Orexin / Hypocretin

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

• 1. Formation of orexin
• 2. Binding of orexin
• 3. Effects/influences of Orexin
• 4. Orexin and ADHD

1. Formation of orexin¶

• Formation in the hypothalamus (first increment 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 orexin A and orexin B receptor blockade and also mice with orexin B receptor blockade show normal sleep behavior, but are significantly more vulnerable to Disorders.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, indicating 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. Orexin and ADHD¶

Children with ADHD were found to have significantly decreased serum orexin levels. MPH further reduced the serum orexin level¹⁸

One study found a significantly lower basal orexin A level in ADHD-I than in ADHD-HI, ADHD-C and non-affected individuals.¹⁹

Dysfunction of the orexin system appears to play an important role in neurodevelopmental symptoms, such as:²⁰

• 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 showed:²¹

• 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.²¹