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Wake-Promoting Agents, Insights into Clinical Use and Molecular Perspectives

April 2016
Journal of Advanced Medical Sciences and Applied Technologies 2(1):129-140

DOI:10.18869/nrip.jamsat.2.1.129

Authors:

Bijan Zare

Shiraz University of Medical Sciences

Mohammad Nami

Canadian University of Dubai

Wake-Promoting Agents (WPAs) such as amphetamine-like stimulants or modafinil, armodafinil, methyl phenidate, caffeine and nicotine reinforce the level of vigilance through an stimulated release of neurotransmitters implicated in the arousal threshold maintenance, hence shift the drive from the sleep-promoting to wake-promoting system. The modulatory effects of WPAs on cortical activation pathways give rise to enhanced vigilance. For example, cholinergic neurons of the basal forebrain and the adenosine receptors on these neurons are agonized and antagonized by nicotine andcaffeine, respectively. Caffeine similarly antagonizes adenosine receptors on the GABAergic neurons and intensifies the inhibitory drive in preoptic/anterior hypothalamus which involve in sleep induction. Modafinil however exerts its wake promoting effects through stimulating the tuberomammillary nucleus and the hypocretinergic neurons which activate the ascending reticular activating system. Although many neurotransmitter systems such as dopamine are thought to be involved upon the effects of WPAs, the empirical evidence to explain the exact mechanisms need to gain strength.

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Journal of Advanced Medical Sciences and Applied Technologies (JAMSAT). 2016; 2(1)

Review Article

Wake-Promoting Agents, Insights into

Clinical Use and Molecular Perspectives

Bijan Zare1, Behrooz Moosavi2,3, Mohammad Torabi-Nami4,5*

1Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz

University of Medical Sciences, Shiraz, Iran

2Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China

Normal University, Wuhan, China

3Laboratory of Organometallics, Catalysis and Ordered Materials, State Key Laboratory of Advanced Technology

for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan, China

4Department of Neuroscience, School of Advanced Medical Sciences and Technologies,

Shiraz University of Medical Sciences, Shiraz, Iran

5Shiraz Neuroscience Research Center,

Shiraz University of Medical Sciences, Shiraz, Iran

The Burden of Excessive Daytime

Sleepiness

Sleepiness is in fact resulted from the less-

maintained arousal threshold which relieves the

inhibition exerted on the sleep-promoting system

upon wakefulness. Daytime somnolence,

characterized by inability to keep awake and vigilant

during the typical waking hours of the day, can turn

into persistent drowsiness or unintended sleep.

Moreover, sleepiness may significantly vary in

intensity and tend to occur in situations which

require minimal or no active participation (1).

The practice of general medicine encounters

frequent cases with sleep-related complaints

including excessive daytime sleepiness (EDS). EDS

is shown to leave strongly negative effects on

individuals’ quality of life, mood, interpersonal

communications, and functionality. Despite such a

significance, EDS is often under-diagnosed in

clinical practice. While EDS is known to significantly

interfere with patients’ health and functional status,

surveys have revealed that almost in 60% of

Abstract

Wake-Promoting Agents (WPAs) such as amphetamine-like stimulants or modafinil,

armodafinil, methyl phenidate, caffeine and nicotine reinforce the level of vigilance

through an stimulated release of neurotransmitters implicated in the arousal threshold

maintenance, hence shift the drive from the sleep-promoting to wake-promoting

system. The modulatory effects of WPAs on cortical activation pathways give rise to

enhanced vigilance. For example, cholinergic neurons of the basal forebrain and the

adenosine receptors on these neurons are agonized and antagonized by nicotine and

caffeine, respectively. Caffeine similarly antagonizes adenosine receptors on the

GABAergic neurons and intensifies the inhibitory drive in preoptic/anterior

hypothalamus which involve in sleep induction. Modafinil however exerts its wake-

promoting effects through stimulating the tuberomammillary nucleus and the

hypocretinergic neurons which activate the ascending reticular activating system.

Although many neurotransmitter systems such as dopamine are thought to be involved

upon the effects of WPAs, the empirical evidence to explain the exact mechanisms

need to gain strength.

*Corresponding author:

M. Torabi-Nami

Department of Neuroscience,

School of Advanced Medical

Sciences and Technologies,

Shiraz University of Medical

Sciences, Shiraz, Iran

torabinami@sums.ac.ir

Received: 10.03.2016

Revised: 26.03.2016

Accepted: 02.04.2016

Keywords:

Sleepiness; Wake-promoting

agents; Modafinil;

Stimulants Molecular

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129

Journal of Advanced Medical Sciences and Applied Technologies (JAMSAT). 2016; 2(1)

instances, the primary physicians do not track this

in patients (2, 3).

