Background β3 containing γ–aminobutyric acid type A receptors (GABAA-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 GABAA-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. Methods 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. Results Etomidate equally suppressed conditional fear for both genotypes. The knockout showed resistance to the suppression of conditional fear produced by isoflurane compared to control littermates. Controls and knockouts did not differ in isoflurane MAC values. Conclusions These results suggest that β3 containing GABAA-Rs in the forebrain contribute to hippocampal dependent memory suppressed by isoflurane, but not etomidate.
Clinical and experimental data suggest dysregulation of Nmethyl-D-aspartate receptor (NMDAR)-mediated glutamatergic pathways in schizophrenia. The interaction between NMDARmediated abnormalities and the response to novel environment has not been studied. Mice expressing 5 to 10% of normal N-methyl-D-aspartate receptor subunit 1 (NR1) subunits [NR1 neo (Ϫ/Ϫ)] were compared with wild-type littermates for positive deflection at 20 ms (P20) and negative deflection at 40 ms (N40) auditory event-related potentials (ERPs). Groups were tested for habituation within and across five testing sessions, with novel environment tested during a sixth session. Subsequently, we examined the effects of a GABA A positive allosteric modulator (chlordiazepoxide) and a GABA B receptor agonist (baclofen) as potential interventions to normalize aberrant responses. There was a reduction in P20, but not N40 amplitude within each habituation day. Although there was no amplitude or gating change across habituation days, there was a reduction in P20 and N40 amplitude and gating in the novel environment. There was no difference between genotypes for N40. Only NR1 neo (Ϫ/Ϫ) mice had reduced P20 in the novel environment. Chlordiazepoxide increased N40 amplitude in wild-type mice, whereas baclofen increased P20 amplitude in NR1 neo (Ϫ/Ϫ) mice. As noted in previous publications, the pattern of ERPs in NR1 neo (Ϫ/Ϫ) mice does not recapitulate abnormalities in schizophrenia. In addition, reduced NR1 expression does not influence N40 habituation but does affect P20 in a novel environment. Thus, the pattern of P50 (positive deflection at 50 ms) but not N100 (negative deflection at 100 ms) in human studies may relate to subjects' reactions to unfamiliar environments. In addition, NR1 reduction decreased GABA A receptormediated effects on ERPs while causing increased GABA B receptor-mediated effects. Future studies will examine changes in GABA receptor subunits after reductions in NR1 expression.
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