Gamma-Aminobutyric Acid Type A Receptor beta 3 Subunit Forebrain-Specific Knockout Mice Are Resistant to the Amnestic Effect of Isoflurane
Department of Anesthesia, S-455, University of California San Francisco, San Francisco, CA 94143-0464, USA. Anesthesia and analgesia
(Impact Factor: 3.47).
09/2011; 113(3):500-4. DOI: 10.1213/ANE.0b013e3182273aff
β3 containing γ-aminobutyric acid type A receptors (GABA(A)-Rs) mediate behavioral end points of IV anesthetics such as immobility and hypnosis. A knockout mouse with targeted forebrain deletion of the β3 subunit of the GABA(A)-R shows reduced sensitivity to the hypnotic effect of etomidate, as measured by the loss of righting reflex. The end points of amnesia and immobility produced by an inhaled anesthetic have yet to be evaluated in this conditional knockout.
We assessed forebrain selective β3 conditional knockout mice and their littermate controls for conditional fear to evaluate amnesia and MAC, the minimum alveolar concentration of inhaled anesthetic necessary to produce immobility in response to noxious stimulation, to assess immobility. Suppression of conditional fear was assessed for etomidate and isoflurane, and MAC was assessed for isoflurane.
Etomidate equally suppressed conditional fear for both genotypes. The knockout showed resistance to the suppression of conditional fear produced by isoflurane in comparison with control littermates. Controls and knockouts did not differ in isoflurane MAC values.
These results suggest that β3 containing GABA(A)-Rs in the forebrain contribute to hippocampal-dependent memory suppressed by isoflurane, but not etomidate.
Available from: Robert A Pearce
[Show abstract] [Hide abstract]
ABSTRACT: Inhibition mediated by γ-aminobutyric acid type A (GABA A) receptors has long been considered an important target for a variety of general anesthetics. In the hippocampus, two types of phasic GABA A receptor-mediated inhibition coexist: GABA A,fast, which is expressed primarily at peri-somatic sites, and GABAA,slow, which is expressed primarily in the dendrites. Their spatial segregation suggests distinct functions: GABA A,slow may control plasticity of dendritic synapses, whereas GABA A,fast controls action potential initiation at the soma. We examined modulation of GABA A,fast and GABA A,slow inhibition by isoflurane at amnesic concentrations, and compared it with modulation by behaviorally equivalent doses of the GABA A receptor-selective drug etomidate.
Whole cell recordings were obtained from pyramidal cells in organotypic hippocampal cultures prepared from C57BL/6 × 129/SvJ F1 hybrid mice. GABA A receptor-mediated currents were isolated using glutamate receptor antagonists. GABAA,slow currents were evoked by electrical stimulation in the stratum lacunosum-moleculare. Miniature GABA A,fast currents were recorded in the presence of tetrodotoxin.
100 μM isoflurane (approximately EC50,amnesia) slowed fast- and slow-inhibitory postsynaptic current decay by approximately 25%. Higher concentrations, up to 400 μM, produced proportionally greater effects without altering current amplitudes. The effects on GABA A,slow were approximately one-half those produced by equi-amnesic concentrations of etomidate.
Isoflurane enhances both types of phasic GABA A receptor-mediated inhibition to similar degrees at amnesic concentrations. This pattern differs from etomidate, which at low concentrations selectively enhances slow inhibition. These effects of isoflurane are sufficiently large that they may contribute substantially to its suppression of hippocampal learning and memory.
[Show abstract] [Hide abstract]
ABSTRACT: Although general anesthetics have been provided effectively for many years, their exact molecular underpinnings remain relatively unknown. In this article, we discuss the recent findings associated with resistance to anesthetic effects as a way of shedding light on these mechanisms.
The original theories of anesthetic action based upon their effects on cellular membranes have given way to specific theories concerning direct effects on ion channel proteins. These molecular targets are intimately involved in the conduct of neuronal signaling within the central nervous system and are thought to be essential in the modulation of conscious states. It is the lack of a thorough understanding of unperturbed consciousness that fosters great difficulty in understanding how anesthetics alter this conscious state. However, one very fruitful line of analysis in the quest for such answers lies in the examination of both in-vitro and in-vivo ion channel systems that seem to maintain variable levels of resistance to anesthetics.
Information about the possible targets and molecular nature of anesthetic action is being derived from studies of anesthetic resistance in γ aminobutyric acid receptors, tandem pore potassium channels, and an apparently wide variety of protein systems within the nematode, Caenorhabditis elegans.
Available from: Sylviane Marouillat Vedrine
[Show abstract] [Hide abstract]
ABSTRACT: The gabra5 gene is associated with pharmacological properties (myorelaxant, amnesic, anxiolytic) of benzodiazepines. It is tightly located (0.5 cM) close to the pink-eyed dilution (p) locus which encodes for fur color on mouse chromosome 7. We tested the putative role of the gabra5 gene in pharmacological properties of the full non specific agonist chlordiazepoxide (CDP), using behavioral and molecular approaches in mutated p/p mice and wild type F2 from crosses between two multiple markers inbred strain ABP/Le and C57BL/6By strain. From our results, using rotarod, light-dark box, elevated maze and radial arm maze tests, we demonstrate that p/p mice are more sensitive than WT to the sensory motor, anxiolytic and amnesic effect of CDP. This is associated with the presence of a haplotypic block on the murine chromosome 7 and with an up regulation of gabra5 mRNAs in hippocampi of p/p F2 mice.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.