Clinically, when subjects obtain the score of 10

and more in a self-rated questionnaire known as

Epworth Sleepiness Scale (ESS), they will be

regarded as cases of EDS. On the other hand, the

Psychomotor Vigilance Task (PVT) or steer clear test

are utilized as objective assessments of sustained

vigilant attention in the practice of sleep medicine

in cases who present with the complaint of

excessive sleepiness. Some more comprehensive

sleep laboratory-based tests to confirm the

diagnosis of EDS include multiple-sleep latency test

(MSLT) and maintenance of wakefulness test

(MWT) (4-8).

When EDS is a chronic condition secondary to

continued sleep deprivation (intense shift work, for

instance) and especially when subjects are critical

job holders who need to deal with sensitive vehicles,

catastrophic accidents may occur. Whatever the

cause of EDS might be, drowsy driving is known to

result in many traffic road accidents and this has

lately turned to be among the foremost health

priorities in many countries (9-12).

EDS may result from numerous sleep-related

insufficiencies and long-lasting disorders including

obstructive or central sleep apnea/hypopnea

syndrome, circadian rhythm disorder and shift work,

chronic insomnia, parasomnias, restless-leg

syndrome, drug effects, narcolepsy, idiopathic

hypersomnia (with or without long sleep time) and

several related medical disorders. These conditions

not only potentially give rise to EDS but also affect

cardiovascular, neurological and psychiatric status

of the sufferers (13-15).

In general, EDS may present in various qualities.

For instance, narcolepsy and idiopathic

hypersomnia may both represent EDS, however

unlike narcolepsy which is characterized by sleep

attacks and propensity to fall sleep during the day,

idiopathic hypersomnia with long sleep time is

mainly described by sleep inertia or inability to

terminate sleep(16-18).

With regard to the prevalence of EDS, overall

standardized prevalence is shown to range from 10-

15% of general population in different studies.

However, EDS is more prevalent among older-age

strata with almost involving 35% of the subjects

over the age of 80 (19-27).

The management of EDS largely depends of

targeting and overcoming the underlying cause of

sleep inefficiency and related disorders. However, in

the event of unexplained EDS, wake-promoting

agents (WPAs) are prescribed and expected to

assist patient’s performance. Howbeit, these

agents have always had a true potential of abuse

(28).

WPAs such as amphetamine-like stimulants or

modafinil, armodafinil, methylphenidate, caffeine

and nicotine reinforce the level of vigilance through

an stimulated release of neurotransmitters

implicated in the arousal threshold maintenance,

hence shift the drive from the sleep-promoting to

wake-promoting system. The modulatory effects of

WPAs on cortical activation pathways give rise to

enhanced vigilance. For example, cholinergic

neurons of the basal forebrain and the adenosine

receptors on these neurons are agonized and

antagonized by nicotine and caffeine, respectively.

Caffeine similarly antagonizes adenosine receptors

on the GABAergic neurons and intensifies the

inhibitory drive in preoptic/anterior hypothalamus

which involve in sleep induction.

Modafinil however exerts its wake-promoting

effects through stimulating the tuberomammillary

nucleus and the hypocretinergic neurons which

activate the ascending reticular activating system.

Although many neurotransmitter systems such as

dopamine are thought to be involved upon the

effects of WPAs, the empirical evidence to explain

the exact mechanisms remain thin (28-35).

Understanding how wake-promoting drugs interact

with different components of the dopamine system

to induce arousal remains a challenge for future

research to establish new stimulant treatments

(31).

This paper provides an overview on different drugs

used as WPAs.

Wake Promoting Agents (WPAs)

Problems of ‘wakefulness’, including states of

impaired alertness, vigilance and attention affect

millions of individuals (36). Several drugs belong to

different chemical classes are used as wake-

promoting medications. Direct-acting

sympathomimetics (e.g. phenylephrine), indirect-

acting sympathomimetics (e.g., methylphenidate,

amphetamine), and non-sympathomimetic

stimulants (e.g. caffeine, modafinil and armodafinil)

are pharmacologic interventions to treat excessive

sleepiness. Hypothalamic neuropeptide (hypocretin

or orexin) are recently reported to have an important

role in the regulation of sleep and arousal states

(37, 38).

Some well-known untoward effects of psycho-

stimulants including increased feelings of anxiety

and agitation, erectile dysfunction, insomnia,

decreased libido, and in some cases, mania are

reported. Below, the main drugs used as wake

promoting agents are reviewed.

