Buy Modafinil Online is used to treat sleep disorders, such as narcolepsy and obstructive sleep apnea. It works by promoting wakefulness and alertness. Many mechanisms are involved in the arousal effects of modafinil. The orexinergic system is one of these. However, this system may not be the primary center of action for modafinil's arousal effects.

Activation of the hypocretin/orexin system

The wakefulness-promoting agent modafinil has been shown to activate specific arousal regions in the brain. The activity of these regions is associated with a reduction in sleepiness and an increase in arousal and cognitive performance in patients suffering from narcolepsy. Modafinil has also been shown to enhance memory in patients with schizophrenia.

These effects are mediated by the hypocretin/orexin system. This system consists of two G-protein coupled receptors and their natural ligands, orexin A and orexin B, which are expressed exclusively in the lateral hypothalamic area. In vivo studies in rats show that the sleep-promoting drug modafinil increases Fos immunoreactivity in the lateral hypothalamus, and this increase is paralleled by increased TMN activity.

This increase in TMN activity is likely to be caused by the release of orexin A and orexin B, a peptide that promotes food intake. The TMN neurons also release histamine, and this neurotransmitter is necessary for the production of normal wakefulness. It was also found that microinjection of histamine into the ventrolateral preoptic nucleus (VLPO) decreases wakefulness, and this effect is abolished by modafinil treatment.

Fos immunoreactivity in the cortex was increased by modafinil administration, but this effect was not seen in the cingulate or pyriform cortex. These observations suggest that orexin neurons are necessary for a normal state of wakefulness. Further experiments are needed to determine whether orexin neurons play a critical role in wakefulness and to test the hypothesis that modulation of these cells may help to treat narcolepsy and other sleep disorders.

Attenuation of GABAergic inhibition

Although modafinil is not a direct antagonist of the DAT, it does increase the DAT-mediated stimulation of extracellular GABA in cultured cortical neurons (Sesack et al, 1998). This attenuation of GABAergic inhibition can also occur when modafinil is given in conjunction with methylphenidate and is associated with increased performance on a simulated night shift work task. Modafinil is also able to prevent the effects of glutamate cytotoxicity on reducing GABA release in the hippocampus (Cruz-Perez de la Mora et al, 1999).

Modafinil ( Waklert 150 mg ) has also been found to interact with the trace amine receptor 1 (TA1), although it does not bind to this receptor in vitro. However, modafinil does augment the stimulation of TA1 by phenylethylamine in cells that express both DAT and NET.

This interaction may be mediated by the inhibition of dopamine uptake. In addition, modafinil increases DA neuron activity in the locus coeruleus of monkeys and enhances arousal and working memory performance in rhesus monkeys performing an oculomotor delayed response task.

The arousal and activity-promoting effects of modafinil are largely mediated by activation of the adrenergic system, with a and b adrenergic receptors being implicated. The DA systems are also involved, but they do not seem to be as important as the catecholamines. For example, pre-treatment with the NE-selective neurotoxin DSP-4 does not affect modafinil effects on waking or activity, whereas both clonidine and the DA autoreceptor agonist quinpirole blunt these effects.

Attenuation of adenosine release

Modafinil increases arousal in the locus coeruleus by blocking the adenosine A1 and a1D receptors. It also blocks the a1B adrenergic receptor, which controls locomotor activity. However, it has minimal effects on gross movement in a1B knockout mice. Pretreatment with a1B antagonists WB4101 and BMY7378 and the adrenergic receptor blocker terazosine significantly attenuates modafinil-induced arousal in these animals. The effect is not associated with a change in pupillary diameter, suggesting that the a1B receptor mediates movement but not arousal (Hou et al, 2005).

Modafinil also attenuates adenosine release by inhibiting the adenosine A2 autoreceptor. This attenuation is a critical component of its wake-promoting action and appears to be a consequence of a reduction in adenosine-induced cholinergic depolarization (Lin et al, 1992).

Pretreatment with yohimbine potentiates modafinil-induced arousal and activity but reduces the increase in pupillary diameter. This is because low doses of yohimbine act on the inhibitory terminal A2 autoreceptor to enhance NE release and augment post-synaptic adrenergic receptor activation, while higher doses act on post-synaptic A2 receptors, attenuating modafinil-induced arousal.

Moreover, modulation of adenosine receptors by modafinil does not appear to involve the GABAergic system and does not affect acetylcholine transmission. In addition to its wake-promoting effects, modafinil also has antidepressant and neuroprotective properties. It is not clear how modafinil elicits these properties, but it may involve disruption of the positive feedback loop of increased free radical production and reduced ATP availability.

Attenuation of free radical production

Modafinil is a racemic compound that is rapidly absorbed after oral administration. It reaches a high concentration in the blood after single or multiple doses and has a half-life of about 6-14 hours. In addition, it inhibits the enzyme CYP2C9, which is involved in the conversion of serotonin to 5-HT and dopamine. Inhibition of CYP2C9 has been shown to potentiate the antioxidative and wake-promoting actions of modafinil.

Modafinil increases the release of adenosine triphosphate (ATP) from rat brain cells, which may contribute to its effect on arousal and learning. It also increases the levels of monoamines, including adenosine triphosphate and 5-HT, in the prefrontal cortex of rats. In one study, Fuxe and coworkers used microdialysis to measure monoamine levels in the medial prefrontal cortex and ventromedial hypothalamus of awake rats. They found that modafinil enhanced the increase in cortical serotonin, DA, and NE levels caused by the antidepressant drugs fluoxetine and imipramine.

Modafinil also enhances the activity of acetylcholine (HA) in the prefrontal cortex. HA is an important neurotransmitter that regulates several cognitive functions. Moreover, HA acts to modulate the activity

of NMDA receptors and may play a role in memory processes. However, the exact mechanism by which modafinil affects HA is unclear. Some researchers believe that the effect is mediated by its action on 5HT, DA, and GABA.