Received for publication September 29, 2008.
Revised November 24, 2008.
Accepted for publication November 24, 2008.

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

Abstract

Eszopiclone (Lunesta^®) and zolpidem (Ambien^®) 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-Rs (GABA_A receptors), ₁₂₂ and ₃₃₂, are expressed in thalamocortical neurons from relay nuclei and interneurons from RTN (reticular thalamic nucleus) respectively. Thalamocortical neurons also express extrasynaptic GABA_A-Rs composed of ₄₂ subunits. In this study, we compared the effects of eszopiclone and zolpidem on tonic currents, miniature IPSCs (inhibitory postsynaptic currents) and spontaneous IPSCs in mouse thalamus. Eszopiclone (0.1 -1 µM) slowed the decay phase of IPSCs recorded from RTN neurons, while zolpidem was less effective and increased the decay time constant only at 0.3 µM. 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 µM) prolonged the decay of IPSCs from VB neurons, while eszopiclone increased the decay time constant only at 0.3 µM. Neither of the hypnotics affected tonic inhibition in thalamocortical 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.

Key words: GABA, alpha-1 subunit, brain slice, hypnotic, inhibitory postsynaptic current, tonic inhibition