Muscimol has been regarded as a universal agonist for all GABAA receptor subtypes. However, brain regional distribution of muscimol’s high-affinity binding sites greatly differs from those of other binding sites of the GABAA receptor. To test whether behavioral effects of muscimol correlated with the density of high-affinity [3H]muscimol binding, we examined several GABAA receptor subunit gene-modified mouse lines: α1, α4, or δ knockouts (KO), α4+δ double KO, and Thy1.2 promoter-driven α6 transgenic mice (Thy1α6). We determined the high-affinity [3H]muscimol binding in brain sections by quantitative autoradiography and sedative/ataxic effects induced in vivo by muscimol using a constant speed rotarod. α4-KO mice had reduced [3H]muscimol binding in the caudate-putamen, thalamus and hippocampus, and were less sensitive to the behavioral impairment by muscimol. Similarly, δ-KO mice also had reduced binding to forebrain regions and a lower behavioral sensitivity to muscimol than their wild-type controls. In contrast, α1-KO mice had unaltered behavioral sensitivity to muscimol and unaltered [3H]muscimol binding, even though previous studies have demonstrated dramatically reduced binding to various other GABAA receptor sites in these mice. Finally, Thy1α6 mice exhibited increased behavioral sensitivity to muscimol, and to another direct GABA-site agonist gaboxadol, and increased [3H]muscimol binding in the cerebral cortex and hippocampus. Thus, the differences in sedative and motor-impairing actions of muscimol in various mouse models correlated with the level of forebrain high-affinity [3H]muscimol binding. These data suggest that a small special population of GABAA receptors, most likely extrasynaptic non-α1 containing receptors, strongly contributes to the in vivo pharmacological effects of muscimol.

The major inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), has only partial efficacy at certain subtypes of GABAA receptors. To characterize these minor receptor populations in rat and mouse brains, we used autoradiographic imaging of t-butylbicyclophosphoro[35S]thionate ([35S]TBPS) binding to GABAA receptors in brain sections and compared the displacing capacities of 10 mM GABA and 1 mM 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a competitive GABA-site agonist. Brains from GABAA receptor α1, α4, δ, and α4 + δ subunit knockout (KO) mouse lines were used to understand the contribution of these particular receptor subunits to “GABA-insensitive” (GIS) [35S]TBPS binding. THIP displaced more [35S]TBPS binding than GABA in several brain regions, indicating that THIP also inhibited GIS-binding. In these regions, GABA prevented the effect of THIP on GIS-binding. GIS-binding was increased in the cerebellar granule cell layer of δ KO and α4 + δ KO mice, being only slightly diminished in that of α1 KO mice. In the thalamus and some other forebrain regions of wild-type mice, a significant amount of GIS-binding was detected. This GIS-binding was higher in α4 KO mice. However, it was fully abolished in α1 KO mice, indicating that the α1 subunit was obligatory for the GIS-binding in the forebrain. Our results suggest that native GABAA receptors in brain sections showing reduced displacing capacity of [35S]TBPS binding by GABA (partial agonism) minimally require the assembly of α1 and β subunits in the forebrain and of α6 and β subunits in the cerebellar granule cell layer. These receptors may function as extrasynaptic GABAA receptors.

Fractional exhaled nitric oxide (F) assesses eosinophilic inflammation of the airways, but F values are also influenced by oral nitric oxide (NO). The aim of this pilot study was to measure F and compare the effect of two different mouthwashes on F and analyse the duration of the effect. F was measured in 12 randomized volunteers (healthy or asthmatic subjects) with a NIOX VERO® analyser at an expiratory flow rate of 50 mL/s. After a baseline measurement, a mouthwash was performed either with tap water or carbonated water and was measured during 20 min in 2 min intervals. The procedure was repeated with the other mouthwash. We found that both mouthwashes reduced F immediately at the beginning compared to the baseline (p < .001). The carbonated water mouthwash effect lasted 12 min (p ranging from <0.001 to <0.05). The tap water mouthwash reduced F statistically significantly only for 2 min compared with the baseline. We conclude that a single carbonated water mouthwash can significantly reduce the oropharyngeal NO contribution during a 12 min time interval.

Routine follow-up is unnecessary after intramedullary fixation of trochanteric femoral fractures -analysis of 995 cases, Injury (2020), doi: