*2.3.3 Orexin and addiction*

The orexinergic system has broad projections and connections to different brain area which are concerned with drug-induced neuro-adaptation, including midbrain dopaminergic neurons, ventral tegmental area (VTA), nucleus accumbens (NA),

**Figure 3.** *Chemical structure of modafinil.*

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

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 addiction.

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 risk of smoking relapse.

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 of alcoholic patients during the abstinence period [56].

#### *2.3.4 Orexin and sleep disorders*

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.

**53**

**Table 3.**

*Orexin and psychiatric disorders.*

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

**2.4 Orexin in neurodegenerative diseases**

patients compared to the healthy control [63].

psychiatric disorders.

*2.4.1 Parkinson's disease*

the activation of HIF-α [66].

re-evaluated in this context [69].

Likewise, human postmortem study found that orexin peptide and prepro-orexin mRNA are deficient in the pons and cerebral cortex [62]. Therefore, these findings unveil that orexin is an important neuropeptide in the regulation of sleep and consolidated wakefulness. **Table 3** summarized the potential role of orexin in common

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

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

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

**Psychiatric disorders Species Orexin levels References** Depression Human Decreased Kok et al. [29]

Schizophrenia Human Decreased Mereu et al. [42]

Chronic smoking Animals Increased Al'Absi et al. [54] Drug addictions Human Increased James et al. [53] Alcoholism Human Increased Pan et al. [56] Narcolepsy Human Decreased Gabelle et al. [62]

Human Increased Grady et al. [30]

Patel et al. [20]

Likewise, human postmortem study found that orexin peptide and prepro-orexin mRNA are deficient in the pons and cerebral cortex [62]. Therefore, these findings unveil that orexin is an important neuropeptide in the regulation of sleep and consolidated wakefulness. **Table 3** summarized the potential role of orexin in common psychiatric disorders.
