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Orexin / Hypocretin


Orexin / Hypocretin

Orexin A / B (other name: Hypocretin-1/-2) are neuropeptide hormones.1

1. Formation of orexin

  • Formation in the hypothalamus (first stage of the HPA axis)
    • In the posterior lateral part of the hypothalamus2
  • Primarily phasic production3

2. Binding of orexin

  • Orexin A
    • Binds to both orexin receptors with the same affinity.4
  • Orexin B
    • Binds to orexin B receptors with 10 times the affinity of orexin A receptors.4
    • This model is reminiscent of the binding of cortisol to MR and GR. Cortisol binds 10 times more strongly to MR, so that GR is only addressed when cortisol levels are extremely high (during acute stress).
  • Antagonists
    • SB-334867 is a selective orexin A antagonist4
    • Suvorexant-A is a dual orexin A and orexin B antagonist5
    • Compound 9, 1-(2,4-dibromo-phenyl)-3-(.(4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea is a selective orexin B antagonist6
    • TCSOX229 is a selective orexin B antagonist4

3. Effects/influences of Orexin

  • Energy metabolism
    • Eating behavior
    • Weight
      • Receptor deficiency in fatter rats
      • Weight gain when administered directly into the brain
  • Sleep rhythm
    • Deficiency: Narcolepsy7
    • Mice with an orexin A and orexin B receptor blockade and also mice with an orexin B receptor blockade show normal sleep behavior, which is, however, significantly more susceptible to disturbances.8 Sleep regulation appears to occur via the orexin B receptor.
  • Autonomic nervous system
  • Fluid balance
  • Presence: Increase in body temperature
  • Attention
    • Presence in the hypothalamus: increased alertness9
    • Presence: Alertness
    • Mice with a homozygous genetic orexin deficiency showed impaired task switching in females improved the first reversal learning phase in males. These orexin-mediated sex-specific modulations of cognitive flexibility did not correlate with anxiety behavior, narcoleptic episodes, or reward consumption.10
  • Motivation
    • Via orexin A receptor9
  • Activity and drive11
    • Deficiency: Hypoactivity
      • Orexin antagonists reduce stimulant-induced motor hyperactivity12
    • Presence: increased drive
      • Orexin is synthesized in the hypothalamus during a state of arousal13
      • Orexin increases the release of14
        • Noradrenaline
          • Nucleus coreuleus
          • Thalamus
          • PFC
        • Dopamine
          • Ventral tegmentum
          • Nucleus accumbens
      • Noradrenaline from the nucleus coeruleus moderates the effect of orexin on arousal.15
  • Fear
    • Orexin is essential in the anchoring of fear experiences4
    • Orexin A receptors are located in the amygdala, among other places, where they are involved in anxiety regulation, unlike orexin B receptors. Orexin A receptor antagonists reduce conditioned anxiety1
    • Orexin A antagonists in the amygdala (but not in the PFC or dorsal hippocampus) reduce anxiety,4
    • Orexin B antagonists also reduce anxiety, but to a lesser extent.4
    • A study of girls with ADHD-I found significant differences from controls in the posterior cingulate cortex, cingulate gyrus and precuneus, suggesting delayed brain maturation in the posterior region in ADHD-I.16
  • Glutamate
    • Orexin A receptors modulate the release of glutamate1
    • Addressing the vesicular glutamate transporter VGLUT2 and to a lesser extent VGLUT2 17
  • GABA
    • No GABAergic addressing by orexin17

4. Influence on ADHD-HI/ADHD-I:

One study found a significantly lower basal orexin A level in ADHD-I than in ADHD-HI, ADHD-C and non-affected individuals.18
Dysfunctions of the orexin system appear to play an important role in neurodevelopmental symptoms, such as:19

  • Arousal
  • Wakefulness
  • Sleep
  • motor and sensory processing
  • Mood and emotional regulation
  • Anxiety processing
  • Reward
  • Nutrition
  • Attention
  • Executive functions
  • Sociability

Mice in which the hypocretin receptor-2 (Hcrtr2, orexin-B) was deactivated in dopamine neurons:20

  • a dramatic increase in electroencephalographic (EEG) theta activity (7-11 Hz) both during wakefulness and REM sleep
  • spent more time in an active (or theta-enriched) sub-state of wakefulness
  • prolonged REM phase
  • increased theta-gamma phase-amplitude coupling during wakefulness and REM sleep
  • reduced infra-theta but increased theta power in the baseline awake EEG
    • both are characteristics of EEG hyperarousal
    • however, both were not linked to the movement activity
  • in novel, either rewarding or stress-inducing environments, DAHcrtr2-deficient mice exhibited the following compared to their littermates
    • more pronounced theta and fast-gamma (52-80 Hz) EEG activity spikes (indication of increased alertness)
  • in an operant conditioning paradigm for increasingly demanding tasks
    • faster task entry
    • greater decision-making accuracy
  • maladaptive behavior pattern in the search for rewards
  • Behavioral indicators for increased impulsivity and compulsiveness

None of the EEG changes observed in DA-Hcrtr2-deficient mice occurred in DA-Hcrtr1-ablated mice, which tended to exhibit opposite EEG phenotypes.20

  1. Dustrude, Caliman, Bernabe, Fitz, Grafe, Bhatnagar, Bonaventure, Johnson, Molosh, Shekhar (2018): Orexin Depolarizes Central Amygdala Neurons via Orexin Receptor 1, Phospholipase C and Sodium-Calcium Exchanger and Modulates Conditioned Fear. Front Neurosci. 2018 Dec 18;12:934. doi: 10.3389/fnins.2018.00934. eCollection 2018.

