Protection against seizures The anticonvulsant activity of diazepam, assessed by its protection against pentylcneterazole-induced tonic convulsions, was reduced in α1(H101R) mice compared with kinase inhibitor Pacritinib wild-type animals.45 Sodium phénobarbital remained fully effective as anticonvulsant in α1(H101R) mice. These results show that the anticonvulsant activity of benzodiazepines is partially, but not fully mediated by α1-GABAA receptors. The anticonvulsant action of Zolpidem is exclusively mediated by α1-GABAA receptors, since its anticonvulsant action is completely absent in 1(H101R) mice.“48 Anxiolysis New strategies

for the Inhibitors,research,lifescience,medical development of daytime anxiolytics that are devoid of drowsiness and sedation are of high priority. Experimentally, the anxiolytic-like Inhibitors,research,lifescience,medical activity of diazepam can be assessed by exposing wild-type animals to naturally aversive stimuli. For instance, in an elevated plus-maze test, the time spent on an open arm is enhanced after diazepam treatment, as is the time spent in the lit area of a light/dark choice test. In contrast, mice with a benzodiazepine-insensitive α2-GABAA receptor (α2(H101R)) were resistant to the effect of diazepam in these Inhibitors,research,lifescience,medical test paradigms.46 Thus, the anxiolytic-like

action of diazepam is attributed to the modulation of α2-GABAA receptors. They are highly specific targets for the development of future Inhibitors,research,lifescience,medical selective anxiolytic drugs. The α2GABAA receptors, which comprise only about 15% of all diazepam-sensitive GABAA receptors, are mainly expressed in the amygdala and in principal cells of the cerebral buy inhibitor cortex and the hippocampus with particularly high densities on their axon initial segments.50,51 Thus, the Inhibitors,research,lifescience,medical inhibition of the output of these principal neurons appears to be a major mechanism of anxiolysis. It had previously been assumed that the anxiolytic action of diazepam is based on the dampening of the reticular activating system. It is mainly represented by noradrenergic and serotonergic neurons of the

brain stem, which express exclusively α3-GABAA receptors. The analysis of the α3-point-mutated mice (α3(H126R)) indicated that the anxiolytic effect of benzodiazepine drugs, measured as described above, is not mediated by Brefeldin_A α3-GABAA receptors.46 The reticular activating system therefore does not appear to be a major contributor to anxiolysis. The role of α3-GABAA receptors remains to be identified. Myorelaxation The muscle relaxant effect of diazepam is largely mediated by α2-GABAA receptors, as shown by the failure of diazepam to induce changes in muscle tone in the α2point-mutated mouse line.52 In addition to the areas described above, α2-GABAA receptors are expressed in the spinal cord, notably in the superficial layer of the dorsal horn and in motor neurons,53 the latter being most likely implicated in muscle relaxation.