*2.4.1 Parkinson's disease*

*Weight Management*

addiction.

risk of smoking relapse.

*2.3.4 Orexin and sleep disorders*

amygdala, and medial prefrontal cortex (mPFC). Drug abuse leads to augmentation of dopaminergic activity in NA through activation of orexinergic neurons at mesocorticolimbic pathway [49]. Correspondingly, experimental studies illustrated that OX1R and OX2R are highly expressed in the NA leading to inhibitory effect instead of excitatory effects seen on the VTA, amygdala, and mPFC. Therefore, a

Acute administration of addicting drugs such as methamphetamine, nicotine, and amphetamine leads to activation of orexinergic neurons at the lateral hypothalamus. However, acute administration of cocaine and morphine does not affect orexinergic neurons. Besides, chronic administration of addict drugs causes activation of orexinergic neurons mainly at OX2R receptors, but chronic increasing dose of addict drugs leads to downregulation of orexinergic receptors [51]. Carr and Kalivas reported that orexin is an important mediator which enables cocaine to induce addiction-like behavior in rats due to dopaminergic neuronal changes [52]. Also, James et al. verified that orexinergic neurons at the lateral hypothalamus play a vital role in expression of addiction-like phenotype [53]. Thus, the orexinergic system is regarded as an important novel target for drug therapies to treat

Orexin serum level in chronic smoker subjects is related to craving in the phase of abstinence since it increased during addiction phase and reduced during withdrawal phase. This reduction leads to increase in craving and risk of relapse [54]. Therefore, orexin serum level is regarded as a potential biomarker predicts time and

Furthermore, Tsai and Huang reported that the orexin serum level is increased in heroin addicts who shifted to methadone maintenance therapy compared with controls suggesting that methadone increases orexin serum levels [55]. Similarly, orexin serum level is increased in chronic alcoholism, which is positively correlated with the severity of alcohol withdrawal. Alleviation of alcohol withdrawal syndrome is linked with reduction of the orexin serum level, which monitors the status

Narcolepsy is a sleep disorder that causes excessive daytime sleepiness or an intractable urge to sleep in, in which duration of rapid eye movement sleep (REM) is reduced. Cataplexy is a sudden reduction in muscle tones with preserved consciousness. Narcolepsy is commonly associated with cataplexy, which is triggered by emotional stimuli [57]. Methylphenidate, modafinil, and other psychostimulants are effective in the management of these sleep disorders [58]. Dysregulation of NREM sleep leads to narcolepsy only, whereas dysregulation of REM sleep leads to combined narcolepsy with cataplexy [59]. It has been reported that orexin increases vigilance through increasing awaking time and decreasing REM and NREM sleep periods. Both OX1R and OX2R are involved in the maintenance of arousal state directly or indirectly through the activation of monoaminergic neurons (noradrenalin, dopamine, histamine, and serotonin). Also, orexin activates cholinergic neurons in the basal forebrain, which is also important for arousal statues [60]. Yamanaka et al. study illustrated that activation of OX2R by orexin leads to wakefulness which is mediated by a histamine neurotransmitter since antihistamine blocks the excitatory effect of orexin, while activation of OX1R by orexin leads to wakefulness, through noradrenalin neurotransmitter [61]. Reduction of orexin level in the cerebrospinal fluid was documented in patients with narcolepsy and nowadays is regarded as one of the diagnostic criteria in the diagnosis of narcolepsy.

differential effect of orexin is receptor type dependent [50].

of alcoholic patients during the abstinence period [56].

**52**

Orexinergic neurons are severely affected in Parkinson's disease (PD); previously Fronczek et al. confirmed that orexinergic neuron density was reduced in the prefrontal cortex by 40% with significant reduction in CSF orexin levels in PD patients compared to the healthy control [63].

Furthermore, animal model study illustrated that 15% damage to the orexinergic neurons did not affect CSF orexin, while damage more than 70% leads to 50% decline in the CSF orexin [64]. These findings may explain the association of narcolepsy with PD since both dopamine and orexin interplay in the regulation of sleep pattern through activation of midbrain and thalamocortical pathway [65]. Feng et al. illustrated that in PD, there is a deficiency in hypoxia inducible factor 1 alpha (HIF1-α) due to mitochondrial dysfunction and the administration of orexin-A leads to significant neuroprotective effect on the dopaminergic neurons through the activation of HIF-α [66].