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Journal of Advanced Medical Sciences and Applied Technologies (JAMSAT). 2016; 2(1)

Modafinil

Modafinil, holds the chemical name, molecular

formula and the molecular weight 2-

[(diphenylmethyl) sulfinyl] acetamide,

C15H15NO2S and 273.35 g/mol, respectively. It is

a white to off-white, crystalline powder, practically

insoluble in water and cyclohexane while sparingly

to slightly soluble in methanol and acetone.

Modafinil is shown to improve the activity of wake-

promoting neurons through increasing dopamine

extracellular concentration partly through the

blockade of dopamine transporters (39-41). While

many studies have predetermined its possible

action on dopamine, adrenalin, noradrenalin,

serotonin and GABA systems, the precise

mechanism of action of modafinil has remained

unclear (41, 42). Although the dopaminergic and

norepinephrinergic systems appear to be crucial

targets for modafinil action, they seem not to be

exclusive and modafinil’s mechanism of action is

found to be far more complex. According to earlier

reports, modafinil directly or indirectly modulates

several neurotransmitters other than

catecholamine such as histamine and orexin (43).

As reported in a double-blind placebo-controlled

trials, 200–400 mg per day modafinil significantly

reduced sleepiness, hence the medication is

recommended as a first-line therapy for sleepiness

(44, 45).

Modafinil with an elimination half-life of 13.8

hours is a long-acting compound. Its maximum

concentration is achieved in 2–4 hours after intake.

Generally, response to modafinil depends on the

catechol-O-methyltransferase genotype (46). The

drug is initially prescribed at 100 mg twice daily for

1–2 weeks and then increased to 200 mg twice

daily. Most common adverse events are mild and

comprise headache (13%), nervousness (8%) and

nausea (5%), with no evidence of tolerance and low

potential for abuse. Modafinil can raise hepatic

cytochrome P450 enzyme concentrations and

increase the metabolism of different drugs such as

oral contraceptives (47, 48).

A systematic review and meta-analysis of the

efficacy of modafinil in narcolepsy has proposed

significant benefits of modafinil for the treatment of

EDS as assessed by ESS (ESS declined by 2.73

points), multiple sleep latency test (MSLT prolonged

by 1.11 min) and MWT(MWT increased by 2.82 min)

(48, 49). Modafinil appears to lack the similar

addiction potential of other dopamine transporter

(DAT) inhibitors, such as amphetamine,

methylphenidate and cocaine. Modafinil is also

shown to reduce the excessive sleepiness observed

in patients with shift work disorder (SWD) and

results in a notably improved performance. Shift

workers with EDS underwent treatment with 200

mg of modafinil or placebo before the start of each

shift with their symptoms studied for 3 months (50).

Although modafinil reduced lapses of attention in

tests, it resulted in no loss in daytime sleepiness as

compared to placebo (51).

A review of several aspects of modafinil, focusing

on its use for ES in patients with SWD, narcolepsy

and residual sleepiness in the syndrome of

obstructive sleep apnea is published by Schwartz

(51). Generally with modafinil treatment, there was

an objective reduction in sleepiness and

improvement in general clinical conditions related

to the severity of sleepiness. The improvement in

wakefulness was associated with an improvement

in both behavioral alertness and functional status

as well as in health and quality of life. In patients

with SWD, there were decreases in the maximum

level of sleepiness during night work, in the level of

sleepiness during the travel to home and in the

incidence of accidents. Modafinil as a drug was well-

tolerated with no impairment in sleep or

cardiovascular parameters. Long-term studies

suggest that the efficacy is maintained with little

likelihood of tolerance and there were no adverse

effects on scheduled sleep, demonstrating the

beneficial effect of modafinil on daily-life and well-

being (51).

Armodafinil

The R-enantiomer of modafinil known as

armodafinil, has recently been approved to treat

excessive sleepiness associated with OSA, SWD,

and narcolepsy. Armodafinil has a longer half-life

and is approved for the treatment of ES associated

with SWD in some countries. Armodafinil has been

shown to improve alertness and performance (52).

Armodafinil is used similarly in the treatment of

EDS associated with the narcoleptic syndrome,

obstructive sleep apnea, and shift-work sleep

disorder. Plasma concentration following

armodafinil administration lasts longer than that

following modafinil administration, resulting in a

more prolonged effect during the day and potential

improvement in sleepiness in the late afternoon in

patients with narcolepsy. A single dose of 150 or

250 mg armodafinil is given orally in the morning for

treatment of the narcoleptic syndrome or

obstructive sleep apnea and a single dose (150 mg)

is prescribed 1 hour before starting work for the

management of shift-work sleep disorder. Reduced

doses are recommended in the elderly and in

patients with severe hepatic impairment (52, 53).

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Journal of Advanced Medical Sciences and Applied Technologies (JAMSAT). 2016; 2(1)

Amphetamines

Stimulants include naturally occurring substances

such as cocaine and caffeine or synthetic drugs for

example amphetamine and dexamphetamine,

methamphetamine, pemoline, bupropion,

ephedrine/pseudoephedrine and methylphenidate

broadly acting as both dopaminergic and

noradrenergic reuptake inhibitors at varying

degrees (54).

Amphetamines including L-amphetamine, D-

amphetamine and methamphetamine were coined

from amphetamine that was initially synthesized as

1-methyl-2-phenethylamine and initially used to

treat narcolepsy (55, 56).

Amphetamine was initially synthesized in Berlin in

1887 as 1-methyl-2-phenethylamine (55).

Amphetamines have been used for narcolepsy

since the 1930s (53). At low doses, the main effect

of amphetamine is to release dopamine and to a

lesser degree, norepinephrine through reverse

efflux via monoamine, dopamine and

norepinephrine transporters. At higher doses,

monoaminergic depletion and inhibition of reuptake

occurs. Similar to modafinil, amphetamines are

racemic compounds with their D-isomers more

potent on dopamine transmission than L-isomers

and subsequently have a greater stimulating effect

(57).

The methylated form of amphetamine named

methamphetamine exerts a potent wake-promoting

effect because it more efficiently crosses the blood

brain barrier.

Beside the effectiveness of amphetamines in

reducing sleepiness, they showed adverse effects

including disturbances of mood and behavior in

addition to cardiac and gastrointestinal effects. The

most common drug related effects are loss of

appetite, insomnia, emotional labiality,

nervousness, fever, irritability and impulsivity and at

worst, psychotic reactions. On the other hand,

insomnia, hypertension and abnormal movements

can also occur at large doses (60 mg/day and

beyond) (53, 55).

Amphetamine is effective at the dose of 10- 60

mg/day. The therapeutic effects begin within

45−60 min after ingestion of an immediate-release

tablet, with peak effect in 2 to 3 hours, and a total

duration of 4−6 h. Effects peak about 4−7 h after

ingestion of extended-release doses, and last about

12 h, depending on the dose (57).

Methylphenidate

Methylphenidate, another N-methyl derivative of

amphetamine, with a shorter half-life, milder side

effects, and low abuse potential has been used

since 1970 instead of amphetamine (58). It is a

potent stimulant that primarily acts by blocking of

the reuptake of monoamines (mainly dopamine)

and, unlike amphetamines, does not inhibit the

vesicular monoamine transporter. It improves

daytime sleepiness in patients with narcolepsy at

daily doses of 10–60 mg, going up to 100 mg daily

at most for severe cases (59).

The effect of methylphenidate is thought be

similar to effect of amphetamines. However, there

is an argue for a slight superiority of amphetamines.

Adverse effects of methylphenidate are similar to

amphetamines adverse effect, but to a lesser

degree. Methylphenidate probably has a better

therapeutic index than D-amphetamine and showed

less reduction of appetite or increase in blood

pressure. Methylphenidate with relatively short

duration of action (3–4 h) supposed to be useful in

cases that needs to maximum alertness or at a

specific time of day (59, 60).

Gamma hydroxybutyrate

Gamma-hydroxybutyrate (GHB) (sodium

oxybate®) is a short-chain fatty acid derivative of

gamma-aminobutyric acid (GABA). This compound

readily crosses the blood-brain barrier to enter the

central nervous system (57, 61). It is a GABAB

receptor agonist at a pharmacological doseand

leaves a positive effect on EDS. Gamma-

hydroxybutyrate, is approved by the EMA for the

treatment of narcolepsy and by the US FDA for the

treatment of cataplexy and EDS in patients with

narcolepsy (58, 59). The frequency of inadvertent

daytime naps and night-time awakenings reduced

with GABA (58). However, common side effects of

gamma aminobutyrate are dizziness, headache,

nausea, pain, somnolence, sleep disorder,

confusion, infection, vomiting, and enuresis

(58).The major problem with GHB is its non-medical

use. GHB is misused in athletes for its metabolic

effects (growth hormone-releasing effects).

However, post marketing follow-up studies indicate

that abuse potential in patients with narcolepsy

receiving sodium oxybate is low (59, 61). Overall,

gamma hydroxybutyrate is effective, and

recommended for treatment of cataplexy, EDS, and

disrupted sleep due to narcolepsy (58).

Orexin (Hypocretin)

The neuropeptides orexin produced in

hypothalamic neurons also known as hypocretin. In

this system two neuropeptide was recognized orexin

A and orexin B. Recently, the critical role of orexin

system in regulation of arousal and maintenance of

wakefulness as well as other behavioral traits such

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Journal of Advanced Medical Sciences and Applied Technologies (JAMSAT). 2016; 2(1)

as feeding and reward processes have been proven

in several studies.

On the other hand, orexin deficiency is seen in

narcolepsy in humans, suggesting that the orexin

system is particularly important for maintenance of

wakefulness.

Orexin stimulates waking active monoaminergic

and cholinergic neurons in the hypothalamus and

brainstem regions to maintain a long, consolidated

waking period. Also orexin system effects complex

interactions between monoaminergic/cholinergic

wake–promoting and GABAergic sleep–promoting

neuronal systems.

Research for the orexin agonist and antagonist for

the treatment of sleep disorders has forcefully

increased over the past decades. As a result, this

system may be a potentially important therapeutic

target for the treatment of sleep disorders, and

orexin replacement therapy would probably be an

alternative promising strategy for both sleepiness

and cataplexy (62-64).

Since a drug should be delivered to the site of

action to show its effect, orexin with peptide

structure encounter blood brain barriers as an

obstacle. It is the main reason for defeat in

peripherally and systemically administration

approach. Intra-cerebro-ventricular route for orexin

administration is possibly the most effective, but

unsuitable for the treatment of patients. Other

noninvasive method such as intranasal delivery that

targets drugs to the brain along olfactory and

trigeminal neural pathways, bypassing the BBB and

minimizing systemic exposure and side effects (62).

Orexin-producing cell transplantation might

theoretically provide a cure for patients with

narcolepsy. Recent improvements in stem cell

technology open a new insight to overcome the

problems of cell therapy approach such as graft

rejection, low survival rate of implant and lack of

supply for graft availability (57).

Thyrotropin-releasing hormone

Thyrotropin-releasing hormone (TRH) and its

agonists have alerting properties and could help in

improving the waking system. TRH at high doses

and TRH agonists increase alertness and have been

showed to be wake-promoting and anti-cataplectic

in the canine narcoleptic model.

However, older clinical trials, mainly on

depression, reported little efficacy on mood and on

alerting effects (57,59).

Caffeine/paraxanthine

Caffeine is a widely an earliest used stimulant

and often used in the treatment against daytime

sleepiness and narcolepsy (59). Caffeine as a

natural alkaloid, rapidly absorbed through the

gastrointestinal tract. It is primarily metabolized in

the liver, by demethylation, to 1,7-dimethylxanthine

via cytochrome P-450 1A2. The variable effect of

caffeine within a population may be explained by

differing cytochrome P450 activities between

individuals (56). Because of low potency of wake-

promoting effect of caffeine high dose is need to

reach the best effect, where cardiovascular side

effect is the bottleneck (58, 59). However, caffeine

is known as an adenosine A1 and A2a receptor

antagonist. Zhi-Li et al used knockout mouse to

show that caffeine-related increase in wakefulness

depends on adenosine A2a receptors (65).

Paraxanthine, is a metabolite of caffeine with

greater stimulant properties and longer-lasting

wake promoting potency, lower toxicity and lesser

anxiogenic effects (56, 59).

Pitolisant

Pitolisant is a histamine H3 inverse agonist which

has passed phase-III clinical trials for the treatment

of EDS and narcolepsy. Histamine H3 receptors

reduce the synthesis and release of histamine (66).

In a double-blind randomized trial, Dauvilliers et al.

showed that pitolisant at doses up to 40 mg was

efficacious on EDS compared with placebo and well-

tolerated compared with modafinil. They suggested

that pitolisant could offer a new treatment option for

patients with narcolepsy and EDS (67).

Other wake-promoting drugs

Mazindol, an imidazole derivative, has similar

pharmacological effects to the amphetamines.

However, it is a weak releasing agent for dopamine,

it also blocks dopamine and adrenaline reuptake

with high affinity and holds some efficacy on

sleepiness. Adverse events are frequent, including

weight-loss, dry mouth, nervousness, constipation

and, less frequently, nausea, vomiting, headache,

dizziness and tachycardia. A careful cardiology

follow-up is recommended. Mazindol has less

potential for abuse and tolerance than

amphetamines (57).

The challenges of studying

wakefulness at molecular level

Studying arousal has been facing several

challenges including involvement of various neural

circuits and neurotransmitter systems. Sometimes

arousal-inducing drugs may not be specific for a

particular target resulting in other effects.

