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Pflugers Arch - Eur J Physiol (2012) 463:187199 DOI 10.1007/s00424-011-0988-4
NEUROSCIENCE
GABAA receptors involved in sleep and anaesthesia: 1- versus 3-containing assemblies
Yevgenij Yanovsky & Stephan Schubring & Wiebke Fleischer & Gnter Gisselmann &
Xin-Ran Zhu & Hermann Lbbert & Hanns Hatt & Uwe Rudolph & Helmut L. Haas &
Olga A. Sergeeva
Received: 1 April 2011 /Revised: 6 June 2011 /Accepted: 15 June 2011 /Published online: 7 July 2011 # Springer-Verlag 2011
Abstract The histaminergic neurons of the posterior hypothalamus (tuberomamillary nucleusTMN) control wakefulness, and their silencing through activation of GABAA receptors (GABAAR) induces sleep and is thought to mediate sedation under propofol anaesthesia. We have previously shown that the 1 subunit preferring fragrant dioxane derivatives (FDD) are highly potent modulators of GABAAR in TMN neurons. In recombinant receptors containing the 3N265M subunit, FDD action is abolished and GABA potency is reduced. Using rat, wild-type and 3N265M mice, FDD and propofol, we explored the relative contributions of 1- and 3-containing GABAAR
to synaptic transmission from the GABAergic sleep-on ventrolateral preoptic area neurons to TMN. In 3N265M mice, GABA potency remained unchanged in TMN neurons, but it was decreased in cultured posterior hypothalamic neurons with impaired modulation of GABAAR by propofol. Spontaneous and evoked GABAer-
gic synaptic currents (IPSC) showed 1-type pharmacology, with the same effects achieved by 3 M propofol and 10 M PI24513. Propofol and the FDD PI24513 suppressed neuronal firing in the majority of neurons at 5 and 100 M, and in all cells at 10 and 250 M, respectively. FDD given systemically in mice induced sedation but not anaesthesia. Propofol-induced currents were abolished (1 6 M) or significantly reduced (12 M) in 3N265M mice, whereas gating and modulation of GABAAR by PI24513 as well as modulation by propofol were unchanged. In conclusion, 1-containing (FDD-sensitive) GABAAR represent the major receptor pool in TMN neurons responding to GABA, while 3-containing (FDD-insensitive) receptors are gated by low micromolar doses of propofol. Thus, sleep and anaesthesia depend on different GABAAR types.
Keywords Hypothalamus . Histamine . Sleep . GABA . Patch clamp
Introduction
Propofol is the most frequently used intravenous anaesthetic. The essential goal of anaesthesia is immobility and hypnosis (unconsciousness) without awareness or memory about surgical procedures. Mild sedation and impairment of memory occurs...