Moreover, orexin-A improves dopaminergic neurons in PD through the reduction of tyrosine hydroxylase (TH) and activation of brain-derived neurotrophic factor (BDNF) in the substantia nigra [43]. Therefore, orexin antagonist may increase risk of PD due to reduction of the neuroprotective and stimulating effects on the dopaminergic neurons at substantia nigra [67]. Sheng et al. found that orexin plays important roles in activation of the subthalamic nucleus which may give a new evidence for the participation of the subthalamic orexinergic system in PD. Importantly, orexin-A increased the protein level of brain-derived neurotrophic factor in dopaminergic neurons of the substantia nigra. The upregulation of BDNF is mainly via OX1R [68]. Long-term therapy with ropinirole in PD leads to significant reduction in the orexin activity which might explain the adverse effect of ropinirole-induced sleep disorder through inhibition of glutamatergic excitatory effect on the orexinergic neurons. Therefore, pharmacotherapy of PD should be re-evaluated in this context [69].


#### **Table 3.**

*Orexin and psychiatric disorders.*

#### *2.4.2 Alzheimer's disease*

Alzheimer's disease (AD) is a neurodegenerative disease affecting different brain areas characterized by cognitive deficit and progressive memory loss [70]. AD also affects hypothalamic orexinergic neurons leading to excessive daytime sleepiness, which is correlated with low orexin CSF levels, as reduction 40% of the brain cell number is linked with a 14% reduction in orexin CSF levels [71]. Normally, orexin regulates cholinergic and monoaminergic neuron firing during sleep and wakefulness. In AD a reduction in the cholinergic pathway leads to disturbance in sleep patterns leading to daytime sleepiness and insomnia at night which are a hallmark of sleep rhythm in AD [72]. Besides, reduction of cholinergic activity causes overactivity of orexinergic neurons, which causes abnormal sleep and cognitive functions. These changes lead to an elevation of the orexin CSF level, which is linked with reduced REM sleep [73].

Dementia with Lewy bodies is characterized by an elevation in α-synuclein level, which is accumulated in orexin-containing neurons at the hypothalamus causing interference in orexin axonal transport. This effect leads to a reduction in the activity of the orexinergic system in dementia with Lewy bodies but not in AD [74]. Therefore, there are complexities in the orexinergic system according to the clinical presentation and sleep pattern in patients with AD.

#### *2.4.3 Huntington's disease*

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by personality changes, motor disturbances, cognitive decline, and weight loss [75]. HD is caused by a defect in the gene encoding huntingtin, a protein with unclear function, which is essential for cell survival during development and in adult life [76]. In HD there is neurodegeneration involving the neostriatum and cerebral cortex, with the manifestation of intraneuronal aggregates of misfolded huntingtin. Moreover, in patients with end-stage HD, there is about 90% of neuronal loss in the tuber nucleus of the lateral hypothalamus**.** Orexin-A and orexin-B are synthesized from the same precursor gene and are expressed in the same neurons with their cell bodies concentrated to the lateral hypothalamus [77]. Preclinical and clinical studies observed that orexin serum and CSF levels are decreased by 72% in HD. In healthy subjects, orexin CSF level is >200pg/ml, but in HD and narcolepsy, this level is decreased below 110 pg/ml, due to degeneration of orexinergic neurons in the lateral hypothalamus. Therefore, CSF orexin level is regarded as a biomarker to evaluate the disease progression and usefulness of therapeutic intervention in patients with HD [78, 79]. However, Meier et al. illustrated that CSF and serum orexin levels are of no diagnostic value in prediction and follow-up of HD [80].

Recently, Cabanas et al. observed that orexin in HD has aberrant effects leading to abnormal sleep pattern, and thus orexin antagonist suvorexant may be of great value in restoring normal sleep and behavioral disturbance in HD [81] in addition, these neurons remain functional and illustrate paradoxical effect, it become more modifiable and affect by serotonine and noradrenaline, and less sensitive to the effect of suprachiasmatic nucleus (the master clock of the brain) causing abnormal biological circadian rhythm [81, 82].

Therefore, orexin level in HD is reduced, but the remaining functional orexinergic neurons lead to abnormal circadian biological rhythm causing behavioral, motor, and sleep disturbances.

**55**

*Orexin and Psychoneurobiology: A Hidden Treasure DOI: http://dx.doi.org/10.5772/intechopen.91852*

the advancement of the disease [83, 84].

system by a person's own immune system [85].

tion of the severity of MS.

*2.4.5 Amyotrophic lateral sclerosis*

orexin levels, in clinical and preclinical studies in ALS.