Additionally, target proteins might be distributed

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Journal of Advanced Medical Sciences and Applied Technologies (JAMSAT). 2016; 2(1)

throughout the brain raising the question “whether

all the targets required for the drug effect to be

observed?” Understanding the wakefulness and

sleep phenomena at molecular level in eukaryotes

such as zebra fish, fruit fly, and mouse can solve at

least some of the issues raised. Conservation of

sleep genetics and pharmacology, simplicity of the

organism and the control which can be posed over

the interfering factors has provided the opportunity

to decipher molecular events occurring during

wakefulness and sleep. This particularly has

advanced as a result of development of molecular

biology tools such as conditional knockout

technology, virus-mediated gene transfer and RNAi

technology using the model organisms (66).

Pharmacogenetics of sleep-wake

therapeutics

Over years, sleep medicine has been witnessing a

great deal of advancement in therapeutics

discovered against EDS disorder. Modafinil as a

novel non-amphetamine wake-promoting drug

replaced benzodiazepines which themselves have

been initiated subsequent to the emergence of

barbiturates (molecular genetic advances). Here,

we discuss the molecular mechanisms of action of

the wake promoting therapeutics used against EDS.

The focus will be on modafinil, metamphetamine

and orexin (68, 69).

Modafinil

The precise mechanism of action of modafinil

remains to be established. However several lines of

evidence provide clues on how it may act. Modafinil

has been reported to increase HA, NE, 5-HE, and DA

levels in the brain, though some of these effects

might be indirect. At least parts of the modafinil

effect might be exerted through DAT and NET.

Additionally, although orexin similar to modafinil

has the wake-promoting effect, modafinil does not

act through orexin and its receptors. Modafinil

increases fos expression and HAergic tone in TMN,

but this effect was not observed when the drug was

administered directly into TMN. Modafinil also

affects the glutamate level and this appears to be

dependent on the brain region. However its effect

on the GABA level is more consistent with no effect

in the thalamus and hippocampus and a reduction

in the cortex, medial preoptic area of the

hypothalamus, posterior hypothalamus, nucleus

accumbens, pallidum, and striatum. This effect

presumably is mediated by serotonin (70).

Modafinil has neuroprotective (antioxidant)

effects as well, but this might not be totally

irrelevant to its wake-promoting effect. The target of

antioxidant activity of modafinil is still not clear, but

it may be the enzymes responsible for free-radical

scavenging system. Since mitochondrion is the

main source of the generation of free radicals, it is

also possible that modafinil acts on the enzymes in

this organ such as cytochrome c which affects the

levels of free radicals and ATP. Similarly, modafinil

may reduce the activity of the inhibitory K-ATP

channels the suppress neurotransmitter release

with the end result of increased neurotransmitter

release. Furthermore modafinil may suppress other

enzymes such as cytochrome p450 which has been

shown to be a source of reactive oxygen species in

coronary artery ischemia and reperfusion injury.

CYP2C a member of C p450 family may also be

involved in the metabolism of arachidonic acid in

the brain and altering the effect of

neurotransmitters. Therefore the inhibitory effect of

modafinil might be exerted through this pathway.

Modafinil may suppress CYP2C either directly or

through the release of serotonin and epinephrine

(40, 42, 71-75).

At least parts of the effects of free radicals might

be exerted through an increase in extracellular level

of adenosine; a sleep promoting factor throughout

the brain. Although the antioxidant effect of

modafinil might be scattered throughout the brain,

since adenosine exert its sleep-inducing effect in

the basal forebrain, this region might be mainly

influenced by modafinil (40, 42, 71).

An alternative target of modafinil might be a

receptor or an intracellular protein. One such

candidate is sodium or calcium channels as

changes in sodium homeostasis and calcium influx

can affect neurotransmitter release. However this

does not explain its neuroprotective effects.

Accumulating evidence suggest that

neurodegeneration and sleep may have a common

or related mechanisms, thus there may be a single

site of action for these phenomena. Sine

mitochondria, oxidative stress and calcium

homeostasis have also been implicated in the

pathogenesis of a number of neurodegenerative

diseases, it seems plausible that mitochondria is

the main culprit both for neurodegeneration and

sleep-inducing factors (76-83).

Metamphetamines (MAs)

The vesicular monoamine transporter-2 (VMAT-2)

and the plasmalemmal dopamine transporter (DAT)

are the two main substrates of amphetamine on

dopamine neuronal terminals. MAs are substrates

of the Na+/Cl- dependent dopamine transporters.

