Is the awakening produced by benzodiazepines due to excitatory actions of GABA?

Abstract

Benzodiazepines (BZDs) such as Zolpidem can produce a temporary revival of patients who have been akinetic and apathic for years. The mechanisms underlying this “awakening” reaction are suggested globally to be related to an activation of gamma-aminobutyric acid (GABA) inhibitory systems. However, brain trauma or cerebro-vascular infarcts, like many other pathological insults, are associated with a shift of the polarity of GABA from inhibition to excitation consequently to an increase of intracellular chloride concentration ([Cl−]i) levels. Experimental and clinical observations suggest that BZDs generate paradoxical reactions in these conditions, hence the transient “awakening”. The NKCC1 (Na-K-2Cl co-transporter isoform 1) chloride importer antagonist Bumetanide restores low [Cl−]i levels and an efficient inhibitory drive. It is therefore suggested that the administration of Bumetanide might provide a persistent “awakening” by shifting GABAergic actions from excitation to inhibition and attenuating the mechanism underlying the apathic/akinetic state.

Deep brain stimulation of the central thalamus restores arousal and motivation in a zolpidem-responsive patient with akinetic mutism after severe brain injury

“…While some patients only experience a temporary effect of the drug, others may have consistent responses over years or build up a complexity of behaviors with repeated dosing 2 – 4 . For most patients, the ‘awakening’ effects of zolpidem, such as return of movement, speech, or other cognitive functions are relatively short-lived, only lasting for a couple of minutes or hours, possibly related to the relatively brief duration of peak concentration in the blood after administration of the drug 5 , 6 . Moreover, there is a significant wearing-off effect, often resulting in a situation wherein zolpidem can only be given on a couple of consecutive days with a subsequent ‘drug-holiday’ that remains necessary for the drug to regain its positive initial effects.…”