagonist for 1 week before administration of Modafinil. Figure 1A-H shows that the arousal effect of low dose Modafinil (22.5, 45, and 90 mg/kg) was completely abolished when the D1R antagonist was administered before the drug, but not when the D2R antagonist was administered before the drug.
GABAergic Receptors
Although Modafinil (Modawake 200 mg) increases activity in the raphe nucleus and induces high concentrations of 5HT in vivo, its arousal effects are largely mediated by changes in extracellular catecholamine levels and not alterations in glutamate or GABA. Modafinil-induced elevations of extracellular adrenergic monoamines are abolished by the adrenergic antagonist clonidine and are partially restored by the DA autoreceptor antagonist raclopride, suggesting that Modafinil exerts its arousal effects primarily via DA receptors (Wisor et al., 2001).
Modafinil-induced wakefulness is also eliminated in D2R knockout mice, indicating that both D1R and D2R are involved in the arousal actions of Modafinil. Moreover, pretreatment of WT mice with the D1R antagonist SCH23390 before Modafinil administration completely abolishes Modafinil-induced wakefulness and reduces total time spent in NREM and REM sleep to less than half that observed in vehicle-treated control mice. (Figs. 1A-G).
TMN Neurons
Neurons in the tuberomammilary nucleus (TMN) project extensively throughout the brain and control many processes, including sleep-wake cycles, appetite, and neuroendocrine signaling. Histaminergic TMN neurons, which contain histamine H1 and H3 receptors, send out projections that promote wakefulness by activating GABAergic inhibitory neurons.
Histamine-evoked membrane hyperpolarization in histaminergic TMN neurons was potently enhanced by Modafinil, but not nomifensine. These results suggest that Modafinil interacts with histaminergic neurons through a mechanism that involves adenosine A1 receptors, GABAergic inhibition, and the DAT autoreceptor.
The effect of Modafinil on histaminergic TMN neurons appears to be cooperative or synergistic with dopamine, as the arousal effects of Modafinil are abolished in DAT-knockout mice. However, the adenosine A1 antagonist quinpirole blocks modafinil’s arousal effects in these mice, suggesting that D2R is also involved in this response.
In addition, Yu et al found that histaminergic TMN neurons express the vesicle transporter vgat, which imports GABA into vesicles for release. Modafinil evokes a slow-developing increase in vesicle release, which may be due to tonic activation of extrasynaptic inotropic GABA receptors.
Orexin Neurons
Researchers are beginning to understand the role that orexin neurons play in maintaining wakefulness. Orexins are hypothalamic neuropeptides that bind to the orexin 1 and orexin 2 receptors (OX1R, OX2R). Orexin neurons increase activity of many brain nuclei that regulate sleep-wakefulness, including dopaminergic, noradrenergic, serotonergic, and cholinergic neurons.
Orexin neurons also project to brain regions that influence goal-directed behaviour, including the ventral tegmental area and the nucleus accumbens. Functionally null mutations in orexin or its receptors have been associated with distinct narcoleptic phenotypes.
