What are the mechanisms of action of benzodiazepines and benzodiazepine receptor agonists for insomnia?

Updated: Sep 11, 2018
  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Selim R Benbadis, MD  more...
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Benzodiazepine receptor agonists (BZRAs) work through GABAA receptors to promote sleep by inhibiting brainstem monoaminergic arousal pathways, through facilitation of VLPO inhibitory GABAergic projections to arousal centers such as the anterior hypothalamus TMN, the posterolateral hypothalamic hypocretin neurons, and the brainstem arousal regions.

The GABAA receptor consists of 5 protein subunits arranged in a ring around a central pore. Most GABAA receptors consist of 2 alpha subunits, 2 beta subunits, and 1 gamma subunit. Upon GABAA receptor activation, chloride ions flow into the cell, resulting in neuronal hyperpolarization. [22, 23] (See the image below.)

GABAA receptor complex subunits and schematic repr GABAA receptor complex subunits and schematic representation of agonist binding sites.

BZRAs enhance the effect of GABA by lowering the concentration of GABA required to open the GABA channel. BZRAs bind to a modulatory site on the GABAA receptor that is distinct from the GABA binding site and change the receptor complex allosterically to increase the affinity of the receptor to GABA, thus producing a larger postsynaptic current prolonging inhibition. Although BZRAs do not directly open the chloride channel, they modulate the ability of GABA to do so, thus enhancing its inhibitory effect.

Synaptic GABAA receptors typically contain a γ subunit in combination with an α1, α2, and α3 subunit. Most GABAA receptors expressed in the CNS are α1 β2 γ2, α2 β3 γ2, α3 β3 γ2, α5 β3 γ2.

While GABA binds at the junction between subunits α and β, BZRAs bind at the interface between α and γ. The α subunits of the GABAA receptor mediate sedative, amnestic, anxiolytic, myorelaxant, ataxic, and sedative effects. GABAA receptors containing the α1 subunit mediate the sedative-hypnotic and amnestic effects and, to some degree, the anticonvulsant effects of BZRAs.

For example, studies of knockout mice that express a benzodiazepine-insensitive α1 subunit fail to show the sedative, amnestic effects of diazepam. The nonbenzodiazepine receptor agonists (ie, zaleplon, zolpidem, eszopiclone) have relative selectivity for GABAA receptors containing the α1 subunit, thereby producing fewer adverse effects (ie, ataxia, anxiolytic, myorelaxation properties) than nonselective BZRAs. (See the image below outlining the GABAA receptor subunit functions.)

GABAA receptor subunit function(s). GABAA receptor subunit function(s).

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