Multiple sclerosis (MS) is a demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Specific symptoms can include double vision, blindness in one eye, muscle weakness, and trouble with sensation or coordination. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). Between attacks, symptoms may disappear completely; however, permanent neurological problems often remain, especially with

The three main characteristics of MS are the formation of lesions in the central nervous system, inflammation, and the destruction of myelin sheaths of neurons. These features interact in a complex and not yet fully understood manner to produce the breakdown of nerve tissue and in turn the signs and symptoms of the disease. Cholesterol crystals are believed to both impair myelin repair and aggravate inflammation. MS is believed to be an immune-mediated disorder that develops from an interaction of the individual's genetics and as yet unidentified environmental causes. Damage is believed to be caused, at least in part, by attack on the nervous

Considering the multiplicity of symptoms associated with multiple sclerosis (MS), there is possibility that hypocretin system function might be involved in the pathogenesis of the disease. Papuc et al. showed that high orexin CSF level in patients with MS as compared with healthy controls, but it positively correlated with fatigue level, suggesting a compensatory mechanism for the production of orexin in MS [86]. On the other hand, Nozaki et al. illustrated that orexin CSF level is reduced and correlated with symmetrical hypothalamic lesion and spinal cord damage in MS. Therefore, low orexin level was implicated in the pathogenesis of hypersomnia and cognitive deficit in patients with MS [87]. Recently, Pallais et al. confirmed that orexin has a neuroprotective effect in MS through inhibition of inflammatory and proinflammatory mediators mainly matrixmetaloproteinases (MMP-3, MMP-9) which are involved in damage of neuronal matrix proteins. Consequently, low CSF orexin level indicates underlying active disease [88].

Therefore, CSF orexin level is a valuable biomarker in the diagnosis and predic-

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a disease that leads the death of neurons controlling voluntary muscles. The underlying mechanism involves damage to both upper and lower motor neurons. ALS is characterized by stiff muscles, muscle twitching, and muscle weakness is still unknown. The cause of ALS is not known in 90% of cases but is believed to involve both genetic and environmental factors. The remaining 10% of cases is inherited [89]. Previously, Van Rooij et al. illustrated that CSF orexin level was normal in patients with ALS and not correlated with age and gender. However, a disturbance in the orexinergic system is involved in the pathogenesis of ALS [90]. Moreover, the pathogenesis of ALS is associated with lateral hypothalamic lesions, a site of the orexinergic system leading to sleep disturbances and hypersomnia [91]. Despite different and large body of literature survey, little is known about CSF

*2.4.4 Multiple sclerosis*

#### *2.4.4 Multiple sclerosis*

*Weight Management*

*2.4.2 Alzheimer's disease*

reduced REM sleep [73].

*2.4.3 Huntington's disease*

Alzheimer's disease (AD) is a neurodegenerative disease affecting different brain areas characterized by cognitive deficit and progressive memory loss [70]. AD also affects hypothalamic orexinergic neurons leading to excessive daytime sleepiness, which is correlated with low orexin CSF levels, as reduction 40% of the brain cell number is linked with a 14% reduction in orexin CSF levels [71]. Normally, orexin regulates cholinergic and monoaminergic neuron firing during sleep and wakefulness. In AD a reduction in the cholinergic pathway leads to disturbance in sleep patterns leading to daytime sleepiness and insomnia at night which are a hallmark of sleep rhythm in AD [72]. Besides, reduction of cholinergic activity causes overactivity of orexinergic neurons, which causes abnormal sleep and cognitive functions. These changes lead to an elevation of the orexin CSF level, which is linked with

Dementia with Lewy bodies is characterized by an elevation in α-synuclein level,

which is accumulated in orexin-containing neurons at the hypothalamus causing interference in orexin axonal transport. This effect leads to a reduction in the activity of the orexinergic system in dementia with Lewy bodies but not in AD [74]. Therefore, there are complexities in the orexinergic system according to the clinical

