Orexin / Hypocretin

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

• 1. Orexin formation
• 2. Orexin binding
• 3. Effects/influences of orexin
• 4. Impact on ADHD-HI/ADHD-I:

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 fear 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 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. 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
Dysfunction of the orexin system appears to play an important role in neurodevelopmental symptoms, such as:¹⁹

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