The Modulation of Synaptic GABA_A Receptors in the Thalamus by Eszopiclone and Zolpidem

Abstract

Eszopiclone (Lunesta; Sepracor, Marlborough, MA) and zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)-imidazo(1,2-a)pyridine-3-acetamide] are among the most commonly prescribed hypnotics in use in the United States. The thalamus plays a pivotal role in sleep regulation and rhythmicity. Two distinct subtypes of synaptic GABA A receptors (GABA A -Rs), ␣ 1 ␤ 2 ␥ 2 and ␣ 3 ␤ 3 ␥ 2 , are expressed in thalamocortical relay neurons and in interneurons of the RTN (reticular thalamic nucleus), respectively. Thalamocortical neurons also express extrasynaptic GABA A -Rs composed of ␣ 4 ␤ 2 ␦ subunits. In this study, we compared the effects of eszopiclone and zolpidem on miniature inhibitory postsynaptic currents (IPSCs), spontaneous IPSCs, and tonic inhibition in the mouse thalamus. Eszopiclone (0.1-1 M) slowed the decay phase of IPSCs recorded from RTN neurons, whereas zolpidem was less effective and increased the decay time constant only at Ն0.3 M. IPSCs of RTN neurons were more sensitive to eszopiclone than zolpidem at all concentrations tested. On the other hand, IPSCs of relay neurons in the ventrobasal nucleus (VB) were more sensitive to zolpidem than eszopiclone. Zolpidem (0.1-1 M) prolonged the decay of IPSCs from VB neurons, whereas eszopiclone increased the decay time constant only at Ն0.3 M. Neither of these two hypnotics affected tonic inhibition in relay neurons. Our results demonstrate that eszopiclone has greater efficacy at synaptic GABA A -Rs of RTN neurons than in relay neurons, whereas zolpidem exerts bigger effects on relay neurons than RTN neurons. This distinct pattern of activity on thalamic neurons may contribute to some of the observed differences in the clinical effects of these two hypnotics.

Coordination of Slow Waves With Sleep Spindles Predicts Sleep-Dependent Memory Consolidation in Schizophrenia

“…In a small preliminary study, eszopiclone, which acts on γ-aminobutyric acid (GABA)-ergic neurons in the TRN 73 , significantly increased spindles in schizophrenia but not sleep-dependent memory 30 . In another study that did not include PSG, longerterm administration of eszopiclone improved working memory in schizophrenia, but not symptoms 74 .…”

Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

“…To isolate the effects of picrotoxin at GlyRs, picrotoxin was applied concurrently with the GABA A R-specific antagonist gabazine, as has been done previously (41). While it has been suggested that gabazine is unable to unmask tonic GABA A R-mediated currents, we have previously used this concentration to reveal tonic GABA A R conductance in the thalamus (42). Here, we found that applications of picrotoxin in combination with gabazine produced significant shifts in the holding currents of MSNs (Fig.…”

Zolpidem and eszopiclone prime α1β2γ2 GABAA receptors for longer duration of activity

“…Their molecular mechanisms of action have never been investigated in detail. The little information currently available suggests that zolpidem is a more potent modulator than eszopiclone of currents mediated by native α1β2γ2 GABAA receptors in mouse thalamocortical relay neurons (Jia et al, 2009). However, in recombinant α1β2γ2 GABAA receptors expressed in Xenopus laevis oocytes, estimates of the apparent affinities of the two drugs were similar, at 50-60 nM (Hanson et al, 2008).…”

“…This later effect could be because GABA release at some synapses is sub-saturating. As zolpidem and eszopiclone appear to achieve these effects via identical mechanisms and similar potencies at the α1β2γ2 GABAA receptors, their differing therapeutic profiles must be due to either different pharmacological effects at other CNS receptors (Jia et al, 2009;Nutt and Stahl, 2010), or to different pharmacokinetic or distribution profiles.…”