TY - JOUR T1 - The Modulation of Synaptic GABA<sub>A</sub> Receptors in the Thalamus by Eszopiclone and Zolpidem JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1000 LP - 1006 DO - 10.1124/jpet.108.146084 VL - 328 IS - 3 AU - Fan Jia AU - Peter A. Goldstein AU - Neil L. Harrison Y1 - 2009/03/01 UR - http://jpet.aspetjournals.org/content/328/3/1000.abstract N2 - 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 GABAA receptors (GABAA-Rs), α1β2γ2 and α3β3γ2, are expressed in thalamocortical relay neurons and in interneurons of the RTN (reticular thalamic nucleus), respectively. Thalamocortical neurons also express extrasynaptic GABAA-Rs composed of α4β2δ 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 μM) slowed the decay phase of IPSCs recorded from RTN neurons, whereas 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, whereas eszopiclone increased the decay time constant only at ≥0.3 μM. Neither of these two hypnotics affected tonic inhibition in relay neurons. Our results demonstrate that eszopiclone has greater efficacy at synaptic GABAA-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. The American Society for Pharmacology and Experimental Therapeutics ER -