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by personality changes, motor disturbances, cognitive decline, and weight loss [75]. HD is caused by a defect in the gene encoding huntingtin, a protein with unclear function, which is essential for cell survival during development and in adult life [76]. In HD there is neurodegeneration involving the neostriatum and cerebral cortex, with the manifestation of intraneuronal aggregates of misfolded huntingtin. Moreover, in patients with end-stage HD, there is about 90% of neuronal loss in the tuber nucleus of the lateral hypothalamus**.** Orexin-A and orexin-B are synthesized from the same precursor gene and are expressed in the same neurons with their cell bodies concentrated to the lateral hypothalamus [77]. Preclinical and clinical studies observed that orexin serum and CSF levels are decreased by 72% in HD. In healthy subjects, orexin CSF level is >200pg/ml, but in HD and narcolepsy, this level is decreased below 110 pg/ml, due to degeneration of orexinergic neurons in the lateral hypothalamus. Therefore, CSF orexin level is regarded as a biomarker to evaluate the disease progression and usefulness of therapeutic intervention in patients with HD [78, 79]. However, Meier et al. illustrated that CSF and serum

orexin levels are of no diagnostic value in prediction and follow-up of

Recently, Cabanas et al. observed that orexin in HD has aberrant effects leading to abnormal sleep pattern, and thus orexin antagonist suvorexant may be of great value in restoring normal sleep and behavioral disturbance in HD [81] in addition, these neurons remain functional and illustrate paradoxical effect, it become more modifiable and affect by serotonine and noradrenaline, and less sensitive to the effect of suprachiasmatic nucleus (the master clock of the brain) causing abnormal

Therefore, orexin level in HD is reduced, but the remaining functional orexinergic neurons lead to abnormal circadian biological rhythm causing behavioral,

presentation and sleep pattern in patients with AD.

**54**

HD [80].

biological circadian rhythm [81, 82].

motor, and sleep disturbances.

Multiple sclerosis (MS) is a demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Specific symptoms can include double vision, blindness in one eye, muscle weakness, and trouble with sensation or coordination. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). Between attacks, symptoms may disappear completely; however, permanent neurological problems often remain, especially with the advancement of the disease [83, 84].

The three main characteristics of MS are the formation of lesions in the central nervous system, inflammation, and the destruction of myelin sheaths of neurons. These features interact in a complex and not yet fully understood manner to produce the breakdown of nerve tissue and in turn the signs and symptoms of the disease. Cholesterol crystals are believed to both impair myelin repair and aggravate inflammation. MS is believed to be an immune-mediated disorder that develops from an interaction of the individual's genetics and as yet unidentified environmental causes. Damage is believed to be caused, at least in part, by attack on the nervous system by a person's own immune system [85].

Considering the multiplicity of symptoms associated with multiple sclerosis (MS), there is possibility that hypocretin system function might be involved in the pathogenesis of the disease. Papuc et al. showed that high orexin CSF level in patients with MS as compared with healthy controls, but it positively correlated with fatigue level, suggesting a compensatory mechanism for the production of orexin in MS [86]. On the other hand, Nozaki et al. illustrated that orexin CSF level is reduced and correlated with symmetrical hypothalamic lesion and spinal cord damage in MS. Therefore, low orexin level was implicated in the pathogenesis of hypersomnia and cognitive deficit in patients with MS [87]. Recently, Pallais et al. confirmed that orexin has a neuroprotective effect in MS through inhibition of inflammatory and proinflammatory mediators mainly matrixmetaloproteinases (MMP-3, MMP-9) which are involved in damage of neuronal matrix proteins. Consequently, low CSF orexin level indicates underlying active disease [88].

Therefore, CSF orexin level is a valuable biomarker in the diagnosis and prediction of the severity of MS.

#### *2.4.5 Amyotrophic lateral sclerosis*

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a disease that leads the death of neurons controlling voluntary muscles. The underlying mechanism involves damage to both upper and lower motor neurons. ALS is characterized by stiff muscles, muscle twitching, and muscle weakness is still unknown. The cause of ALS is not known in 90% of cases but is believed to involve both genetic and environmental factors. The remaining 10% of cases is inherited [89]. Previously, Van Rooij et al. illustrated that CSF orexin level was normal in patients with ALS and not correlated with age and gender. However, a disturbance in the orexinergic system is involved in the pathogenesis of ALS [90]. Moreover, the pathogenesis of ALS is associated with lateral hypothalamic lesions, a site of the orexinergic system leading to sleep disturbances and hypersomnia [91].

Despite different and large body of literature survey, little is known about CSF orexin levels, in clinical and preclinical studies in ALS.

Therefore, orexin CSF level and orexinergic activity in different neurodegenerative diseases are summarized in **Table 4**.

