GABA and physiology of sleep

Gamma-aminobutyric acid (GABA)-positive allosteric modulators (PAMs) are efficacious for insomnia.

GABA and physiology of sleep

• GABA is the main inhibitory neurotransmitter of the CNS
  • promotion of sleep is regulated by a number of other neurotransmitters; primary amongst these is GABA, the main inhibitory neurotransmitter in the brain
  • majority of brain cells are inhibited by GABA so increasing its function reduces arousal and produces sleep, and eventually anaesthesia
  • is well established that activation of GABA(A) receptors favors sleep
  • GABA-A receptor is activated when its ligand, GABA, binds to the ligand-binding site. GABA is the main inhibitory neurotransmitter of the central nervous system. When GABA binds to the ligand site of the GABA-A receptor, the channel opens to allow chloride into the cell. This action results in hyperpolarization of the cell and subsequently diminished action potential, preventing the release of excitatory neurotransmitters
  • positive allosteric modulators operate by increasing the frequency with which the chlorine channel opens when an agonist binds to its own site on the GABA receptor
• many subsets of GABA neurones distributed throughout the brain but a particular cluster in the hypothalamus (ventrolateral preoptic nucleus) can be considered to be the sleep ‘switch’
  • GABA neurones ‘switch off’ brain arousal systems at the level of the cell bodies and therefore promote sleep
  • GABA receptors in the cortex can also promote sedation and sleep by inhibiting the target neurones of the arousal system
• benzodiazepines, so-called ‘Z drugs’ and barbiturates all enhance the effects of GABA at the GABAA receptor (GABA-PAMs)
• are a number of subtypes of this receptor which are relevant for sleep not only because of their different location in the brain but also because of the fact that some drugs for insomnia are selective for a particular subtype
  • alpha-1 subtype is highly expressed in the cortex and probably mediates the sedative and hypnotic effects of many drugs that act at the benzodiazepine site; zolpidem targets this subtype preferentially
  • alpha-3 subtype predominates in the reticular nucleus of the thalamus which plays an important role in regulating sleep
    • particularly targeted by eszopiclone
  • traditional benzodiazepine drugs for insomnia act on the alpha-1, alpha-2, alpha-3 and alpha-5 subtypes

Reference:

• Wilson S et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: An update. J Psychopharmacol. 2019 Aug;33(8):923-947
• Edwards Z, Pruess CV. GABA Receptor Positive Allosteric Modulators.StatPearls 2020.