  2. Li, Hu, de Lecea (2014): The hypocretins/orexins: integrators of multiple physiological functions. Br J Pharmacol. 2014 Jan;171(2):332-50. doi: 10.1111/bph.12415.

  3. Mileykovskiy, Kiyashchenko, Siegel (2005): Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron. 2005 Jun 2;46(5):787-98.

  4. Flores, Valls-Comamala, Costa, Saravia, Maldonado, Berrendero (2014): The hypocretin/orexin system mediates the extinction of fear memories. Neuropsychopharmacology. 2014 Nov;39(12):2732-41. doi: 10.1038/npp.2014.146.

  5. Winrow, Gotter, Cox, Doran, Tannenbaum, Breslin, Garson, Fox, Harrell, Stevens, Reiss, Cui, Coleman, Renger (2011): Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist. J Neurogenet. 2011 Mar;25(1-2):52-61. doi: 10.3109/01677063.2011.566953.

  6. McAtee, Sutton, Rudolph, Li, Aluisio, Phuong, Dvorak, Lovenberg, Carruthers, Jones (2004): Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4225-9.

  7. Grossberg (2011): Warum Krankheiten schlapp machen

  8. Mochizuki, Arrigoni, Marcus, Clark, Yamamoto, Honer, Borroni, Lowell, Elmquist, Scammell (2011): Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4471-6. doi: 10.1073/pnas.1012456108.

  9. Gentile, Simmons, Watson, Connelly, Brailoiu, Zhang, Muschamp (2017): Effects of Suvorexant, a Dual Orexin/Hypocretin Receptor Antagonist, on Impulsive Behavior Associated with Cocaine. Neuropsychopharmacology. 2018 Apr;43(5):1001-1009. doi: 10.1038/npp.2017.158. PMID: 28741623; PMCID: PMC5854790.

  10. Durairaja, Fendt (2021): Orexin deficiency modulates cognitive flexibility in a sex-dependent manner. Genes Brain Behav. 2021 Mar;20(3):e12707. doi: 10.1111/gbb.12707. Epub 2020 Nov 3. PMID: 33070452.

  11. Grossberg, Zhu, Leinninger, Levasseur, Braun, Myers, Marks (2011): Inflammation-Induced Lethargy Is Mediated by Suppression of Orexin Neuron Activity; Journal of Neuroscience 3 August 2011, 31 (31) 11376-11386; DOI:

  12. Gentile, Simmons, Watson, Connelly, Brailoiu, Zhang, Muschamp (2018): Effects of Suvorexant, a Dual Orexin/Hypocretin Receptor Antagonist, on Impulsive Behavior Associated with Cocaine. Neuropsychopharmacology. 2018 Apr;43(5):1001-1009. doi: 10.1038/npp.2017.158.

  13. Wolf, Calabrese (2020): Stressmedizin & Stresspsychologie, S. 160

  14. Peyron, Tighe, van den Pol, de Lecea, Heller, Sutcliffe, Kilduff (1998): Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998 Dec 1;18(23):9996-10015. doi: 10.1523/JNEUROSCI.18-23-09996.1998. PMID: 9822755; PMCID: PMC6793310.

  15. Carter, de Lecea, Adamantidis (2013): Functional wiring of hypocretin and LC-NE neurons: implications for arousal. Front Behav Neurosci. 2013 May 20;7:43. doi: 10.3389/fnbeh.2013.00043. PMID: 23730276; PMCID: PMC3657625.

  16. Chang, Yang, Chiang, Ouyang, Wu, Yu, Lin. Delay Maturation in Occipital Lobe in Girls With Inattention Subtype of Attention-Deficit Hyperactivity Disorder. Clin EEG Neurosci. 2020 Jan 14;1550059419899328. doi: 10.1177/1550059419899328. PMID: 31933379.

  17. Rosin, Weston, Sevigny, Stornetta, Guyenet (2003): Hypothalamic orexin (hypocretin) neurons express vesicular glutamate transporters VGLUT1 or VGLUT2. J Comp Neurol. 2003 Oct 27;465(4):593-603.

  18. Baykal, Albayrak, Durankuş, Güzel, Abbak, Potas, Beyazyüz, Karabekiroğlu, Donma (2019): Decreased serum orexin A levels in drug-naive children with attention deficit and hyperactivity disorder. Neurol Sci. 2019 Jan 7. doi: 10.1007/s10072-018-3692-8. n = 96

  19. Knez R, Stevanovic D, Fernell E, Gillberg C (2022): Orexin/Hypocretin System Dysfunction in ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations). Neuropsychiatr Dis Treat. 2022 Nov 15;18:2683-2702. doi: 10.2147/NDT.S358373. PMID: 36411777; PMCID: PMC9675327.

  20. Bandarabadi M, Li S, Aeschlimann L, Colombo G, Tzanoulinou S, Tafti M, Becchetti A, Boutrel B, Vassalli A (2023): Inactivation of hypocretin receptor-2 signaling in dopaminergic neurons induces hyperarousal and enhanced cognition but impaired inhibitory control. Mol Psychiatry. 2023 Dec 21. doi: 10.1038/s41380-023-02329-z. PMID: 38123729.