#### **2.5 Orexin antagonists and neurobiology**

Regarding orexin antagonists, suvorexant is a dual orexin receptor antagonist was approved by the Food and Drug Administration (FDA) on 13 August 2014 [92]. Other orexin antagonists are almorexant, lemborexant, and filorexant are used in the management of insomnia and other sleep disorders. Also, these drugs may be of great value in the control of depressive disorders and peripheral diabetic neuropathy [93].

Suvorexant (**Figure 2**) is the first orexin antagonists approved in the United States for treatment of insomnia, which is effective in reduction of time to sleep onset and increase of total sleeping time [94]. Moreover, administration of SB-33867 which is an orexin antagonist leads to significant reduction of sympathetic tone causing a reduction in blood pressure, heart rate, and plasma noradrenalin. These findings suggest that orexin through OX1 receptor regulates sympathetic tone since intravenous administration of orexin leads to parallel increases in noradrenalin plasma levels [95].

Hatta et al. study confirmed the significant effect of suvorexant in the management of delirium in elderly patients in acute care units. The anti-delirium effect is due to the regulation of circadian biology [96]. Delirium is proposed to be related of suvorexant to disturbances and disorders in sleep pattern in critically ill patients in the intensive care unit. Also, attention disorders are caused by disturbances in the ascending reticular activating system (ARAS) which is responsible for maintenance of human arousal. Normally, the arousal state is regulated and stimulated by ARAS neurotransmitters and by hypothalamic orexin [97]. Therefore, orexin receptor antagonists may play important role in the regulation of hypothalamic and brain stem stress during acute injury. Moreover, a recent study by Kawada et al. illustrated that suvorexant add-on therapy to ramelteon in the management of sleep disorders in patients with acute stroke is more effective than when combined with benzodiazepines [98].

It has been verified that prolonged alcohol consumption is associated with sleep disturbance which is a powerful factor for relapse and setback to alcohol use. Suvorexant reduces the motivation properties of alcohol, so it plays a crucial role in the prevention of alcoholism [99].

Beside, Gentile et al. study revealed the possible role of suvorexant in reduction of motor impulsivity of cocaine-induced psychostimulant effects. Thus suvorexant may be effective in attenuation of cocaine withdrawal syndrome [100].

As well, suvorexant had placebo-like effect on EEG in comparison with zolpidem which has a significant reduction in the spectral density of rapid eye movement and non-rapid eye movement sleep (NREM) pattern [101].


**57**

*Orexin and Psychoneurobiology: A Hidden Treasure DOI: http://dx.doi.org/10.5772/intechopen.91852*

mented by Vermeeren et al. study [102].

induction of feeding and obesity [104].

activity of endogenous orexinergic system.

predict relapse and withdrawal of addict patients.

**3. Conclusion**

**Conflict of interest**

**Funding and support**

None.

None.

In spite of the wide uses of suvorexant in the management of sleep disorders and

controlling insomnia, it did not reduce the psychomotor performances as docu-

Orexin-A is involved in regulation of feeding; it stimulates nocturnal feeding through OX1 receptor. Therefore, OX1 receptor antagonist regulates feeding and reduced nocturnal feeding; thus, orexin antagonist could be useful in the treatment of obesity [103]. Orexin-A is implicated in the pathogenesis of obesity; it promotes hyperphagia through central activation of cannabinoid receptors and inhibition of melanocyte-stimulating hormone [104]. Both orexin-A and endocannabinoid increases glucose response of neuronal excitability in the arcuate nucleus leading to

In summary, more research is required to reinforce the extant information on the importance of the limited number of factors studied to date and provide data on additional potentially relevant effects. Similarly, rubric for such research should shift from preclinical and animal model studies to clinical studies to illustrate disease progression and treatment effects in relation to orexin neurobiology. This study suggests that orexin system is a future target in the management of different psychoneurological disorders after delineating the specific role of orexin receptor agonists and antagonists. Moreover, measurement of orexin serum level which is an easy method may be of great value in evaluation and assessment of different neurological disorders. Also, ratio of orexin serum level/CSF orexin level may reflect the

Orexin system is regarded as a potential novel target in the management of schizophrenia, depression, addiction, and sleep disorders. Orexin serum level might

#### **Table 4.**

*Orexin and neurodegenerative diseases.*

*Orexin and Psychoneurobiology: A Hidden Treasure DOI: http://dx.doi.org/10.5772/intechopen.91852*

*Weight Management*

neuropathy [93].

tive diseases are summarized in **Table 4**.

the prevention of alcoholism [99].