"Exchange diffusion model" predicts that

metamphetamines compete with extracellular

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Journal of Advanced Medical Sciences and Applied Technologies (JAMSAT). 2016; 2(1)

synaptic dopamine on the DAT. Binding of

extracellular MA to the DAT leads to the cytosolic

dopamine to be reverse transported to the outside

the cell. At higher concentrations, amphetamines

can diffuse directly through the plasmalemmal

membrane. According to this model, the DAT activity

is regulated by cell signaling mechanisms such as

calmodulin-dependent protein kinase-II and

phosphotydyl inositol 3-kinase. Through another

mechanism, DAT can assume a channel-like

conformation, enabling brief release of dopamine

as well. Furthermore MAs in-vitro can promote

internalization of DAT through endocytosis which

ablates the DAT capacity to decrease synaptic levels

of dopamine(84). The VMAT-2, a membrane protein,

transports monoamines from the cytosol into

synaptic vesicles. This activity is coupled to a

vacuolar type H+-pumping ATPase. Amphetamines

at concentrations higher than 100 µM can disrupt

the proton gradient between inside and outside of

the vesicle leading to the monoamine leak into the

cytosol. Additionally, multiple high doses of AMs

(40mg/kg) lead to the redistribution of VMAT-2 to an

unknown cellular location in a rat model. On the

other hand, AMs at physiological concentrations

bind to VMAT-2 and inhibit monoamine uptake in

vesicles with the end result of increased cytosolic

and synaptic monoamine concentration. MAs also

influence DAT uptake through other proteins such

as trace amine-associated receptor-1 (TAAR1). This

is a G-protein coupled receptor for trace amines.

Activated TAAR1 decreases DAT dopamine uptake,

increases dopamine efflux, and promotes DAT

endocytosis. MA is an agonist of TAAR1. Another

mechanism of action of MAs is the inhibition of

monoamine; an enzyme on the outer membrane of

mitochondria with a role in amine catabolism in

presynaptic terminals (85, 86).

Orexin

Orexin has two G-protein coupled receptors, OX1R

and OX2R. Distinct G protein may contribute to

different physiological roles of orexin in certain

neurons. Both voltage-dependent calcium channels

and G-protein-gated inwardly-rectifier potassium

channels (GIRKs) can be modulated by G-protein-

coupled neurotransmitter receptors; however the

receptors might be selectively coupled to one or

more of the channels in neurons. Studies suggest

that OX1R couples exclusively to PTX-insensitive G

proteins, and OX2R couples to both PTX-sensitive

and insensitive proteins. Several lines of evidence

suggest that OX1R and OX2R signaling not only

activate neurons but also may have other roles in

the tips of developing neuritis and on presynaptic

terminals. These functions eventually lead to growth

cone collapse and increased release of

neurotransmitters. Orexin in addition can cell-

dependently increase or decrease cAMP which

might be the result of coupling the receptor with

different G-proteins. The latter might be influenced

by the receptor density. Furthermore, orexin

receptors can interact with other signaling receptors

such as cannabinoid receptors which is reported to

cause an enhancement of the orexin-A capability to

activate the mitogen-activated protein kinase

pathway. Therefore, such observations indicate that

orexin signaling events might be more complex than

initially thought (87-89).

Future directions in molecular

research

Various eukaryotic model systems can be used to

investigate the molecular mechanism of wake-

promoting drugs. For example modafinil can

promote wakefulness in fruit fly. The simplicity of

this model compared with higher eukaryotes allows

identification of the principle genes, proteins and

pathways involved in wakefulness regulation

(molecular genetics advances). Approaches such as

Large-scale random mutagenesis can be applied

to identify some of the genes involved.

Yeast is the simplest eukaryote which can exist

either haploid or diploid. This facilitates the study of

the role of genes in cellular processes. Yeast can be

grown with or without functional mitochondria and

therefore may provide an ideal model to study the

effect of modafil on mitochondria function and

oxidative stress. Yeast can also be beneficial to

study the mechanism of inhibition of monoamine

oxidase by MAs as this enzyme can be expressed in

yeast and its function can be studied in the

presence of MAs.

Moreover, several proteins involved in

waking/sleep states can be expressed in yeast.

Some of which may then create a particular

phenotype in yeast such as growth defect that can

be overcome by complementation studies with a

certain mammalian protein. This may provide the

proteins associated with each other in the

wake/sleep states and thereby provide evidence to

understand the signaling pathways. The results

obtained with the yeast model system can then be

established in higher eukaryotes such as fruit-fly

and zebrafish. Identifying the neurons responsible

for drug's effect in fruit fly can pave the way to

investigate the effect of other internal and external

regulatory systems such as food, light, motivational

states, homeostatic processes, circadian rhythms,

and memory formation.

135

Journal of Advanced Medical Sciences and Applied Technologies (JAMSAT). 2016; 2(1)

Table 1. An overview of the key features of the mostly-studied wake-promoting agents.

Zebrafish is particularly-useful model for studying

the effect of small molecule on wake/sleep states.

This approach in combination with the gene

expression profiling can identify the drug-activated

neurons. Subsequently, gene ablation methods can

determine whether the gene is essential for drug-

induced effect.

Additionally, viral-mediated focal replacement of

certain genes in this model can provide valuable

information for deciphering the wake/sleep

circuitry. Since there is significant homology

between zebrafish and mammalian brain structure,

observations made in this model can have

correspondence in mammals.

Conditional knockout technology in which viruses

injected in the brain of adult mice provides both

temporal and spatial control of wake/sleep gene

function. Moreover siRNA-mediated mRNA

knockdown has facilitated investigating the function

of certain proteins and receptors.

136

Journal of Advanced Medical Sciences and Applied Technologies (JAMSAT). 2016; 2(1)

Another approach is comparing the

transcriptome/proteom profile of the wakefulness

with the sleep state. This has already resulted in the

identification of several genes associated with

either wakefulness or sleep state. Genes such as

those responsible for expressing cytokines, TNFR1,

TNFR2, TNF-α, and lymophotaxin which regulate the

wake/sleep state can also be studied using

mutagenesis as well as polymorphism and

association with known wake/sleep genes.

Optogenetic inhibition or activation of the desired

genes permits identification of drug targets without

altering the function of a certain gene for good.

However studying wake/sleep states through "locus

by locus" approach might be hindered by the

redundancy of the circuitry involved (87-89).

Conclusion

The present review was an attempt to provide an

overview on wake-promoting therapeutics within

the basic-clinical spectrum. The use of wake-

promoting agents in the event of EDS need to be

carefully assessed since it may masquerade the

underlying sleep-related disorder. Novel

therapeutics in this vein are being developed

through targeting new molecular targets. Given the

health-related and societal consequences of EDS,

basic, translational and clinical research to unravel

its various dimensions should gain impetus.

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14. Rose D, Gelaye B, Sanchez S, Castaneda B, Sanchez E, Yanez

ND, et al. Morningness/eveningness chronotype, poor sleep quality, and

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Peruvian college students. Psychology, health & medicine.

2015;20(3):345-52.

15. Haregu A, Gelaye B, Pensuksan WC, Lohsoonthorn V,

Lertmaharit S, Rattananupong T, et al. Circadian rhythm characteristics,

poor sleep quality, daytime sleepiness and common psychiatric disorders

among Thai college students. Asia-Pacific psychiatry : official journal of the

Pacific Rim College of Psychiatrists. 2015;7(2):182-9.

16. Suzuki K, Miyamoto M, Miyamoto T, Inoue Y, Matsui K,

Nishida S, et al. The Prevalence and Characteristics of Primary Headache

and Dream-Enacting Behaviour in Japanese Patients with Narcolepsy or

Idiopathic Hypersomnia: A Multi-Centre Cross-Sectional Study. PloS one.

2015;10(9):e0139229.

17. Pereira D, Lopes E, da Silva Behrens NS, de Almeida Fonseca

H, Sguillar DA, de Araujo Lima TF, et al. Prevalence of periodical leg

movements in patients with narcolepsy in an outpatient facility in Sao

Paulo. Sleep Science. 2014;7(1):69-71.

18. Heier MS, Evsiukova T, Wilson J, Abdelnoor M, Hublin C, Ervik

S. Prevalence of narcolepsy with cataplexy in Norway. Acta neurologica

Scandinavica. 2009;120(4):276-80.

19. Bjorvatn B, Lehmann S, Gulati S, Aurlien H, Pallesen S, Saxvig

IW. Prevalence of excessive sleepiness is higher whereas insomnia is

lower with greater severity of obstructive sleep apnea. Sleep & breathing

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20. Signal TL, Paine SJ, Sweeney B, Priston M, Muller D, Smith A,

et al. Prevalence of abnormal sleep duration and excessive daytime

sleepiness in pregnancy and the role of socio-demographic factors:

comparing pregnant women with women in the general population. Sleep

medicine. 2014;15(12):1477-83.

21. Liviya Ng W, Freak-Poli R, Peeters A. The prevalence and

characteristics associated with excessive daytime sleepiness among

Australian workers. Journal of occupational and environmental medicine /

American College of Occupational and Environmental Medicine.

2014;56(9):935-45.

22. Bjorvatn B, Pallesen S, Gronli J, Sivertsen B, Lehmann S.

Prevalence and correlates of insomnia and excessive sleepiness in adults

138