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Orexin / Hypocretin

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Orexin / Hypocretin

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

1. Orexin formation

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

2. Orexin binding

  • Orexin A
    • Binds to both orexin receptors with equal 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 only when cortisol levels are extremely high (during acute stress) are GR also addressed.
  • 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 fatty rats
      • Weight gain when administered directly to the brain
  • Sleep rhythm
    • Deficiency: Narcolepsy7
    • Mice with orexin A and orexin B receptor blockade, and likewise mice with orexin B receptor blockade, show normal sleep behavior, but are significantly more vulnerable to disruption.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 attention9
    • Presence: Alertness
    • Mice with a homozygous genetic orexin deficit showed impaired task switching in females enhanced first reversal learning 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
      • During a state of arousal orexin is synthesized in the hypothalamus13
      • Orexin increases secretion of14
        • Norepinephrine
          • Nucleus coreuleus
          • Thalamus
          • PFC
        • Dopamine
          • Ventral tegmentum
          • Nucleus accumbens
      • Norepinephrine from the nucleus coeruleus moderates the effect of orexin on arousal.15
  • Fear
    • Orexin is essential in anchoring fear experiences4
    • Orexin A receptors are located in the amygdala, among other regions, and are involved in anxiety regulation there, unlike orexin B receptors. Orexin A receptor antagonists reduce conditioned fear1
    • 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 posterior cingulate cortex, cingulate gyrus, and precuneus, suggesting delayed brain maturation in the posterior area in ADHD-I.16
  • Glutamate
    • Orexin A receptors modulate the output of glutamate1
    • Addressing the vesicular glutamate transporter VGLUT2 and to a lesser extent VGLUT2 17
  • GABA
    • No GABAergic addressing by orexin17

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

In ADHD-I, one study found significantly lower basal orexin A levels than in ADHD-HI, ADHD-C, and nonaffected individuals.18


  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: https://doi.org/10.1523/JNEUROSCI.2311-11.2011

  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