**2.5 Orexin antagonists and neurobiology**

Therefore, orexin CSF level and orexinergic activity in different neurodegenera-

Regarding orexin antagonists, suvorexant is a dual orexin receptor antagonist was approved by the Food and Drug Administration (FDA) on 13 August 2014 [92]. Other orexin antagonists are almorexant, lemborexant, and filorexant are used in the management of insomnia and other sleep disorders. Also, these drugs may be of great value in the control of depressive disorders and peripheral diabetic

Suvorexant (**Figure 2**) is the first orexin antagonists approved in the United States for treatment of insomnia, which is effective in reduction of time to sleep onset and increase of total sleeping time [94]. Moreover, administration of SB-33867 which is an orexin antagonist leads to significant reduction of sympathetic tone causing a reduction in blood pressure, heart rate, and plasma noradrenalin. These findings suggest that orexin through OX1 receptor regulates sympathetic tone since intravenous administration of orexin leads to parallel increases in noradrenalin plasma levels [95]. Hatta et al. study confirmed the significant effect of suvorexant in the management of delirium in elderly patients in acute care units. The anti-delirium effect is due to the regulation of circadian biology [96]. Delirium is proposed to be related of suvorexant to disturbances and disorders in sleep pattern in critically ill patients in the intensive care unit. Also, attention disorders are caused by disturbances in the ascending reticular activating system (ARAS) which is responsible for maintenance of human arousal. Normally, the arousal state is regulated and stimulated by ARAS neurotransmitters and by hypothalamic orexin [97]. Therefore, orexin receptor antagonists may play important role in the regulation of hypothalamic and brain stem stress during acute injury. Moreover, a recent study by Kawada et al. illustrated that suvorexant add-on therapy to ramelteon in the management of sleep disorders in patients with

acute stroke is more effective than when combined with benzodiazepines [98]. It has been verified that prolonged alcohol consumption is associated with sleep disturbance which is a powerful factor for relapse and setback to alcohol use. Suvorexant reduces the motivation properties of alcohol, so it plays a crucial role in

may be effective in attenuation of cocaine withdrawal syndrome [100].

**Psychiatric disorders Species CSF orexin levels References** Parkinson's disease Human Decreased Fronczek et al. [63] Alzheimer's disease Human Increased Liguori et al. [73] Huntington's disease Human Decreased Mignot et al. [78]

Multiple sclerosis Human Decreased Nozaki et al. [87] ALS Human Normal Van Rooij et al. [90]

non-rapid eye movement sleep (NREM) pattern [101].

Beside, Gentile et al. study revealed the possible role of suvorexant in reduction of motor impulsivity of cocaine-induced psychostimulant effects. Thus suvorexant

As well, suvorexant had placebo-like effect on EEG in comparison with zolpidem which has a significant reduction in the spectral density of rapid eye movement and

Animals Normal Papuc et al. [86]

**56**

**Table 4.**

*Orexin and neurodegenerative diseases.*

In spite of the wide uses of suvorexant in the management of sleep disorders and controlling insomnia, it did not reduce the psychomotor performances as documented by Vermeeren et al. study [102].

Orexin-A is involved in regulation of feeding; it stimulates nocturnal feeding through OX1 receptor. Therefore, OX1 receptor antagonist regulates feeding and reduced nocturnal feeding; thus, orexin antagonist could be useful in the treatment of obesity [103]. Orexin-A is implicated in the pathogenesis of obesity; it promotes hyperphagia through central activation of cannabinoid receptors and inhibition of melanocyte-stimulating hormone [104]. Both orexin-A and endocannabinoid increases glucose response of neuronal excitability in the arcuate nucleus leading to induction of feeding and obesity [104].

In summary, more research is required to reinforce the extant information on the importance of the limited number of factors studied to date and provide data on additional potentially relevant effects. Similarly, rubric for such research should shift from preclinical and animal model studies to clinical studies to illustrate disease progression and treatment effects in relation to orexin neurobiology. This study suggests that orexin system is a future target in the management of different psychoneurological disorders after delineating the specific role of orexin receptor agonists and antagonists. Moreover, measurement of orexin serum level which is an easy method may be of great value in evaluation and assessment of different neurological disorders. Also, ratio of orexin serum level/CSF orexin level may reflect the activity of endogenous orexinergic system.

### **3. Conclusion**

Orexin system is regarded as a potential novel target in the management of schizophrenia, depression, addiction, and sleep disorders. Orexin serum level might predict relapse and withdrawal of addict patients.

#### **Conflict of interest**

None.

#### **Funding and support**

None.

*Weight Management*
