The modulation of synaptic GABA(A) receptors in the thalamus by eszopiclone and zolpidem.
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), alpha(1)beta(2)gamma(2) and alpha(3)beta(3)gamma(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 alpha(4)beta(2)delta 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 microM) slowed the decay phase of IPSCs recorded from RTN neurons, whereas zolpidem was less effective and increased the decay time constant only at > or = 0.3 microM. 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 microM) prolonged the decay of IPSCs from VB neurons, whereas eszopiclone increased the decay time constant only at > or = 0.3 microM. 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.
Jia
Fan
F
C.V. Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology, Weill Cornell Medical College, NewYork, New York 10065, USA.
Goldstein
Peter A
PA
Harrison
Neil L
NL
D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D000069582:Eszopiclone; D018755:GABA Agonists / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D013787:Thalamic Nuclei / Q000187:drug effects / Q000502:physiology*; D013788:Thalamus / Q000187:drug effects / Q000502:physiology*; D000077334:Zolpidem
D053961:Azabicyclo Compounds; D018755:GABA Agonists; D006993:Hypnotics and Sedatives; D010879:Piperazines; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem; D000069582:Eszopiclone