Zolpidem modulation of phasic and tonic GABA currents in the rat dorsal motor nucleus of the vagus.
Zolpidem is a widely prescribed sleep aid with relative selectivity for GABA(A) receptors containing alpha1-3 subunits. We examined the effects of zolpidem on the inhibitory currents mediated by GABA(A) receptors using whole-cell patch-clamp recordings from DMV neurons in transverse brainstem slices from rat. Zolpidem prolonged the decay time of mIPSCs and of muscimol-evoked whole-cell GABAergic currents, and it occasionally enhanced the amplitude of mIPSCs. The effects were blocked by flumazenil, a benzodiazepine antagonist. Zolpidem also hyperpolarized the resting membrane potential, with a concomitant decrease in input resistance and action potential firing activity in a subset of cells. Zolpidem did not clearly alter the GABA(A) receptor-mediated tonic current (I(tonic)) under baseline conditions, but after elevating extracellular GABA concentration with nipecotic acid, a non-selective GABA transporter blocker, zolpidem consistently and significantly increased the tonic GABA current. This increase was suppressed by flumazenil and gabazine. These results suggest that alpha1-3 subunits are expressed in synaptic GABA(A) receptors on DMV neurons. The baseline tonic GABA current is likely not mediated by these same low affinity, zolpidem-sensitive GABA(A) receptors. However, when the extracellular GABA concentration is increased, zolpidem-sensitive extrasynaptic GABA(A) receptors containing alpha1-3 subunits contribute to the I(tonic).
Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.
Hong
H
Gao
Bret N
BN
Smith
D000200:Action Potentials; D000818:Animals; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology*; D058805:GABA Uptake Inhibitors; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D055369:Miniature Postsynaptic Potentials; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D009118:Muscimol / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D014630:Vagus Nerve / Q000187:drug effects* / Q000502:physiology; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D018755:GABA Agonists; D058805:GABA Uptake Inhibitors; D009557:Nipecotic Acids; D011725:Pyridines; D011963:Receptors, GABA-A; C030278:nipecotic acid; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem