Sleep problems in ADHD - Neurophysiological correlates

A number of substances are involved in sleep/wake regulation in the brain.

• 1. Neurotransmitters and sleep/wake regulation
• 2. Other substances of the brain and sleep-wake regulation
• 3. Circadian rhythm and influence of genes
  • 3.1. Circadian rhythm
  • 3.2. Gene variants that influence the circadian rhythm
  • 3.3. Remdesivir alters circadian gene expression

1. Neurotransmitters and sleep/wake regulation¶

• Serotonin¹²³⁴
• Norepinephrine¹⁵
• Histamine⁵
• Acetylcholine⁶⁵
• GABA⁷³
• Glutamate⁵
• Dopamine⁸⁵
  • Selective dopamine reuptake inhibitors may promote wakefulness better than selective norepinephrine reuptake inhibitors in normal and sleep-disordered narcoleptic animals⁹
  • Severe sleep disturbances are common in people with Parkinson’s disease or Huntington’s disease who have dopaminergic dysfunction¹⁰¹¹
  • Dopamine metabolism and dopamine receptor abnormalities are also implicated in excessive daytime sleepiness (e.g., narcolepsy)¹²
  • Sleep disorders are associated with ADHD¹³
  • DAT gene variants appear to predispose humans to susceptibility to sleep-wake disorders⁸
  • Dopamine and melatonin are involved in the regulation of fatigue and sleep.
    The dopaminergic system is influenced by the circadian system.¹⁴¹⁵
    Dopamine is produced rhythmically in the amacrine cells of the retina. The retina is controlled by dopamine as by melatonin. The retina transmits light information to the suprachiasmatic nucleus, which is the master biological clock. The suprachiasmatic nucleus sends timing information for rhythmic regulation of dopaminergic brain regions and behavior controlled by them (locomotion, motivation). Dopamine produced in the substantia nigra and ventral tegmentum may be rhythmically regulated by the suprachiasmatic nucleus through various neural pathways (including by means of the orexin system or the medial preoptic nucleus of the hypothalamus).¹⁶ Orexin deficiency is a possible cause of narcolepsy. ⇒ Orexin/hypocretin Light uptake by the retina affects circadian rhythms. Changes in light and light rhythm can affect circadian rhythms.¹⁷
    Dopamine and melatonin inhibit each other.¹⁸
    Dopamine is released mainly in the early morning and during the day. Melatonin is inhibited by daylight and released mainly in the evening and at night.¹⁹
    A dopamine deficiency (as is typical for ADHD) could therefore cause too little melatonin inhibition. This could possibly explain the severe daytime sleepiness reported by some ADHD sufferers.
    We discuss whether retinal disorders could cause the shifts in chronorhythms common in ADHD and whether these could be a major cause of ADHD.²⁰

2. Other substances of the brain and sleep-wake regulation¶

• Melatonin
  For details, see ⇒ Melatonin in ADHD im section ⇒ Medications for ADHD - Overview / ⇒ Suitable medications for ADHD in the section ⇒ Treatment and therapy.
• GHRH has a sleep-inducing effect²¹²²
  • The D1 receptor in the bovine hypothalamus mediated a 50% reduction in hypothalamic GHRH release in vitro²³
• Orexin (hypocretin)⁵
  • Neuropeptide
• Adenosine²²
  • Nucleoside
  • Blocks the release of activating neurotransmitters, e.g.:
    • Norepinephrine
    • Dopamine
    • Acetylcholine
• Proinflammatory cytokines²²
• Prostaglandin D2²²
• CRH has a sleep-inhibiting effect²¹

3. Circadian rhythm and influence of genes¶

3.1. Circadian rhythm¶

The following presentation is predominantly based on GeneCards.org.²⁴

The circadian clock, an internal timekeeping system, regulates various physiological processes by generating approximately 24-hour circadian rhythms in gene expression that translate into rhythms in metabolism and behavior. It is an important regulator of a variety of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immunological, cardiovascular, and renal functions. The circadian clock consists of two main components:

• the central clock in the suprachiasmatic nucleus (SCN)
• the peripheral clocks, which occur in almost all tissues and organ systems

Central as well as peripheral clocks can be reset by environmental stimuli as zeitgebers. The most important zeitgeber for the central clock is light, which is perceived by the retina and transmitted directly to the SCN. The central clock controls the peripheral clocks through neuronal and hormonal signals, body temperature, and feeding-related signals, so that all clocks are tuned to the external light-dark cycle. Circadian rhythms enable an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression such that a peak in protein expression occurs once every 24 hours to control when a particular physiological process is most active relative to the solar day. Transcription and translation of key clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1, and CRY2) plays a critical role in rhythm formation, while delays due to post-translational modifications (PTM) are important in determining the period (tau) of rhythms (tau refers to the period of a rhythm and is the temporal length of a complete cycle).

Diurnal rhythm: synchronized with the day-night cycle
Ultradian and infradian rhythms have a shorter and longer period than 24 hours, respectively.

Disturbances in circadian rhythms contribute to the pathology of cardiovascular disease, cancer, metabolic syndromes, and aging.

At the core of the molecular mechanism of the circadian clock is a transcription/translation feedback loop (TTFL).

• Positive link of the feedback loop: The transcription factors CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2. They act in the form of a heterodimer and activate the transcription of nuclear clock genes and clock-controlled genes (involved in important metabolic processes) that carry E-box elements (5’-CACGTG-3’) in their promoters.
• Negativea members of the feedback loop are the major clock genes: PER1/2/3 and CRY1/2, which are transcriptional repressors and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer, by inhibiting its activity and thereby negatively regulating their own expression. The CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and activate and repress ARNTL/BMAL1 transcription, respectively.

3.2. Gene variants that influence the circadian rhythm¶

A homozygous polymorphism in the 3’-flanking region of the clock gene CLK (T3111C) appears to be associated with a posteriorly shifted sleep-wake rhythm and a decreased need for sleep, independent of age, sex, or ethnicity.²⁵.
The longer allele of exon 18 in the PER3 gene is associated with a “morning type”, the shorter allele with an “evening type”. Homozygous carriers of the shorter allele suffer more frequently from difficulties in falling asleep.²⁶
The amino acid exchange T44A in the CSNK1D gene leads to a prolonged circadian rhythm in Drosophila flies, but to a shortened circadian rhythm in mice, as it occurs in mice,²⁷

Polymorphisms in CLK or PER genes are also associated with different sleep-wake rhythms in humans.²⁸

The circadian clocks control²⁹

• Immune system
• Virus replication
• Pharmacokinetics
• Effectiveness of therapeutics

3.3. Remdesivir alters circadian gene expression¶

Remdesivir alters circadian gene expression in primary human dermal fibroblast cultures.²⁹ In subjects without a neuropsychiatric diagnosis who did not exhibit eveningness in chronorhythms, remdesivir caused a slight phase shift in Clock, Per1, and Per2 and significantly altered expression of Bmal1 and Per3. The difference between chronotype and circadian gene expression of Bmal1, Cry1, and Per3 was significant. Remdesivir affected circadian function and shifted chronotype toward eveningness, as is also known from ADHD