Elsevier

Neuroscience

Volume 111, Issue 2, 10 May 2002, Pages 231-239
Neuroscience

Commentary
GABA mechanisms and sleep

https://doi.org/10.1016/S0306-4522(02)00034-9Get rights and content

Abstract

GABA is the main inhibitory neurotransmitter of the CNS. It is well established that activation of GABAA receptors favors sleep. Three generations of hypnotics are based on these GABAA receptor-mediated inhibitory processes. The first and second generation of hypnotics (barbiturates and benzodiazepines respectively) decrease waking, increase slow-wave sleep and enhance the intermediate stage situated between slow-wave sleep and paradoxical sleep, at the expense of this last sleep stage. The third generation of hypnotics (imidazopyridines and cyclopyrrolones) act similarly on waking and slow-wave sleep but the slight decrease of paradoxical sleep during the first hours does not result from an increase of the intermediate stage. It has been shown that GABAB receptor antagonists increase brain-activated behavioral states (waking and paradoxical sleep: dreaming stage). Recently, a specific GABAC receptor antagonist was synthesized and found by i.c.v. infusion to increase waking at the expense of slow-wave sleep and paradoxical sleep.

Since the sensitivity of GABAC receptors for GABA is higher than that of GABAA and GABAB receptors, GABAC receptor agonists and antagonists, when available for clinical practice, could open up a new era for therapy of troubles such as insomnia, epilepsy and narcolepsy. They could possibly act at lower doses, with fewer side effects than currently used drugs. This paper reviews the influence of different kinds of molecules that affect sleep and waking by acting on GABA receptors.

Section snippets

GABAA binding site

The function of the GABA receptor binding site is to open a chloride channel. Some time ago it was shown that the global central increase of GABA by i.c.v. infusion of GABA or inhibition of GABA transaminase increased slow-wave sleep and induced a 64% drop of paradoxical sleep without rebound effect in cats (Karadzic, 1966, Holmes and Sugden, 1975), and did not influence the recovery of paradoxical sleep after selective deprivation in rats (Juan de Mendoza et al., 1973). In humans it seemed to

GABAB receptors

These receptors are involved in sleep–waking regulation as shown by lethargic (lh/lh) mice which have increased numbers of GABAB receptors in the cortex and thalamus (Lin et al., 1993, Lin et al., 1995). Moreover, GABAB receptor antagonists infused in the thalamus decrease EEG slow waves and deep slow-wave sleep while light slow-wave sleep is increased (Juhasz et al., 1994). These compounds are used to alleviate absence-epilepsy in humans (Marescaux et al., 1992, Bittinger et al., 1993) partly

GABAC receptors

Hitherto, it has been difficult to study the influence of the GABAC receptor on behavior since the agonist trans-4-aminocrotonic acid (TACA) and its cis-enantiomer CACA, the first compounds acting on this receptor to be identified, were not specific, like the first antagonists (Bormann and Feigenspan, 1995, Quian and Dowling, 1996). However, in 1996 the first selective antagonist was uncovered: (1,2,5,6-tetrahydropyridine)-methylphosphonic acid (TPMPA) (Murata et al., 1996, Ragozzino et al.,

Conclusion

The three currently identified GABA receptors have similar hypnotic effects when stimulated. Some differences appear when the quality of sleep is examined. Slow-wave sleep is enhanced in all cases. It can be strongly hypothesized that when antagonists promote waking, agonists, where available, will increase sleep. The intermediate stage is extended at the expense of paradoxical sleep by barbiturates, most benzodiazepines and steroids but not by new-generation hypnotics. GABAB and GABAC receptor

Note added in proof

Kauer et al. (2001) confirmed that the medulla prepositus hypoglossi nucleus regulates paradoxical sleep by GABAergic neurons which inhibit locus coeruleus neurons.

Acknowledgements

I thank Professor G. Morgan for correction of the English.

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